ID: 2553775
Title: Phagocytosis of aged human neutrophils by macrophages is mediated by a novel "charge-sensitive" recognition mechanism.
Abstract: The removal of neutrophils and their histotoxic contents from the inflamed site is a prerequisite for resolution of tissue injury, and a point at which factors critical to the pathogenesis of chronic inflammation may act. Engulfment of intact, senescent neutrophils by macrophages represents an important neutrophil disposal process. In this study the mechanism by which human monocyte-derived macrophages (M phi) recognized and ingested human neutrophils that had been aged in culture was studied using an in vitro phagocytic assay. Inhibition of M phi receptors for Ig Fc and the opsonic complement fragments C3b and iC3b with MAbs to M phi FcR, CR1, CR3, and CR4 had no effect on recognition, and the pattern of inhibition observed when polyanions were included in the medium at 1 mg/ml was different from that reported for the M phi receptor for protein advanced glycosylation end products (AGE), indicating a recognition mechanism different from those proposed for M phi phagocytosis of senescent erythrocytes. Furthermore, although aging neutrophils undergo programmed cell death (or apoptosis), which is directly related to recognition by M phi, the pattern of inhibition observed with monosaccharides was different from that reported to inhibit the binding of apoptotic mouse thymocytes to isologous M phi. By contrast, evidence was obtained for a novel recognition mechanism inhibitable by cationic sugars and amino acids in a charge-dependent fashion, and directly modulated by pH but not affected by inhibitors of the mannose-6-phosphate, sheep erythrocyte, mannosyl-fucosyl, asialoglycoprotein, and scavenger receptors of the macrophage. These observations suggest that hydrogen ions and charged molecules may modulate M phi uptake of senescent neutrophils at inflamed sites, and that recognition itself may involve charged structures on the cells.

ID: 2921324
Title: Macrophage phagocytosis of aging neutrophils in inflammation. Programmed cell death in the neutrophil leads to its recognition by macrophages.
Abstract: Mechanisms governing the normal resolution processes of inflammation are poorly understood, yet their elucidation may lead to a greater understanding of the pathogenesis of chronic inflammation. The removal of neutrophils and their potentially histotoxic contents is one prerequisite of resolution. Engulfment by macrophages is an important disposal route, and changes in the senescent neutrophil that are associated with their recognition by macrophages are the subject of this investigation. Over 24 h in culture an increasing proportion of human neutrophils from peripheral blood or acutely inflamed joints underwent morphological changes characteristic of programmed cell death or apoptosis. Time-related chromatin cleavage in an internucleosomal pattern indicative of the endogenous endonuclease activation associated with programmed cell death was also demonstrated. A close correlation was observed between the increasing properties of apoptosis in neutrophils and the degree of macrophage recognition of the aging neutrophil population, and a direct relationship between these parameters was confirmed within aged neutrophil populations separated by counterflow centrifugation into fractions with varying proportions of apoptosis. Macrophages from acutely inflamed joints preferentially ingested apoptotic neutrophils and histological evidence was presented for occurrence of the process in situ. Programmed cell death is a phenomenon of widespread biological importance and has not previously been described in a cell of the myeloid line. Because it leads to recognition of intact senescent neutrophils that have not necessarily disgorged their granule contents, these processes may represent a mechanism for the removal of neutrophils during inflammation that also serves to limit the degree of tissue injury.

ID: 11710909
Title: Age-related alterations in the inflammatory response to dermal injury.
Abstract: Previous studies have documented that the ability to heal wounds declines with age. Although many factors contribute to this age-associated deficit, one variable that has not been carefully examined is leukocyte recruitment and function in wounds. This investigation compares the inflammatory response in excisional wounds of young (age 8 wk) and aged (age 22 mo) mice. In the early inflammatory response, neutrophil content of wounds was similar for both aged and young mice. In contrast, macrophage levels were 56% higher in aged versus young mice (81 +/- 20 vs 52 +/- 13 cells per mm2). In the later inflammatory response, wounds of aged mice exhibited a delay in T cell infiltration, with maximum T cell levels at day 10 in aged mice versus day 7 in young mice. Despite this delay, the eventual peak concentration of T cells was 23% higher in the wounds of aged mice (152 +/- 11 cells per mm2 vs 124 +/- 21cells per mm2). The observed alterations in inflammatory cell content suggested that chemokine production might be altered with age. An elevation of monocyte chemoattractant protein (MCP-1) levels was observed in wounds of aged mice. RNase protection studies, however, revealed that the production of most chemokines, including MIP-2, MIP-1alpha, MIP-1beta, and eotaxin, tended to decline with age. Because optimal wound healing requires both appropriate macrophage infiltration and phagocytic activity, phagocytosis was examined. Compared to young mice, wound macrophages from aged mice exhibited a 37%-43% reduction in phagocytic capacity. Taken together, the data demonstrate age-related shifts in both macrophage and T cell infiltration into wounds, alterations in chemokine content, and a concurrent decline in wound macrophage phagocytic function. These alterations may contribute to the delayed repair response of aging.

ID: 18387441
Title: Aging-related defects are associated with adverse cardiac remodeling in a mouse model of reperfused myocardial infarction.
Abstract: The purpose of this study was to study aging-associated alterations in the inflammatory and reparative response after myocardial infarction (MI) and their involvement in adverse post-infarction remodeling of the senescent heart. Advanced age is a predictor of death and ventricular dilation in patients with MI; however, the cellular mechanisms responsible for increased remodeling of the infarcted senescent heart remain poorly understood. Histomorphometric, molecular, and echocardiographic end points were compared between young and senescent mice undergoing reperfused infarction protocols. The response of young and senescent mouse cardiac fibroblasts to transforming growth factor (TGF)-beta stimulation was examined. Senescence was associated with decreased and delayed neutrophil and macrophage infiltration, markedly reduced cytokine and chemokine expression in the infarcted myocardium, and impaired phagocytosis of dead cardiomyocytes. Reduced inflammation in senescent mouse infarcts was followed by decreased myofibroblast density and markedly diminished collagen deposition in the scar. The healing defects in senescent animals were associated with enhanced dilative and hypertrophic remodeling and worse systolic dysfunction. Fibroblasts isolated from senescent mouse hearts showed a blunted response to TGF-beta1. Although young mice exhibit a robust post-infarction inflammatory response and form dense collagenous scars, senescent mice show suppressed inflammation, delayed granulation tissue formation, and markedly reduced collagen deposition. These defects might contribute to adverse remodeling. These observations suggest that caution is necessary when attempting to therapeutically target the post-infarction inflammatory response in patients with reperfused MI. The injurious potential of inflammatory mediators might have been overstated, owing to extrapolation of experimental findings from young animals to older human patients.

