ID: 23897815
Title: Mitochondria and AMP-activated protein kinase-dependent mechanism of efferocytosis.
Abstract: Defective clearance of apoptotic cells is frequently associated with perpetuation of inflammatory conditions. Our results show a rapid activation of AMP-activated kinase (AMPK) in macrophages upon exposure to apoptotic cells or lysophosphatidylcholine, a specific phospholipid that is produced and released from dying cells. AMPK activation resulted from inhibition of mitochondrial oxygen consumption and ATP production and further depended on Ca(2+) mobilization and mitochondrial reactive oxygen species generation. Once activated, AMPK increased microtubule synthesis and chemokinesis and provided adaptation to energy demand during tracking and engulfment. Uptake of apoptotic cells was increased in lungs of mice that received lysophosphatidylcholine. Furthermore, inhibition of AMPK diminished clearance of apoptotic thymocytes in vitro and in dexamethasone-treated mice. Taken together, we conclude that the mitochondrial AMPK axis is a sensor and enhancer of tracking and removal of apoptotic cell, processes crucial to resolution of inflammatory conditions and a return to tissue homeostasis.

ID: 28671983
Title: Isoflurane promotes phagocytosis of apoptotic neutrophils through AMPK-mediated ADAM17/Mer signaling.
Abstract: A patient's recovery from lung inflammatory injury or development of multi-system organ failure is determined by the host's ability to resolve inflammation and repair tissue damage, both of which require the clearance of apoptotic neutrophils by macrophages (efferocytosis). Here, we investigated the effects of isoflurane on macrophage efferocytosis and resolution of lung inflammatory injury. Treatment of murine bone marrow-derived macrophages (BMDMs) or alveolar macrophages with isoflurane dramatically enhanced phagocytosis of apoptotic neutrophils. Isoflurane significantly increased the surface expression of the receptor tyrosine kinase Mer in macrophages, but markedly decreased the levels of a soluble form of Mer protein in the medium. Isoflurane treatment also caused a decrease in a disintegrin and metalloproteinase 17 (ADAM17) on the cell surface and a concomitant increase in its cytoplasmic fraction. These responses induced by isoflurane were completely reversed by a pharmacological inhibitor or genetic deletion of AMP-activated protein kinase (AMPK). In a mouse model of lipopolysaccharide-induced lung injury, isoflurane accelerated the recovery of lung inflammation and injury that was coupled with an increase in the number of alveolar macrophages containing apoptotic bodies. In alveolar macrophage-depleted mice, administration of isoflurane-pretreated BMDMs facilitated resolution of lung inflammation following lipopolysaccharide challenge. Thus, isoflurane promoted resolution of lipopolysaccharide-induced lung inflammatory injury via enhancement of macrophage efferocytosis. Increased macrophage efferocytosis following isoflurane treatment correlates with upregulation of Mer surface expression through AMPK-mediated blockade of ADAM17 trafficking to the cell membrane.

ID: 29946009
Title: Impaired efferocytosis and neutrophil extracellular trap clearance by macrophages in ARDS.
Abstract: Exaggerated release of neutrophil extracellular traps (NETs) along with decreased NET clearance and inability to remove apoptotic cells (efferocytosis) may contribute to sustained inflammation in acute respiratory distress syndrome (ARDS). Recent studies in experimental models of ARDS have revealed the crosstalk between AMP-activated protein kinase (AMPK) and high-mobility group box 1 (HMGB1), which may contribute to effectiveness of efferocytosis, thereby reducing inflammation and ARDS severity.We investigated neutrophil and NET clearance by macrophages from control and ARDS patients and examined how bronchoalveolar lavage (BAL) fluid from control and ARDS patients could affect NET formation and efferocytosis. Metformin (an AMPK activator) and neutralising antibody against HMGB1 were applied to improve efferocytosis and NET clearance.Neutrophils from ARDS patients showed significantly reduced apoptosis. Conversely, NET formation was significantly enhanced in ARDS patients. Exposure of neutrophils to ARDS BAL fluid promoted NET production, while control BAL fluid had no effect. Macrophage engulfment of NETs and apoptotic neutrophils was diminished in ARDS patients. Notably, activation of AMPK in macrophages or neutralisation of HMGB1 in BAL fluid improved efferocytosis and NET clearance.In conclusion, restoration of AMPK activity with metformin or specific neutralisation of HMGB1 in BAL fluid represent promising therapeutic strategies to decrease sustained lung inflammation during ARDS.