ID: 25597390
Title: Attenuated phagocytosis of secondary necrotic neutrophils by macrophages in aged and SMP30 knockout mice.
Abstract: Secondary necrotic cells generated in vivo induce inflammatory responses; for example, the production of macrophage inflammatory protein-2 (MIP-2) and subsequent infiltration of neutrophils. The aim of the present study was to elucidate the effect of aging on the phagocytosis of secondary necrotic cells and the inflammatory responses by using either wild-type (WT) young mice, WT aged mice or senescence-accelerated mice (SMP30(-/-) mice). The phagocytosis of secondary necrotic neutrophils with resident macrophage from either WT young mice, WT aged mice or SMP30(-/-) mice was examined by coculturing macrophages with secondary necrotic neutrophils in vitro. To investigate the inflammatory response induced by secondary necrotic cells, time-dependent infiltration of neutrophils and production of MIP-2 were determined in the peritoneal cavity on the injection of secondary necrotic cells. The phagocytosis of secondary necrotic cells by macrophages from WT aged and SMP30(-/-) mice was significantly reduced as compared with that by macrophages from WT young mice. On peritoneal injection of secondary necrotic cells, the peak time of neutrophil infiltration was earlier in SMP30(-/-) mice than in WT young mice. The number of neutrophils in SMP30(-/-) mice at the peak time was also greater than that in WT young mice. Our findings showed that the phagocytosis of secondary necrotic cells was attenuated in aged mice and SMP30(-/-) mice, and that the MIP-2 production was enhanced and subsequently neutrophil infiltration was exaggerated on peritoneal injection of secondary necrotic cells into those mice.

ID: 33380498
Title: Inhibition of Efferocytosis by Extracellular CIRP-Induced Neutrophil Extracellular Traps.
Abstract: Phagocytic clearance of apoptotic cells by the macrophages (efferocytosis) is impaired in sepsis, but its mechanism is poorly understood. Extracellular cold-inducible RNA-binding protein (eCIRP) is a novel damage-associated molecular pattern that fuels inflammation. We identify that eCIRP-induced neutrophil extracellular traps (NETs) impair efferocytosis through a novel mechanism. Coculture of macrophages and apoptotic thymocytes in the presence of recombinant murine CIRP (rmCIRP)-induced NETs significantly inhibited efferocytosis. Efferocytosis was significantly inhibited in the presence of rmCIRP-treated wild-type (WT), but not PAD4-/- neutrophils. Efferocytosis in the peritoneal cavity of rmCIRP-injected PAD4-/- mice was higher than WT mice. Milk fat globule-EGF-factor VIII (MFG-E8), an opsonin, increased macrophage efferocytosis, whereas the inhibition of efferocytosis by NETs was not rescued upon addition of MFG-E8, indicating disruption of MFG-E8's receptor(s) αvβ3 or αvβ5 integrin by the NETs. We identified neutrophil elastase in the NETs significantly inhibited efferocytosis by cleaving macrophage surface integrins αvβ3 and αvβ5 Using a preclinical model of sepsis, we found that CIRP-/- mice exhibited significantly increased rate of efferocytosis in the peritoneal cavity compared with WT mice. We discovered a novel role of eCIRP-induced NETs to inhibit efferocytosis by the neutrophil elastase-dependent decrease of αvβ3/αvβ5 integrins in macrophages. Targeting eCIRP ameliorates sepsis by enhancing efferocytosis.

ID: 35830797
Title: Multiomics reveal the central role of pentose phosphate pathway in resident thymic macrophages to cope with efferocytosis-associated stress.
Abstract: Tissue-resident macrophages (TRMs) are heterogeneous cell populations found throughout the body. Depending on their location, they perform diverse functions maintaining tissue homeostasis and providing immune surveillance. To survive and function within, TRMs adapt metabolically to the distinct microenvironments. However, little is known about the metabolic signatures of TRMs. The thymus provides a nurturing milieu for developing thymocytes yet efficiently removes those that fail the selection, relying on the resident thymic macrophages (TMφs). This study harnesses multiomics analyses to characterize TMφs and unveils their metabolic features. We find that the pentose phosphate pathway (PPP) is preferentially activated in TMφs, responding to the reduction-oxidation demands associated with the efferocytosis of dying thymocytes. The blockade of PPP in Mφs leads to decreased efferocytosis, which can be rescued by reactive oxygen species (ROS) scavengers. Our study reveals the key role of the PPP in TMφs and underscores the importance of metabolic adaptation in supporting Mφ efferocytosis.

ID: 39938482
Title: Early-age efferocytosis directs macrophage arachidonic acid metabolism for tissue regeneration.
Abstract: In response to organ injury in adults, macrophages often promote scarring, yet during early life, they are required for tissue regeneration. To elucidate the mechanisms underlying age-associated regeneration, we compared the macrophage injury response in newborn versus adult hearts. Single-cell analysis revealed an accumulation of tissue-resident macrophages in neonates that were selectively polarized for apoptotic cell recognition and uptake (efferocytosis). Ablation of the apoptotic cell recognition receptor Mertk in newborns prevented cardiac regeneration. These findings could be attributed to reprogramming of macrophage gene expression that was required for biosynthesis of the eicosanoid thromboxane A2, which unexpectedly activated parenchymal cell proliferation. Markers of thromboxane A2 production were suppressed in adult macrophages after efferocytosis. Moreover, macrophage-neighboring neonatal cardiomyocytes expressed the thromboxane A2 receptor, whose activation induced a metabolic shift that supported cellular proliferation. Our data reveal a fundamental age-defined macrophage response in which lipid mitogens produced during efferocytosis support receptor-mediated tissue regeneration.

ID: 39945065
Title: Age-Related Impairments in Immune Cell Efferocytosis and Autophagy Hinder Atherosclerosis Regression.
Abstract: Aging is a well-established risk factor for the development and progression of atherosclerosis, but the molecular mechanisms underlying this relationship remain poorly defined, and its role in atherosclerosis regression is unknown. To uncover age-related alterations that may impair atherosclerosis regression, we investigated the response of young and old macrophages to atherogenic lipoproteins in vitro and in vivo. Metabolic and proteomic studies were performed in vitro using macrophages differentiated from the bone marrow of young or old mice. To test the role of immune cell aging in atherosclerosis regression, bone marrow from young and old donors was transplanted into irradiated young recipient mice expressing gain-of-function AAV-PCSK9 (adeno-associated virus-proprotein convertase subtilisin/kexin type 9). Following 14 weeks of Western diet feeding, atherosclerosis regression was induced by switching to a standard laboratory diet for 4 weeks. Compared with young macrophages, old macrophages accumulated more lipid droplets upon lipid loading with the pro-atherogenic lipoprotein aggregated LDL (low-density lipoprotein), accompanied by a failure to proportionally induce autophagy and cholesterol efflux. Proteomic analysis of bone marrow-derived macrophages revealed that pathways related to endocytosis, engulfment, and phagocytosis were downregulated in old lipid-loaded macrophages. Functional studies confirmed a reduction in efferocytic capacity in old macrophages. In recipient mice transplanted with old bone marrow, atherosclerosis regression was impaired, as evidenced by inefficient resolution of circulating inflammatory cell levels, reduced activation of plaque autophagy and apoptotic cell clearance, and persistent plaque CD45+ and CD68+ content. Aging impairs macrophage function through reduced efferocytosis and autophagy activation, limiting atherosclerosis regression. These results highlight the need to better define the mechanisms linking aging to atherosclerosis to develop targeted therapies for the aging population.