ID: 33472399
Title: Resolvin D1 Enhances Necroptotic Cell Clearance Through Promoting Macrophage Fatty Acid Oxidation and Oxidative Phosphorylation.
Abstract: Plaque necrosis is a key feature of defective resolution in atherosclerosis. Recent evidence suggests that necroptosis promotes plaque necrosis; therefore, we sought to determine how necroptotic cells (NCs) impact resolution programs in plaques. Approach and Results: To investigate the role(s) of necroptosis in advanced atherosclerosis, we used mice deficient of Mlkl, an effector of necroptosis. Mlkl-/- mice that were injected with a gain-of-function mutant PCSK9 (AAV8-gof-PCSK9) and fed a Western diet for 16 weeks, showed significantly less plaque necrosis, increased fibrous caps and improved efferocytosis compared with AAV8-gof-PCSK9 injected wt controls. Additionally, hypercholesterolemic Mlkl-/- mice had a significant increase in proresolving mediators including resolvin D1 (RvD1) and a decrease in prostanoids including thromboxane in plaques and in vitro. We found that exuberant thromboxane released by NCs impaired the clearance of both apoptotic cells and NCs through disruption of oxidative phosphorylation in macrophages. Moreover, we found that NCs did not readily synthesize RvD1 and that exogenous administration of RvD1 to macrophages rescued NC-induced defective efferocytosis. RvD1 also enhanced the uptake of NCs via the activation of p-AMPK (AMP-activated protein kinase), increased fatty acid oxidation, and enhanced oxidative phosphorylation in macrophages. These results suggest that NCs derange resolution by limiting key SPMs and impairing the efferocytic repertoire of macrophages. Moreover, these findings provide a molecular mechanism for RvD1 in directing proresolving metabolic programs in macrophages and further suggests RvD1 as a potential therapeutic strategy to limit NCs in tissues. Graphic Abstract: A graphic abstract is available for this article.

ID: 35281442
Title: Macrophage Meets the Circadian Clock: Implication of the Circadian Clock in the Role of Macrophages in Acute Lower Respiratory Tract Infection.
Abstract: The circadian rhythm is a biological system that creates daily variations of physiology and behavior with a 24-h cycle, which is precisely controlled by the molecular circadian clock. The circadian clock dominates temporal activity of physiological homeostasis at the molecular level, including endocrine secretion, metabolic, immune response, coupled with extrinsic environmental cues (e.g., light/dark cycles) and behavioral cues (e.g., sleep/wake cycles and feeding/fasting cycles). The other side of the clock is that the misaligned circadian rhythm contributes to the onset of a variety of diseases, such as cancer, metabolic diseases, and cardiovascular diseases, the acceleration of aging, and the development of systemic inflammation. The role played by macrophages is a key mediator between circadian disruption and systemic inflammation. At the molecular level, macrophage functions are under the direct control of the circadian clock, and thus the circadian misalignment remodels the phenotype of macrophages toward a 'killer' mode. Remarkably, the inflammatory macrophages induce systemic and chronic inflammation, leading to the development of inflammatory diseases and the dampened immune defensive machinery against infectious diseases such as COVID-19. Here, we discuss how the circadian clock regulates macrophage immune functions and provide the potential risk of misaligned circadian rhythms against inflammatory and infectious diseases.

ID: 36359898
Title: Palmitate Inhibits Mouse Macrophage Efferocytosis by Activating an mTORC1-Regulated Rho Kinase 1 Pathway: Therapeutic Implications for the Treatment of Obesity.
Abstract: Every day, billions of our cells die and get cleared without inducing inflammation. When, clearance is improper, uncleared cells undergo secondary necrosis and trigger inflammation. In addition, proper efferocytosis would be required for inducing resolution of inflammation, thus clearance deficiencies in the long term lead to development of various chronic inflammatory diseases. Increasing evidence indicates that obesity, itself being a low-grade inflammatory disease, predisposes to a variety of other chronic inflammatory diseases. Previous studies indicated that this later might be partially related to an impaired efferocytosis induced by increased uptake of circulating saturated fatty acids by macrophages in obese people. Here, we show that palmitate inhibits efferocytosis by bone marrow-derived macrophages in a dose-dependent manner. Palmitate triggers autophagy but also activates an energy-sensing mTORC1/ROCK1 signaling pathway, which interferes with the autophagosome-lysosome fusion, resulting in accumulation of the cellular membranes in autophagosomes. We propose that lack of sufficient plasma membrane supply attenuates efferocytosis of palmitate-exposed macrophages. AMP-activated protein kinase activators lead to mTORC1 inhibition and, consequently, released the palmitate-induced efferocytosis block in macrophages. Thus, they might be useful in the treatment of obesity not only by affecting metabolism thought so far. ROCK1 inhibitors could also be considered.

ID: 38262562
Title: Calorie restriction mimetic, resveratrol, attenuates hepatic ischemia and reperfusion injury through enhancing efferocytosis of macrophages via AMPK/STAT3/S1PR1 pathway.
Abstract: Calorie restriction (CR) mimetic, resveratrol (RSV), has the capacity of promoting phagocytosis. However, its role in hepatic ischemia and reperfusion injury (HIRI) remains poorly understood. This study aimed to investigate the effect of RSV on alleviating HIRI and explore the underlying mechanisms. RSV was intraperitoneally injected in mice HIRI model, while RSV was co-incubated with culture medium for 24 h in RAW 264.7 cells and kupffer cells. Macrophage efferocytosis was assessed by immunostaining of PI and F4/80. The clearance of apoptotic neutrophils in the liver was determined by immunostaining of Ly6-G and cleaved-caspase-3. HE staining, Suzuki's score, serum levels of ALT, AST, TNF-α and IL-1β were analyzed to evaluate HIRI. The efferocytosis inhibitor, Cytochalasin D, was utilized to investigate the effect of RSV on HIRI. Western blot was employed to measure the levels of AMPKα, phospho-AMPKα, STAT3, phospho-STAT3 and S1PR1. SiSTAT3 and inhibitors targeting AMPK, STAT3 and S1PR1, respectively, were used to confirm the involvement of AMPK/STAT3/S1PR1 pathway in RSV-mediated efferocytosis and HIRI. RSV facilitated the clearance of apoptotic neutrophils and attenuated HIRI, which was impeded by Cytochalasin D. RSV boosted macrophage efferocytosis by up-regulating the levels of phospho-AMPKα, phospho-STAT3 and S1PR1, which was reversed by AMPK, STAT3 and S1PR1 inhibitors, respectively. Inhibition of STAT3 suppressed RSV-induced clearance of apoptotic neutrophils and exacerbated HIRI. CR mimetic, RSV, alleviates HIRI by promoting macrophages efferocytosis through AMPK/STAT3/S1PR1 pathway, providing valuable insights into the mechanisms underlying the protective effects of CR on attenuating HIRI.

ID: 38817112
Title: Circadian Regulation of Leishmania Parasite Internalisation in Macrophages and Downstream Cellular Events.
Abstract: Leishmania spp. parasites use macrophages as a host cell during infection. As a result, macrophages have a dual role: clearing the parasite as well as acting as host cells. Recently, studies have shown that macrophages harbour circadian clocks, which affect many of their functions such as phagocytosis, receptor expression and cytokine release. Interestingly, Leishmania major infection in hosts was also shown to be under circadian control. Therefore, we decided to investigate what underlies the rhythms of L. major infection within macrophages. Using a culture model of infection of bone marrow-derived macrophages with L. major promastigotes, we show that the parasites are internalised into macrophages with a 24-h variation dependent on a functional circadian clock in the cells. This was associated with a variation in the number of parasites per macrophage. The cell surface expression of parasite receptors was not controlled by the cells' circadian clock. In contrast, the expression of the components of the endocytic pathway, EEA1 and LC3b, varied according to the time of infection. This was paralleled by variations in parasite-induced ROS production as well as cytokine tumour necrosis factor α. In summary, we have uncovered a time-dependent regulation of the internalisation of L. major promastigotes in macrophages, controlled by the circadian clock in these cells, as well as subsequent cellular events in the endocytic pathway, intracellular signalling and cytokine production.