ID: 40419113
Title: Compromised efferocytosis during aging is related to COVID-19 severity in mice.
Abstract: Aging is one of the greatest risk factors for morbidity caused by the coronavirus disease 2019 (COVID-19). In older individuals, a dysregulated immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection contributes to disease severity; however, the underlying mechanism remains elusive. In this study, we established an aging mouse model of COVID-19, successfully replicating the development of a relatively severe disease in older adults. Further single-cell transcriptome analysis revealed a distinct immune cell landscape in the infected lungs, accompanied by an over-activated inflammatory response, especially in aging mice. Compared to young mice, aging mice showed extensive neutrophil activation, NETosis, and a dramatic decrease in the number of alveolar macrophages (AMs). Moreover, as important executors of efferocytosis, AMs exhibited a low efferocytotic gene signature and downregulation of multiple efferocytosis receptors in aged mice. Further analysis indicated that the efferocytosis of neutrophils, whether undergoing apoptosis or NETosis, was compromised after SARS-CoV-2 infection. Since efferocytosis is a key process in inflammatory resolution, impaired efferocytosis may contribute to hyperinflammation in aging lungs. Our study reveals the characteristics and role of efferocytosis in aging mice after SARS-CoV-2 infection and provides valuable insights for the potential treatment of COVID-19.

ID: 40490493
Title: Temporal single-cell sequencing analysis reveals that GPNMB-expressing macrophages potentiate muscle regeneration.
Abstract: Macrophages play a crucial role in coordinating the skeletal muscle repair response, but their phenotypic diversity and the transition of specialized subsets to resolution-phase macrophages remain poorly understood. Here, to address this issue, we induced injury and performed single-cell RNA sequencing on individual cells in skeletal muscle at different time points. Our analysis revealed a distinct macrophage subset that expressed high levels of Gpnmb and that coexpressed critical factors involved in macrophage-mediated muscle regeneration, including Igf1, Mertk and Nr1h3. Gpnmb gene knockout inhibited macrophage-mediated efferocytosis and impaired skeletal muscle regeneration. Functional studies demonstrated that GPNMB acts directly on muscle cells in vitro and improves muscle regeneration in vivo. These findings provide a comprehensive transcriptomic atlas of macrophages during muscle injury, highlighting the key role of the GPNMB macrophage subset in regenerative processes. Our findings suggest that modulating GPNMB signaling in macrophages may represent a promising avenue for future research into therapeutic strategies for enhancing skeletal muscle regeneration.

ID: 41112042
Title: The microbiome in cancer.
Abstract: The human microbiome is now recognized as a central regulator of cancer biology, intricately shaping tumor development, immune dynamics, and therapeutic response. This comprehensive review delineates the multifaceted roles of bacteria, viruses, and fungi in modulating the tumor microenvironment and systemic immunity across diverse cancer types. We synthesize current evidence on how microbial dysbiosis promotes carcinogenesis via chronic inflammation, metabolic reprogramming, genotoxic stress, immune evasion, and epigenetic remodeling. This review emphasizes organ-specific microbiome signatures and highlights their potential as non-invasive biomarkers for early detection, treatment stratification, and prognosis. Furthermore, we explore the impact of intratumoral microbiota on cancer therapies, uncovering how microbial metabolites and host-microbe interactions shape therapeutic efficacy and resistance. Finally, advances in microbiome-targeted strategies, such as probiotics, fecal microbiota transplantation, and engineered microbes offer new avenues for adjunctive cancer therapy. This review provides a roadmap for future investigation and underscores the transformative promise of microbiome modulation in cancer prevention and treatment.

ID: 41128412
Title: Oral Multi-Enzymatic Manganese-Carbon Dots Alleviate Sepsis-Associated Lung Injury via the Gut-Lung Axis.
Abstract: Sepsis-induced pulmonary injury represents a life-threatening global health challenge due to poorly defined pathological mechanisms. The gut-lung axis has been proven to be widely involved in sepsis-induced lung injury, yet effective interventions targeting gut microbiota homeostasis remain unknown. Single-cell sequencing revealed increased alveolar apoptosis and impaired macrophage efferocytosis during sepsis pathogenesis. Thus, we designed oral manganese-doped carbon dots (Mn-CDs) to alleviate septic lung injury by remodeling gut microbiota homeostasis and targeting the gut-lung axis. Biochemical characterization demonstrated Mn-CDs possess multienzyme mimetic activities (SOD-, CAT-, POD-, GPx-like) and potent ROS scavenging capacity. In murine sepsis models, Mn-CDs significantly improved systemic indices and were associated with macrophage anti-inflammatory states with enhanced efferocytosis, as evidenced by transcriptomic profiling. Integrated metagenomic/metabolomic analyses identified Mn-CDs-mediated enrichment of g_Clostridium and g_Bacteroides, concomitant with elevated indole-3-propionic acid (IPA) production. Subsequent in vitro studies demonstrate that IPA likely binds primarily to the aryl hydrocarbon receptor (AHR), promoting both efferocytosis and anti-inflammatory polarization in macrophages, thereby mitigating septic lung injury. Notably, the fecal microbiota transplantation (FMT) from Mn-CDs-treated mice not only alleviated systemic symptoms but also effectively promoted efferocytic polarization of pulmonary macrophages in septic mice. Depletion of the gut microbiota resulted in a significant loss of the protective efficacy of Mn-CDs in a murine model of septic lung injury. Collectively, the gut-lung axis mediated by microbiota-derived IPA and macrophage efferocytosis contributes to the remediation of septic lung injury, highlighting the potential of Mn-CDs in microbiome-directed critical care.

ID: 41297051
Title: Impaired AMP-Dependent Protein Kinase-Mediated Neutrophil Extracellular Trap Clearance by Aged Macrophages in Sepsis-Induced Liver Injury.
Abstract: This study investigates the role and mechanism of neutrophil extracellular trap (NET) clearance by aged macrophages during sepsis-induced liver injury, as elderly patients show higher rates of organ damage and mortality in sepsis. A sepsis model was established using cecal ligation and puncture (CLP) in aged (100-week-old) and young mice (8-week-old) to study NET clearance by macrophages, assessing liver injury and inflammatory responses with interventions targeting AMP-dependent protein kinase (AMPK) and phagocytosis pathways. Additionally, the study included 40 sepsis patients, with 25 elderly (65-89 years) and 15 young (31-62 years) individuals, and collected peripheral blood samples from all for in vitro experiments. In aged mice, a significant increase in 7-day mortality was observed (hazard ratio [HR] = 2.50, 95% confidence interval [CI], 1.10-5.65, P = .009), alongside heightened inflammatory response and liver injury (histopathology score: 3.2 ± 0.4 vs 2.4 ± 0.6; P = .021), compared to young mice post-CLP. Hepatic NET accumulation markedly increased (mean difference [MD] = 0.43%, 95% CI, 0.25%-0.61%; P < .001), which was attenuated by DNase I-mediated NET inhibition, reducing hepatic enzymes and inflammatory responses. Consistently, transplantation of young bone marrow into aged recipients significantly reduced NET accumulation (MD = -0.33%, 95% CI, -0.43% to -0.22%; P < .001). Mechanistically, the phosphorylation of AMPK (0.68-fold vs young; P < .001) and Ca 2+ /calmodulin-dependent protein kinase kinase 2 (CaMKK2) was suppressed in aged septic mice. Activation of AMPK via 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) led to a decrease in hepatic NET accumulation (MD = -0.30%, 95% CI, -0.41% to -0.19%; P < .001), improved liver injury (histopathology score: 2.49 ± 0.24 vs 3.07 ± 0.28; P = .006), and reduced 7-day mortality (HR = 0.37, 95% CI, 0.15-0.94, P = .038). Critically, elderly patients exhibited elevated NET-related markers, compounded by suppressed AMPK phosphorylation and impaired NET phagocytosis (MD = -16.34%, 95% CI, -24.31% to -8.37%; P = .002). Aging impairs AMPK-mediated macrophage clearance of NETs in the liver, exacerbating liver inflammatory injury. Focusing on NETs could offer a therapeutic strategy to mitigate liver damage and reduce mortality in elderly sepsis patients.

ID: 41554295
Title: Maresin 1 ameliorates myocardial ischaemia‒reperfusion injury by promoting tissue resident macrophage efferocytosis.
Abstract: Myocardial ischaemia‒reperfusion (I/R) injury triggers a robust inflammatory storm cascade that critically compromises reperfusion efficacy following acute myocardial infarction. Enhanced efferocytosis by cardiac resident macrophages (RMs) has therapeutic potential for inflammation resolution. The unsaturated long-chain fatty acid Maresin1 (MaR1) exhibits potent anti-inflammatory properties that is devoid of immunosuppressive effects. However, its therapeutic potential in myocardial I/R injury and regulatory mechanisms in cardiac RMs remains unexplored. A clinical case‒control study was conducted and revealed a negative association between circulating MaR1 levels and inflammatory markers and the severity of I/R injury in patients with ST-elevation myocardial infarction. Mice treated with MaR1 after myocardial I/R injury showed improvements in cardiac function and efferocytosis by cardiac RMs. Genetic ablation of cardiac RMs abolished MaR1-mediated cardioprotection. To explore the mechanism underlying this protection, we performed transcriptomic, metabolomics, and lipidomic analyses and identified fatty acid β-oxidation potentiation as a key metabolic signature in MaR1-treated RMs. Moreover, MaR1 directly bound peroxisome proliferator-activated receptor γ (PPARγ), inducing the transcriptional activation of its downstream efferocytosis-related target CD204. Specific knockout of PPARγ in RMs significantly attenuated MaR1-enhanced efferocytosis. Notably, oral supplementation with the MaR1 precursor docosahexaenoic acid (DHA) recapitulated these cardioprotective effects. Our findings prove that MaR1 plays a protective role in myocardial I/R injury by facilitating efferocytosis by RMs and the resolution of inflammation. These results offer novel therapeutic perspectives for the management of myocardial I/R injury.

ID: 41565804
Title: The transition from monocyte to tissue-resident macrophage requires DHPS.
Abstract: Tissue-resident macrophages (RTMs) form during embryogenesis, self-renew locally, and regulate tissue homeostasis by clearing dead cells and debris1-6. During tissue damage, however, bone-marrow-derived monocytes enter tissues and differentiate into RTMs, repairing the tissue and replenishing macrophages in the niche1. The universal cell-intrinsic mechanisms that control the monocyte-to-RTM transition and the maintenance of mature RTMs across tissues remain elusive3. Here we show that deoxyhypusine synthase (DHPS), an enzyme that mediates spermidine-dependent hypusine modification of translation factor eIF5A5,7, is required for RTM differentiation and maintenance. Mice with myeloid cell lack of DHPS (Dhps-ΔM mice) had a global defect in RTMs across tissues, resulting in persistent but ultimately futile monocyte influx. Transcriptional analyses of DHPS-deficient macrophages indicated a block in their ability to differentiate into mature RTMs, whereas proteomics revealed defects in cell adhesion and signalling pathways. Sequencing of ribosome-engaged transcripts identified a subset of mRNAs involved in cell adhesion and signalling that rely on DHPS for efficient translation. Imaging of DHPS-deficient macrophages in tissues showed differences in morphology and tissue interactions, which were correlated with their failed RTM differentiation. DHPS-deficient macrophages were also defective in critical homeostatic RTM functions including efferocytosis and tissue maintenance. Together, our results demonstrate a cell-intrinsic, tissue-agnostic pathway that drives differentiation of monocyte-derived macrophages into RTMs.

ID: 41643678
Title: Ketogenic diet alleviates septic lung injury via microbial gut-lung axis.
Abstract: Sepsis is characterized by impaired immunity to infection, leading to multi-organ dysfunction, with the lung being the most vulnerable organ. Here, we show that ketogenic diet (KD) alleviates sepsis-induced lung injury through a microbial-gut-lung axis. KD alters the gut microbiota in mice and humans, enriching Limosilactobacillus reuteri and Lactiplantibacillus plantarum. Specific strains of these species produce a flavin-dependent monooxygenase (FMO) that converts oleic acid in KD into azelaic acid (AZA). During sepsis, AZA translocates to the lung, where it promotes neutrophil apoptosis and expands MerTK+ alveolar macrophages (AMs) via PPAR-γ activation, enhancing efferocytosis and resolution of lung injury. In patients with sepsis, elevated AZA correlates with improved clinical outcomes, including survival rates, ventilation-free days (VFDs), and pulmonary function, along with increased MerTK+ AMs and apoptotic neutrophils in patient lungs. These findings uncover a pathway of gut-lung crosstalk mediated by diet-microbiome interactions, highlighting the therapeutic potential of KD and microbiome modulation in sepsis.

ID: 41715099
Title: Indole-acetaldehyde from Rothia mucilaginosa activates the PXR/NRF2 axis to enhance alveolar macrophage phagocytosis and protect against ARDS.
Abstract: BACKGROUND: Despite advances in therapeutic strategies, acute respiratory distress syndrome (ARDS) mortality remains high. Growing evidence links respiratory microbiome composition to ARDS outcomes. This investigation sought to elucidate how colonizing bacteria and their metabolites influence ARDS pathogenesis. METHODS: Bronchoalveolar lavage fluid (BALF) from patients with pulmonary infections was analyzed by metagenomic next-generation sequencing (mNGS) to identify characteristic bacteria. Bacterial culture supernatants were analyzed by untargeted metabolomics (LC-MS) to identify metabolites. A murine ARDS model was established through intratracheal LPS instillation. Single-cell sequencing datasets from the GEO database were analyzed to reveal differential cell populations and functional alterations in murine ARDS. Potential molecular mechanisms were explored through molecular docking, RNA-seq analysis, Western boltting, and targeted gene knockdown in murine and cellular model. RESULTS: R. mucilaginosa demonstrated enrichment in patients without ARDS (nARDS). The bacterial culture supernatant conferred substantial protection in murine models, whereas viable bacteria showed minimal efficacy. LC-MS analysis identified indole-3-acetaldehyde (IAAld) as the predominant metabolite in the supernatant. Single-cell sequencing suggested that resident alveolar macrophages (RAMs) were pivotal cells in murine ARDS model. IAAld enhanced RAMs phagocytosis, facilitating neutrophil and LPS clearance. Mechanistic studies revealed that IAAld likely activated PXR signaling, promoted NRF2 nuclear translocation, and upregulated the phagocytosis-related gene CD36. Targeted PXR knockdown eliminated these protective effects. CONCLUSION: The respiratory commensal R. mucilaginosa synthesizes IAAld, which—independent of bacterial colonization per se—ameliorates ARDS through PXR/NRF2/CD36 axis activation, thereby enhancing macrophage phagocytic function. These findings suggest that therapeutic targeting of microbial metabolites represents a novel ARDS treatment paradigm.