ID: 38863703
Title: The disrupted molecular circadian clock of monocytes and macrophages in allergic inflammation.
Abstract: Macrophage dysfunction is a common feature of inflammatory disorders such as asthma, which is characterized by a strong circadian rhythm. We monitored the protein expression pattern of the molecular circadian clock in human peripheral blood monocytes from healthy, allergic, and asthmatic donors during a whole day. Monocytes cultured of these donors allowed us to examine circadian protein expression in human monocyte-derived macrophages, M1- and M2- polarized macrophages. In monocytes, particularly from allergic asthmatics, the oscillating expression of circadian proteins CLOCK, BMAL, REV ERBs, and RORs was significantly altered. Similar changes in BMAL1 were observed in polarized macrophages from allergic donors and in tissue-resident macrophages from activated precision cut lung slices. We confirmed clock modulating, anti-inflammatory, and lung-protective properties of the inverse ROR agonist SR1001 by reduced secretion of macrophage inflammatory protein and increase in phagocytosis. Using a house dust mite model, we verified the therapeutic effect of SR1001 in vivo. Overall, our data suggest an interaction between the molecular circadian clock and monocytes/macrophages effector function in inflammatory lung diseases. The use of SR1001 leads to inflammatory resolution in vitro and in vivo and represents a promising clock-based therapeutic approach for chronic pulmonary diseases such as asthma.

ID: 39366181
Title: Macrophage corpses for immunoregulation and targeted drug delivery in treatment of collagen-induced arthritis mice.
Abstract: The role of pro-inflammatory macrophages (M1) in rheumatoid arthritis (RA) is significant, as they produce excessive cytokines. Targeting efferocytosis is a potential manner to repolarize M1 macrophages into pro-resolving M2 phenotype, which restores immune homeostasis by releasing anti-inflammatory mediators. In this study, liquid nitrogen-treated dead macrophages (DM) are employed to act as a dead cell-derived active targeted drug carrier for shikonin (SHK) and induce efferocytosis in M1 macrophages with the enhancement of SHK as an AMP-activated protein kinase (AMPK)-activator. The synergistic activation of AMPK leads to uncoupled protein 2 (UCP2) upregulation and reprograms M1 macrophages into M2 phenotypes by promoting oxidative phosphorylation. In the mouse model of collagen-induced arthritis, the intravenous administration of DM/SHK leads to a consistent transformation of M1 macrophages into the M2 phenotype within the infiltrative synovium. This transformation of macrophages results in the restoration of immune homeostasis in the synovium through an increase in the production of pro-resolving mediators. Additionally, it inhibits synovial proliferation and infiltration and provides protection against erosion of cartilage and bone. In summary, LNT-based DM serves as an active targeting drug carrier to M1 macrophages and also acts synergistically with SHK to target immunometabolism.

ID: 39628480
Title: Ozone promotes macrophage efferocytosis and alleviates neuropathic pain by activating the AMPK/Gas6-MerTK/SOCS3 signaling pathway.
Abstract: Neuropathic pain (NPP) is a multifaceted pain syndrome that occurs as a consequence of physical injury or underlying diseases, with an incidence rate of 7%-10%, NPP poses a significant clinical challenge as current treatment options are ineffective. The accumulation of apoptotic cells and neuroinflammation play crucial roles in the pathological mechanisms of NPP. Here, we aim to investigate strategies for effectively clearing apoptotic cells and provide therapeutic interventions for NPP. CCI mice were treated with different concentrations of ozone (15μg, 30μg, 45μg) to investigate the effects on the accumulation of apoptotic cells and neuroinflammation. In vitro, the phagocytic function of BMDM towards apoptotic neutrophils after ozone treatment was examined. We found ozone at a concentration of 30μg significantly alleviated mechanical hypersensitivity in CCI mice and ozone significantly upregulates the phagocytic activity of BMDM. Furthermore, we investigated the mechanisms and found ozone could activate AMPK, upregulate Gas6 (but not Protein S), activate MerTK (a key receptor involved in apoptosis), and enhance the phagocytic function of BMDM towards apoptotic neutrophils. It caused the promotion of SOCS3 expression and the suppression of inflammatory factors IL-1β, IL-6, and TNF-a. Interestingly, the effect of ozone in alleviating CCI-induced pain was abolished by the AMPK inhibitor CC and the MerTK receptor inhibitor UNC2541. Ozone facilitated macrophage clearance of apoptotic cells, decreased neuroinflammation by activation of p-AMPK/Gas6/MerTK/SOCS3 signaling pathway, which may become an effective therapeutic approach for neuropathic pain after further clinical validation.