ID: 41717712
Title: Polydopamine-Encapsulated Probiotics Restore Gut Homeostasis and Reinstate Macrophage Efferocytosis in Systemic Lupus Erythematosus.
Abstract: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by immune dysregulation and chronic inflammation, with increasing evidence implicating the gut microbiota in its pathogenesis. Probiotics, such as Lactobacillus rhamnosus GG (LGG), exert anti-inflammatory effects by enhancing gut barrier function and restoring microbial homeostasis, representing a promising therapeutic strategy for SLE. However, conventional probiotic therapies are hindered by poor survival and colonization in the hostile intestinal environment. Here, a polydopamine-coated LGG (LGG@PDA) with improved viability, adhesion, and resistance to oxidative stress is developed. In murine models of lupus, LGG@PDA treatment restored gut and immune homeostasis, enhanced macrophage efferocytosis, reduced autoantibody levels, and ameliorated renal pathology. Metabolomic analysis further identified L-methionine, a metabolite diminished in both lupus mice and SLE patients, as being enriched by LGG@PDA treatment. Functionally, L-methionine enhanced macrophage efferocytosis in a CX3CR1-dependent manner, thereby contributing to the restoration of immune tolerance. Collectively, these findings establish LGG@PDA as a bioengineered probiotic platform that integrates microbiota modulation with immune regulation, highlighting L-methionine as a key metabolic mediator and a promising microbiota-based therapeutic strategy for SLE.

ID: 41738282
Title: Irgm1 Improves Postinfarction Cardiac Repair by Promoting Neutrophil Clearance and Efferocytosis.
Abstract: Delayed neutrophil clearance after myocardial infarction (MI) significantly disrupts the myocardial microenvironment, but the underlying mechanisms remain unclear. Macrophage-mediated efferocytosis of infiltrating neutrophils is crucial for resolving inflammation and restoring homeostasis post-MI. However, the specific regulatory mechanisms governing neutrophil clearance and efferocytosis remain undefined. This study demonstrates a significant correlation between increased IRGM expression in peripheral blood neutrophils of patients with MI and improved prognostic outcomes. Neutrophil-specific deletion of Irgm1 exacerbates cardiac dysfunction, impairs post-MI repair, and hinders neutrophil clearance and efferocytosis. Irgm1 deficiency further delays neutrophil clearance in the heart and extends neutrophil survival. Mechanistically, Irgm1 directly interacts with PDIA3, promoting its autophagic degradation, which in turn activates the endoplasmic reticulum stress/NF-κB/caspase-3 pathway to facilitate neutrophil clearance and efferocytosis. In vivo administration of LOC14 significantly reduces tissue damage and enhances cardiac recovery in neutrophil Irgm1-deficient mice post-MI. These findings highlight the pivotal role of the Irgm1-PDIA3 axis in facilitating cardiac repair post-MI by promoting neutrophil clearance. LOC14 may serve as a potential therapeutic agent to enhance cardiac function post-MI, particularly in Irgm1-deficient cases.

ID: 41746243
Title: Interleukin-18 Inhibition Aggravates Atherosclerosis in Jak2V617F Clonal Hematopoiesis.
Abstract: Clonal hematopoiesis (CH) driven by JAK2V617F is known to accelerate atherosclerosis through inflammasome activation and release of interleukin (IL)-1β and -18; yet, the specific contribution of IL-18 has remained unclear. In this study, we demonstrate that antibody inhibition of IL-18 in JAK2V617F CH mice increases plaque collagen but paradoxically promotes both early lesion growth and advanced necrotic core formation. Mechanistically, IL-18 blockade reverses absent in melanoma 2 inflammasome activation but shifts cell death toward apoptosis, and together with impaired efferocytosis, results in greater necrosis. These events are coordinated by reduced interferon gamma signaling, which enhances collagen deposition while decreasing expression of efferocytotic genes. Our findings challenge the prevailing notion that IL-18 inhibition stabilizes atherosclerotic plaques and provide new mechanistic insight into the interplay among inflammasome biology, adaptive immunity, and plaque stability.

ID: 41827848
Title: Network Rewiring in the Aging Immune System: From Chronic Inflammation to Age-Related Pathologies.
Abstract: Aging is accompanied by profound alterations in immune function that collectively drive increased susceptibility to infection, reduced vaccine efficacy, impaired tissue repair, and heightened risk of age-related diseases (ARDs). These alterations are characterized by the coexistence of immunosenescence and inflammaging. Rather than reflecting isolated cellular defects, immune aging emerges as a systems-level reprogramming of immune networks that disrupts the initiation, resolution, and regenerative phases of inflammatory responses. In particular, aging is associated with impaired resolution of inflammation, defective efferocytosis, reduced responsiveness to pro-resolving signals, and diminished regenerative capacity, leading to persistent inflammatory milieus and tissue damage. This review summarizes recent advances in the mechanisms underlying immune dysfunction in aging, with a focus on how chronic inflammation, failed resolution, and defective repair reinforce one another. We discuss how alterations in innate and adaptive immunity, immunometabolism, cellular senescence, and immune-tissue interactions drive inflammaging and contribute to major ARDs, including cancer, neurodegenerative, and cardiometabolic diseases. Finally, we highlight emerging therapeutic strategies aimed at restoring immune balance and resolution. By adopting a systems-level and network-based perspective, this review underscores immune aging as a modifiable driver of ARDs and identifies key knowledge gaps and future directions toward interventions that promote healthy aging and extended healthspan.

ID: 41857730
Title: The ErbB-tyrosine kinase inhibitor, neratinib, has anti-inflammatory effects in multimorbidity by increasing macrophage efferocytosis via the upregulation of MerTK.
Abstract: BACKGROUND: Chronic inflammatory disease is responsible for huge and increasing global mortality and morbidity. Unregulated inflammatory cells, including neutrophils and macrophages, are major drivers of chronic inflammatory disease. Efferocytosis plays a critical role in inflammation resolution by removing effete inflammatory cells from tissues. Despite defective efferocytosis being critical in inflammatory disease progression there are no therapies to correct these defects in clinical use. Here, using experimental models of atherosclerosis and lung injury, we identify the ErbB family tyrosine kinase inhibitor (TKI), neratinib, as a putative efferocytosis-targeting therapy. RESULTS: In an experimental model of atherosclerosis and lung injury, two doses of neratinib significantly increased efferocytosis in the lungs of mice concomitant with a reduction in the proportion of lung neutrophils. Neratinib significantly increased human neutrophil apoptosis and efferocytosis of apoptotic neutrophils by monocyte-derived macrophages (MDMs). In addition to increased efferocytosis, neratinib treated macrophages demonstrated both increased phagocytosis and macropinocytosis. Neratinib increased MDM surface expression of the efferocytosis receptor MerTK independent of protein synthesis and transcription which correlated with elevated efferocytosis in MDMs and inhibitors of MerTK blocked neratinib-induced efferocytosis. CONCLUSIONS: Thus, we describe a novel role for neratinib in driving efferocytosis in multimorbidity and suggest that ErbB TKIs may have therapeutic potential in inflammatory disease by restoring macrophage function and promoting inflammation resolution.

ID: 41906552
Title: Obesity Disrupts H3K4me3-Mediated Lactate Accumulation and Efferocytosis in Hypoxic Macrophages.
Abstract: Dysregulated macrophage function drives the development of obesity-associated pathologies. While macrophages adapt to their surrounding environment to maintain tissue homeostasis, the impact of obesity on macrophage adaptation to low oxygen levels remains elusive. Here, we show that hypoxia rapidly increases histone 3 lysine-4 trimethylation (H3K4me3) in bone marrow-derived macrophages (BMDMs) and that this response is impaired in BMDMs from high-fat diet (HFD)-induced obese mice, which significantly affected the expression of genes involved in metabolic pathways, resulting in decreased lactate accumulation, histone lactylation, and expression of genes involved in the maintenance of metabolic homeostasis. Moreover, altered adaptation to hypoxia in BMDMs from HFD mice led to a decreased efferocytosis capacity under hypoxia, which was reversed by supplementation with glucose or lactate. Serial bone marrow transplantation indicated that the maladapted hypoxia response for efferocytosis was imprinted in macrophage precursors in the bone marrow of HFD mice. In BMDMs, genetic disruption of the H3K4me3 demethylase KDM5A further enhances hypoxia-induced H3K4me3 and gene expression, along with lactate accumulation. In a dorsal skin biopsy model, while extracellular lactate levels decreased immediately after wounding but sharply increased in the early phase in normal mice, whereas lactate levels remained low in HFD mice, resulting in delayed wound healing. Our findings suggest that metabolic adaptation to hypoxia involves H3K4me3 and lactate accumulation in macrophages to perform efferocytosis under hypoxic conditions. Diet-induced obesity disrupts this pathway, resulting in impaired efferocytosis and delayed healing, with implications for altered macrophage functions in pathologies associated with obesity.

ID: 41924876
Title: Impairment of Macrophage Functions by the Senescence-Associated Secretory Phenotype of Vascular Smooth Muscle Cells-Brief Report.
Abstract: This study aimed to determine the effect of senescent vascular smooth muscle cells (VSMCs) on foam cell formation and macrophage phagocytic activity in atherosclerotic conditions. We measured the capacity of senescent VSMCs for scavenging oxLDL (oxidized low-density lipoprotein), which was impaired in senescent cells compared with proliferating and quiescent cells. Next, we obtained human peripheral blood monocytes from people >60 years old and differentiated them into macrophages using GM-CSF (granulocyte-macrophage colony-stimulating factor). We treated the macrophages with conditioned media derived from proliferating, quiescent, and senescent VSMCs and measured oxLDL uptake, phagocytosis, and efferocytosis. The results demonstrated that macrophages treated with senescent VSMC conditioned media experienced impaired oxLDL uptake, phagocytic activity, and reduced ability to clear senescent cells. Treatment of senescent VSMCs with senomorphic drugs before conditioned media transfer restored macrophage functions, confirming that the SASP (senescence-associated secretory phenotype) is critical for impairing macrophages during atherosclerotic conditions. Our results suggest that the SASP derived from senescent VSMCs prevents foam cell formation and disrupts the homeostatic function of macrophages in atherosclerosis. By suppressing macrophage function, senescent cells seem to evade immune clearance and accumulate, further propagating disease development.

ID: 42000693
Title: The role of macrophage metabolic reprogramming in efferocytosis: A dual-edged sword in atherosclerosis and tumor progression.
Abstract: Macrophage efferocytosis-the process by which macrophages recognize, engulf, and degrade apoptotic cells (ACs)-is essential for maintaining tissue homeostasis and resolving inflammation. Dysregulation of efferocytosis has been implicated in the progression of various diseases, including atherosclerosis (AS) and cancer. In AS, effective efferocytosis reduces inflammation, stabilizes plaques, and slows disease progression. Conversely, in the tumor microenvironment (TME), efferocytosis contributes to immune suppression, supporting cancer cell survival, proliferation, and metastasis. Impaired efferocytosis leads to the accumulation of secondary necrotic ACs, which exacerbate inflammation. Interestingly, in tumors, this process can paradoxically induce pro-inflammatory, anti-tumor immune responses. Therefore, understanding the regulatory mechanisms controlling efferocytosis is critical for the development of targeted therapies for inflammatory diseases and cancer. Recent findings highlight macrophage metabolic reprogramming as a key modulator of efferocytosis. Metabolic pathways, including glycolysis, amino acid metabolism, and fatty acid oxidation (FAO), provide the energy and biosynthetic intermediates necessary for macrophages to execute efferocytosis efficiently. These pathways influence all stages of efferocytosis-recognition, engulfment, and degradation of ACs-while shaping macrophage function and inflammatory responses. Moreover, metabolic adaptations in macrophages exhibit context-specific roles in atherosclerotic plaques and the TME, underscoring the complex and disease-specific effects of efferocytosis in pathological conditions. This review synthesizes current knowledge on the molecular mechanisms underlying efferocytosis and its regulation through macrophage metabolic reprogramming. It discusses how metabolic shifts impact efferocytosis and explores their broader implications in AS and cancer. Understanding the intricate interplay between macrophage metabolism and efferocytosis presents new opportunities for therapeutic intervention, with the potential to transform the clinical management of inflammatory and neoplastic diseases.

ID: 42030803
Title: Dangshen formula Shengmai-Yin suppresses atherosclerosis through restoring the gut microbiota and homeostatic efferocytosis.
Abstract: Atherosclerosis (AS) is a chronic progressive vascular disease characterized by lipid deposition and aortic inflammation. On the basis of traditional Chinese medicine (TCM) theory, the Dangshen Formula Shengmai-Yin (DS-SMY) has demonstrated unique advantages in treating AS. However, the mechanism by which DS-SMY affects AS has not been revealed. In this study, high-fat diet-induced apolipoprotein E knockout (ApoE-/-) mice were used to construct AS models. The effects of DS-SMY on aortic collagen deposition and inflammatory infiltration were investigated, and atorvastatin (Ato) was used as a positive control. The composition of the gut microbiota was assessed using high-throughput sequencing of the 16S rRNA gene. Colon morphology was observed via TEM, and apoptosis was assessed with TUNEL staining. The main component of DS-SMY in drug-containing serum was determined by HPLC. The effects of DS-SMY components (lobetyolin and schisandrin) were evaluated in PA-induced RAW 264.7 cells using WB, ELISA, and RT-qPCR. Compared with Ato, DS-SMY also had a therapeutic effect on ApoE-/- mice. In addition, DS-SMY inhibited M1 polarization of macrophages in ApoE-/- mice. Additionally, the results demonstrated that DS-SMY alleviated intestinal inflammation and promoted the formation of colon tight junctions. Furthermore, changes in the gut microbiota composition in ApoE-/- mice after DS-SMY treatment were sufficient to induce changes in colon inflammation. Mechanistically, the results revealed that DS-SMY components suppressed proinflammatory cytokine expression and enhanced macrophage efferocytosis. Furthermore, supplementation with butyric acid (a gut microbiota-derived metabolite) enhanced the effect of DS-SMY, which demonstrated that the effect of DS-SMY involved microbiota-dependent mechanisms. In summary, DS-SMY can alleviate atherogenic dyslipidemia and pathological inflammation in AS by targeting the gut microbiota and homeostatic efferocytosis and is accordingly a potential therapeutic agent for AS.