ID: 39744689
Title: Targeting macrophage circadian rhythms with microcurrent stimulation to activate cancer immunity through phagocytic defense.
Abstract: Rationale: Macrophage phagocytosis plays a role in cancer immunotherapy. The phagocytic activity of macrophages, regulated by circadian clock genes, shows time-dependent variation. Intervening in the circadian clock machinery of macrophages is a potentially novel approach to cancer immunotherapy; however, data on this approach are scarce. Microcurrent stimulation (MCS) promotes inflammation, proliferation, and remodeling, suggesting its potential to modulate macrophage function; however, its application has been limited. In this study, we investigated the impact of MCS on macrophage phagocytosis of cancer cells using mouse/human macrophage cell lines and various mouse/human cancer cell lines. Methods: Cells and mice received 300 µA, 400 Hz bidirectional pulsed MCS. Gene expression, protein expression, and phagocytosis activity were assessed in intraperitoneal macrophages collected from mice, as well as in RAW264.7, and THP-1 cells. Flow cytometry, population, phagocytosis activity, RNA-seq, and immunohistochemistry analyses were performed. Results: Noninvasive MCS prevented time-dependent reduction in macrophage phagocytosis of cancer cells by modulating the circadian clock genes. MCS also enhanced phagocytosis in mouse RAW264.7 and human THP-1 cells across various cancer types by promoting actin polymerization; similar in vivo effects were observed in mice. This enhancement occurred in abdominal macrophages of both sexes and was mediated by changes in clock gene expression. Specifically, suppressing the clock gene Per1 nullified the effects of MCS. Moreover, although macrophage phagocytosis typically declined during the dark period, MCS during the light period prevented this reduction. MCS also increased phagocytosis of peritoneally implanted cancer cells (4T1, ID8, and Hepa1-6) in mice, significantly reducing tumor engraftment and growth, and ultimately improving prognosis. Conclusions: The findings of this study suggest that targeting macrophage circadian mechanisms via MCS could enhance cancer immunity, offering new avenues for cancer immunotherapy.

ID: 40027178
Title: Ceramide Complex Ameliorates Metabolically Driven Neutrophil Senescence by Regulating Apoptosis via the cGAS-STING Pathway.
Abstract: Background: Population aging is increasingly recognized as a major global challenge. Researchers have identified a correlation between aging and immunosenescence, leading to dysfunction of the immune system. As a crucial component of the innate immune system, age-related changes in neutrophils have garnered significant attention from researchers, but the underlying mechanisms remain unclear. This study aims to comprehensively evaluate the senescence status and potential mechanisms of neutrophils, and to identify targets for delaying or even reversing senescence. Methods: Blood routine tests and Luminex Multiplex Cytokine Analysis were employed to assess inflammation levels in mice. Flow cytometry and an agarose chemotaxis model were used to evaluate baseline biological functions and stress responses of neutrophils. Transmission electron microscopy and flow cytometry were utilized to compare mitochondrial ultrastructure and function. Metabolomic analysis was performed to examine metabolic patterns. qPCR, Western blotting, and flow cytometry were used to investigate the potential mechanisms of ceramide intervention on neutrophils. Results: Our findings indicate that aged mice exhibit considerable variability in delayed apoptosis among bone marrow neutrophils, alongside a notable reduction in baseline functionality and stress response capabilities. Metabolomic analysis revealed a marked decrease in ceramide levels within aged neutrophils. In vitro ceramide intervention revitalized neutrophil functionality and partially inhibited delayed apoptosis, facilitating the efficient elimination of senescent neutrophils. The underlying mechanism behind these effects might be attributed to ceramide's modulation of mitochondrial permeability, which in turn influences the activation of the cGAS-STING pathway, as well as its regulatory role in maintaining the equilibrium of pro-apoptotic Bcl-2 protein levels. Conclusions: This investigation proficiently assessed neutrophil senescence in terms of both biological functionalities and intrinsic diversity, while concurrently exploring the feasibility and primary mechanisms through which ceramide intervention impacts neutrophil senescence at the levels of signaling pathways, protein expression, and cellular microarchitecture. These findings provide novel insights into evaluating and potentially intervening in immune senescence, with implications for organismal aging.