ID: 42141116
Title: Toll-like receptor 7 constrains efferocytosis in myocardial injury.
Abstract: Toll-like receptor 7 (TLR7) is an endosomal sensor of single-stranded RNA that is highly expressed in macrophages and contributes to post-infarct inflammation. Whether TLR7 also restrains macrophage reparative function, particularly efferocytosis and clearance of inflammatory debris, remain unclear. Using a murine model of myocardial ischemia-reperfusion (I/R) injury, we showed that TLR7 deficiency mitigated inflammation, reduced infarct size and alleviated adverse ventricular remodeling. Beyond its anti-inflammatory effects, TLR7 deficiency reprogrammed macrophages toward a reparative phenotype, characterized by decreased pro-inflammatory cytokine production and increased expression of anti-inflammatory mediators, including IL-10 and TGF-β, consistent with M2-like polarization. Single-cell RNA sequencing revealed a subset-specific mechanism in which TLR7 deficiency suppressed inflammatory signaling in M1 macrophages while enhancing efferocytosis-related pathways in M2 macrophages. This was accompanied by upregulation of key phagocytic receptors and machinery, including CD36, LRP1, MerTK, AXL and Rac1, and functionally translated into enhanced efferocytic capacity and reduced apoptotic burden. Notably, TLR7 deficiency also promoted macrophage-mediated clearance of neutrophil extracellular traps (NETs) without affecting NETosis, identifying a previously unrecognized role for TLR7 in regulating NET resolution. Consistent with these findings, NET formation was observed following myocardial injury in both murine I/R models and patients undergoing percutaneous coronary intervention.In conclusion, our data identify TLR7 as a macrophage-intrinsic checkpoint that limits efferocytosis and NET disposal, thereby impairing inflammation resolution after myocardial injury. Targeting TLR7 may therefore represent a therapeutic strategy to suppress excessive inflammation while restoring pro-resolving macrophage functions and improving cardiac repair.

ID: 42439678
Title: Follistatin Mitigates Atherosclerosis Through Activation of Arginine Metabolism and Adipose Browning.
Abstract: Follistatin (FST) binds to and neutralizes members of the transforming growth factor-beta (TGF-β) superfamily, thereby regulating diverse physiological processes, including regulation of skeletal muscle, adipose, and bone homeostasis. FST also promotes adipose browning and enhances energy metabolism, leading to improved plasma lipid profiles and metabolic health in mice. Given the emerging association between brown adipose tissue (BAT) activation and reduced atherosclerosis, we investigated the anti-atherogenic potential of FST. Transcriptomic and metabolomic analyses of the Hybrid Mouse Diversity Panel (HMDP) revealed that Fst expression was negatively correlated with aortic lesion area and positively correlated with the expression of multiple adipose browning-associated genes. Adeno-associated viral delivery of Fst (AAV1-FST344) in Ldlr-/- mice significantly reduced aortic lesion area, improved plasma lipid profiles, and decreased expression of adhesion (VCAM1) and inflammatory (iNOS, TNF-α) markers in white adipose tissue (WAT), liver, and heart. Fst gene delivery also markedly increased uncoupling protein 1 (UCP1) expression in WAT, consistent with WAT browning. Integrated correlation analyses of Fst expression with tissue metabolites, together with plasma metabolite-lesion associations identified in the HMDP, implicated the arginase 1 (Arg1)-mediated metabolic pathway as a key regulator of atherogenesis. Consistent with these findings, Arg1 expression was significantly elevated in WAT, liver, and heart of AAV1-FST344-treated mice and in wild-type versus Fst-knockout mouse embryonic fibroblasts (MEFs). Immunostaining localized Arg1 predominantly to CD68+ macrophages in heart and liver. Given recent evidence identifying Arg1 as a novel mediator of efferocytosis, these findings suggest that Arg1 may promote macrophage metabolic reprogramming and resolution of inflammation by enhancing the clearance of apoptotic cells. Furthermore, Fst gene delivery increased the expression of fibroblast growth factor 21 (Fgf21) and adiponectin (AdipoQ) in WAT. Collectively, these findings identify Fst as a novel anti-atherogenic regulator that protects against vascular disease by promoting adipose browning, improving lipid metabolism, and activating Arg1-mediated metabolic pathways.

ID: 42462036
Title: Restored clearance of senescent neutrophils by tissue-resident macrophages limits organ aging.
Abstract: Aging disrupts tissue homeostasis across organ systems. Here, we identify tissue-resident macrophages (TRMs) as central coordinators of age-related organ decline through impaired clearance of senescent neutrophils, a process regulated by the immunomodulatory prostaglandin E2 (PGE2) receptor EP2. Reducing TRM EP2 signaling in aged mice preserved youthful mitochondrial fitness and prevented cognitive decline, frailty, sarcopenia, adiposity, cardiac impairment, and systemic inflammation. Plasma proteomics implicated the liver as a major source of age-associated immune change, in which reduced TRM EP2 signaling rescued neutrophil efferocytosis and prevented paracrine stress in neighboring cells. Elevated TRM EP2 expression and senescent neutrophils were also observed in aged and diseased human tissues. Pharmacologic EP2 inhibition restored youthful neutrophil clearance, establishing impaired TRM efferocytosis as a reversible driver of organ decline in aging.