ID: 40593101
Title: Hydrogen sulfide aggravates neutrophil infiltration, vascular remodeling and elastase-induced abdominal aortic aneurysm in male mice.
Abstract: Abdominal aortic aneurysm (AAA) has an 80% mortality rate upon rupture, with no pharmacological treatments available to slow its progression. Hydrogen sulfide (H₂S), produced by cystathionine γ-lyase (CSE), has anti-inflammatory and antioxidant properties, but its role in AAA remains unclear. We evaluated the impact of sodium thiosulfate (STS), a clinically relevant H₂S donor, in a periadventitial elastase-induced AAA model in normotensive male wild-type and Cse-/- mice. Complementary in vitro studies were conducted on primary human vascular smooth muscle cells (VSMCs) to assess the effects of STS on proliferation, senescence and cytokine-induced apoptosis. Contrary to expectations, STS dose-dependently aggravate AAA progression by increasing extracellular matrix degradation. Although STS reduces macrophage and lymphocyte infiltration, it enhances neutrophil accumulation, particularly MMP9⁺ neutrophils, and promotes the formation of c-KIT⁺-MPO⁺ pre-neutrophil clusters. Cse-/- mice show reduced neutrophil infiltration and smaller aneurysms, supporting a pathogenic role of endogenous H₂S. STS also impairs VSMC proliferation and induces senescence, blunting compensatory aortic remodeling. H₂S, delivered via STS, exacerbates AAA progression under normotensive conditions by promoting neutrophil-driven inflammation and impairing VSMC repair. These findings challenge the assumption that H₂S is universally protective in vascular disease and raise caution regarding the therapeutic use of STS in patients at risk for AAA. Abdominal aortic aneurysm (AAA) is a life-threatening condition where a major blood vessel in the abdomen, called the aorta, becomes weak and bulges. There are currently no medications that can slow down AAA growth, and rupture carries a high risk of death. Hydrogen sulfide (H₂S) is a gas naturally produced in the body, that has shown to protect against cardiovascular diseases. This study investigated whether sodium thiosulfate (STS), a H₂S-releasing compound, could reduce AAA progression in mice. Unexpectedly, STS worsened AAA. Our findings highlight the need for caution when considering STS as a treatment for patients at risk of AAA.

ID: 40816293
Title: DNASE1L3-expressing dendritic cells promote CD8+ T cell function and anti-PD-(L)1 therapy efficacy by degrading neutrophil extracellular traps.
Abstract: CD8+ T cell exclusion and dysfunction in the tumor microenvironment (TME) are among the most challenging obstacles for anti-PD-(L)1 therapy. Here, we report that tumor-infiltrating dendritic cell (DC)-specific expression of the deoxyribonuclease, DNASE1L3, is positively correlated with favorable outcomes of anti-PD-(L)1 treatment in cancer patients. DNASE1L3 conditional knockout in DCs leads to enhanced tumor growth and diminishes anti-PD-L1 therapeutic efficacy by impairing infiltration and effector functions of CD8+ T cells. Conversely, injection with DNASE1L3 promotes CD8+ T cell infiltration and reduces exhaustion in the TME, significantly retarding tumor growth and enhancing anti-PD-L1 response. DNASE1L3+ DCs can degrade neutrophil extracellular traps that suppress the spatial distribution of CD8+ T cells in tumors, enabling establishment of cytotoxic CD8+ T cell hubs in human cancers. Our findings reveal a role of DC in regulating intratumoral CD8+ T cells and identify DNASE1L3 as a promising target to improve anti-PD-(L)1 therapy.

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: 41408789
Title: Less Inflammatory Debris, Improved Immunity from Immune Detox: A New Perspective on the Benefits of Exercise in Chronic Disease.
Abstract: The immunological benefits of exercise are commonly attributed to its immune-boosting effects such as the release of exercise-induced factors (e.g., exerkines) and activation of anti-inflammatory molecules. However, this may not fully explain its benefits in chronic inflammatory conditions. We propose a complementary view whereby exercise potentially functions as a biological detoxifier by removing harmful immunological debris such as damage-associated molecular patterns (DAMPs), senescent cells, dysfunctional mitochondria and pro-inflammatory extracellular vesicles (EVs) that drive chronic immune activation. We highlight key mechanisms by which exercise may reduce or remove these harmful signals, including autophagy and mitophagy activation, enhanced efferocytosis, reduced senescence burden, and modulation of EV cargo. This "immune detox" model may help explain the clinical benefits of exercise in conditions where the immune system is overactivated, not deficient. It shifts the narrative from immune boosting to restoring immune balance, and could have potentially important implications for biomarker discovery and personalized exercise prescriptions in chronic disease.

ID: 41557892
Title: Plasmin modulates neutrophilic inflammation and alveolar macrophage function, protecting mice from pneumococcal pneumonia.
Abstract: Accumulating evidence supports the proresolving actions of the plasminogen/plasmin (Plg/Pla) system during inflammation, beyond its classical role in fibrin degradation. Here, we investigated the role of Plg/Pla on key features of inflammation resolution in a murine model of severe pneumococcal pneumonia. High levels of Plg were observed in the airways after infection, accompanied by increased levels of Plg activator inhibitor-1, neutrophil elastase, and Plg degradation fragments as inflammation progressed. Pla treatment of mice infected with Streptococcus pneumoniae decreased neutrophilic infiltration in airways and lungs, accompanied by lower concentrations of the neutrophil chemoattractive chemokines CXCL1 and CXCL2 and the proinflammatory cytokines tumor necrosis factor, interleukin-6 (IL-6), and IL-1β. Pla treatment also enhanced neutrophil apoptosis and efferocytosis and slightly reduced bacterial loads in bronchoalveolar lavage. In addition, Pla decreased damage and fibrin deposition in the lungs, improving pneumonia-driven pulmonary mechanical dysfunction and rescuing mice from lethality. Pla-induced resolution of S pneumoniae-evoked inflammation was associated with neutrophil apoptosis, as the caspase-3-specific inhibitor Z-DEVD-FMK blocked Pla-protective actions. In addition to the effects on neutrophils, intranasal instillation of Pla in naive mice increased the number of alveolar macrophages and guided them toward a regulatory phenotype marked by enhanced efferocytosis of apoptotic neutrophils and increased bacterial phagocytosis, ultimately promoting host protection against pneumococcus-induced inflammation and tissue damage. In sum, our findings demonstrate that Pla modulates the lung inflammatory milieu and promotes key proresolving events, namely neutrophil apoptosis and expansion of alveolar macrophage with enhanced efferocytosis and phagocytic abilities, resulting in improved lung function and survival in pneumococcal pneumonia.

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: 41965689
Title: GPR30-mediated NETs degradation via Trex1 in heart failure of aged female mice.
Abstract: BACKGROUND: The occurrence of cardiovascular diseases increases dramatically in postmenopausal aged women. Accumulating evidence has indicated that estrogen protects hearts from cardiovascular diseases. However, the underlying mechanisms was not fully elucidated. This present study was designed to investigate the function of GPR30 in pathological heart failure of aged female mice with the focus of neutrophil extracellular traps (NETs). METHODS: Transverse aortic constriction (TAC) surgery was performed to induce heart failure in aged female mice. RNA-seq and flow cytometry were employed to study neutrophils activity during heart failure of aged female mice. Heart function and cardiac fibrosis as well as NETs level were assessed. Reduction of NETs by DNase I administration、 G1 treatment and Trex1 overexpression in macrophage were conducted to elucidate the role of NETs in this pathological process. Co-culture of RAW264.7 macrophages and neutrophils were used to examine the function of Trex1 in macrophage. RESULTS: Our bulk RNA-seq analysis showed that neutrophil migration and neutrophil chemotaxis were markedly enhanced at the early stage of pathological cardiac hypertrophy in aged female hearts. We further demonstrated that NETs generated by these activated neutrophils in aged female myocardium at the late stage were significantly increased following TAC surgery accompanied with the reduction of GPR30 expression. GPR30 agonist G1 treatment preserved cardiac function and reduced myocardial fibrosis in aged female mice with heart failure. To further validate the key role of NETs, DNase I administration markedly enhanced cardiac performance and attenuated cardiac fibrosis with the overall neutrophil reduction in the myocardium. Our in vitro results showed that overexpression of Trex1 in RAW264.1 macrophage enhanced neutrophil NETs clearance, thus indicating that GPR30 activation could increase the exonuclease three prime repair exonuclease 1 (Trex1) expression which may be associated with the reduction of NETs level in hypertrophied hearts. CONCLUSION: NETs generated by neutrophils exacerbate pressure overload–induced heart failure in aged female mice. GPR30 activates Trex1 signaling in macrophage to enhance NTEs degradation and thus attenuates TAC-induced cardiac dysfunction, providing an avenue for the novel therapeutics against cardiac dysfunction in postmenopausal women.