ID: 42505091
Title: Itaconate negatively regulates innate immunity during fungal pneumonia.
Abstract: The innate immune response to pathogens often involves metabolic reprogramming, such as disruption of the Krebs cycle, leading to the accumulation of various metabolites that can further influence innate cell responses during infection. Of these, the immunomodulatory metabolite itaconate has been shown to positively or negatively influence lung immune responses, depending on the pathogen. In the current study, we found that mice deficient in aconitate decarboxylase (Acod1-/- mice), the enzyme that produces itaconate from cis-aconitate, cleared the opportunistic mold Aspergillus fumigatus from the lung more effectively than wild-type (WT) control mice. Augmented fungal clearance in Acod1-/- mice correlated with increased type 17 responses, which themselves correlated with higher IL-1β, PGE2, and γδ T cell levels. Intriguingly, we show that alveolar macrophages and neutrophils from naïve Acod1-/- mice kill A. fumigatus more efficiently. Conversely, the addition of exogenous itaconate to alveolar macrophages and neutrophils from naïve WT mice reduced their antifungal capacity. Mechanistically, alveolar macrophages, but not neutrophils, from naïve Acod1-/- mice demonstrated enhanced ROS production when stimulated with A. fumigatus. We further show that mice with macrophage-specific, but not neutrophil-specific, Acod1 deficiency cleared A. fumigatus more effectively. Itaconate deficiency also protected against fungus-induced mortality during corticosteroid-mediated immunosuppression. Finally, itaconate reduced the antifungal activity of human monocyte-derived macrophages. Collectively, these data identify an immune regulatory role for itaconate during A. fumigatus fungal pneumonia and potentially identify a new therapeutic target for enhancing protection against A. fumigatus.IMPORTANCEFungal infections by invasive molds such as Aspergillus fumigatus are leading causes of morbidity and mortality in immunocompromised individuals, such as patients with hematologic malignancies, and recipients of hematopoietic stem cell transplant (HCT), solid organ transplant (SOT), and cellular therapies. A major shift in the increased incidence of these infections is a result of a rapidly expanding global immunocompromised population due to targeted immunotherapies and biologics for the treatment of cancer, combination therapies, cellular therapies, and bispecific and trispecific antibody therapies. The advancement in these immunomodulatory/immunosuppressive therapies is outpacing our understanding of mechanisms that lead to the development of infections such as invasive aspergillosis. Therefore, the continuing evolution of our understanding of protective and immunoregulatory responses would be expected to reveal new mechanisms that govern susceptibility to fungal pneumonia. To this end, in the current report, we show that the TCA cycle intermediate itaconate hinders lung clearance of A. fumigatus via regulating multiple immune mechanisms. Overall, our study uncovers a new mechanism of immune regulation during fungal pneumonia.

ID: 42505352
Title: Macrophage Extracellular Traps in Health and Disease: Current Concepts, Pathogenic Mechanisms and Clinical Implications.
Abstract: Macrophage extracellular traps (METs) are chromatin-based structures released by activated macrophages and are increasingly recognized as distinct, context-dependent effectors of innate immunity. Although initially described in antimicrobial defense, METs are now implicated in sterile inflammation, autoimmunity, fibrosis, metabolic and vascular injury, organ-specific damage, and cancer. This review integrates dispersed evidence on MET biology across physiological and pathological settings, moving beyond neutrophil-centered interpretations of extracellular trap biology. We summarize the molecular composition, structural heterogeneity, major forms of METosis, and key regulatory pathways, including PAD-dependent chromatin remodeling, reactive oxygen species and calcium signaling, mitochondrial DNA release, extracellular DNA sensing, protease-mediated injury, and macrophage-stromal crosstalk. We also discuss the dual nature of METs as protective structures that can contain pathogens and amplify early innate responses, but also as pathogenic platforms when excessive, persistent, or insufficiently cleared. Overall, current evidence supports METs as functionally versatile macrophage-derived immune structures whose biological effects depend on the stimulus, tissue microenvironment, and disease context. By providing a unified framework, this review highlights the relevance of METs as potential biomarkers and therapeutic targets in inflammatory, fibrotic, vascular, autoimmune, and malignant diseases.

ID: 42519831
Title: Neutrophil-promoted macrophage state transition coordinates endothelial migration and barrier resealing in zebrafish microvascular repair.
Abstract: Microvessels are frequently damaged, yet the in vivo temporal logic that couples endothelial gap closure to barrier resealing, and the immune-cell interactions that coordinate these steps, remains poorly defined. Using live imaging of laser-injured zebrafish intersegmental vessels, we define a staged repair program: endothelial cells migrate to bridge the gap, trapped erythrocytes are cleared, and vascular permeability rises transiently before resealing. Neutrophils arrive first, whereas macrophages persist and undergo a neutrophil-dependent functional transition. Early tnfa-associated macrophages promote endothelial migration and erythrocyte debris removal, while later ccl34a.4+ pro-remodeling macrophages support barrier restoration. Neutrophil ablation delays this transition and selectively prolongs permeability defects. Neutrophils release CD63+ extracellular vesicles that are taken up by macrophages, and inhibiting EV/exosome secretion phenocopies key features of neutrophil loss. These findings provide a temporal framework to dissect immune-endothelial coordination during microvascular repair.

ID: 42523712
Title: Impaired NLRP3 inflammasome activation by chitin underlies refractory chromoblastomycosis caused by Fonsecaea pedrosoi muriform cells.
Abstract: Macrophage NLRP3 activation is crucial for antifungal immunity, yet its role in chromoblastomycosis-a chronic subcutaneous mycosis typically caused by Fonsecaea pedrosoi-remains unclear. Unlike prior self-resolving models using conidia and hyphae, clinical disease features muriform cells, a parasitic form resistant to macrophages and linked to chronicity. Notably, chitin, a weak NLRP3 agonist, accumulates on the surface of muriform cells. This study investigates whether chitin accumulation modulates NLRP3 activation and promotes fungal persistence. Human chromoblastomycosis lesions were analyzed by IHC (MPO, CD86, NLRP3) and RT-PCR for cytokine transcripts. WT and NLRP3-/- mice were footpad-inoculated with F. pedrosoi muriform cells for in vivo assessment. Flow cytometric bead array quantified IL-1β, IL-6, IL-10, TNF-α, and IL-17A in footpad homogenates, and the same panel (excluding IL-17A) in stimulated BMDM supernatants. NLRP3 pathway activation in BMDMs was confirmed by western blotting and immunofluorescence. In human lesions, marked MPO+ neutrophil recruitment encapsulated muriform cells, yet multinucleated giant cells sequestered some fungal elements from neutrophils. Despite robust NLRP3 expression and elevated IL-1β, IL-6, TNF-α, and IL-10 versus normal skin (all p < 0.01), muriform cells persisted in tissue. In WT mice, lesions transitioned from purulent (day 7) to granulomatous (day 90), concurrent with declining IL-1β, IL-17A, IL-6, and TNF-α. MPO+ neutrophils abundantly surrounded muriform cells at day 7; at day 90, F4/80+ macrophages enveloped most fungi without elimination, forming multinucleated giant cells-recapitulating human pathology. In NLRP3-/- mice, IL-1β and IL-17A were produced in an NLRP3-independent manner and showed no decline over time. Muriform cells progressively budded and transitioned to hyphae both inside and outside giant cells; MPO+ neutrophils preferentially localized to hyphal areas, while macrophages remained around muriform cells, suggesting compartmentalized inflammation. In vitro, chitinase-treated muriform cells induced higher NLRP3-dependent IL-1β, IL-6, TNF-α, and IL-10 in WT BMDMs versus intact cells (all p < 0.01). Mechanistically, chitin accumulation partially suppressed NF-κB phosphorylation, reducing NLRP3 expression, caspase-1 cleavage, and ASC speck formation. NLRP3 mediates host defense against muriform cells yet fails to resolve chronic infection. Chitin accumulation on muriform cells attenuates NLRP3 activation, thereby promoting chromoblastomycosis chronicity.