ID: 42041175
Title: Corneal Nerves Promote Alkali Burn Repair by Modulating Macrophages and Neutrophils via Calcitonin Gene-Related Peptide.
Abstract: This study aims to investigate the role of calcitonin gene-related peptide (CGRP) in corneal tissue repair in alkali burn and its underlying neuro-immune mechanisms. Mouse corneal nerves were ablated via surgery or resiniferatoxin (RTX) to study their role in tissue healing after an alkali burn. CGRP and its receptor levels were quantified by Western blot and quantitative PCR (qPCR). Alkali-burned corneas were treated topically with CGRP or BIBN-4096. Tissue repair, inflammatory cytokine expression, and immune cell infiltration were subsequently assessed. Macrophages were depleted using PLX5622 to evaluate their effect on healing. Furthermore, mouse macrophages and neutrophils were cultured in vitro, and transcriptomic analysis was performed to elucidate functional and molecular alterations, which were validated experimentally. Corneal nerve ablation significantly delayed corneal alkali burns healing. In alkali burns, corneal nerves released CGRP, leading to elevated CGRP levels in the cornea. Topical CGRP application promoted tissue repair and reduced inflammation, whereas its antagonist BIBN-4096 impeded healing. Macrophage depletion not only delayed repair but also abolished the therapeutic effect of CGRP, indicating that macrophages are crucial for CGRP-mediated repair. Mechanistically, CGRP promoted neutrophil apoptosis and enhanced macrophage apoptosis, efferocytosis, and anti-inflammatory functions via the cAMP-TSP-1 pathway, thereby facilitating tissue repair. This study reveals that in corneal alkali burns, corneal nerves promote tissue repair by secreting CGRP to regulate neuro-immune interactions, providing new insights for the treatment of corneal alkali burns.

ID: 42054454
Title: A robust adhesive microneedle for oral infections therapy via synergistic antibacterial and neutrophil-macrophage axis immunomodulation.
Abstract: Oral infectious diseases are challenging to treat, as conventional therapies struggle to maintain effective drug levels and simultaneously address both infection and immune dysregulation. To address this, we developed a mussel-inspired microneedle patch (PCA@FeCO MN) by incorporating Fe3(CO)12 into a caffeic acid-grafted polyvinyl alcohol network. This design overcomes existing barriers through a dual-adhesion mechanism: a catechol-metal coordination network for strong chemical bonding and an optimized taper geometry for mechanical interlocking in wet oral tissues. Upon near-infrared irradiation, PCA@FeCO MN activates a photothermal-ferroptosis-gas therapy cascade, synergistically eradicating pathogens. Crucially, this strategy also disrupts the inflammation cycle by steering neutrophils toward function activation, timely apoptosis and boosting macrophage efferocytosis. In both rat and beagle dog models of oral infections, PCA@FeCO MN achieved robust tissue adhesion, highly efficient synergistic antibacterial activity, and precise immunomodulation, demonstrating its promising therapeutic potential for future clinical translation.

ID: 42150286
Title: Skull bone marrow-derived IL-10+VEGF-α+neutrophils exert neuroprotective effects in aged TBI.
Abstract: Aging increases the risk and worsens the prognosis of traumatic brain injury. Neutrophils contribute to the secondary neuroinflammatory response after TBI. Nevertheless, the biological functions and underlying mechanisms contributing to the age-related heterogeneity of neutrophils in elderly individuals with TBI remain inadequately understood. The study identified a unique neutrophil subpopulation with elevated IL-10 expression, functionally enriched in young TBI tissues. CellChat analysis revealed significant intercellular communication between IL-10+neutrophils and endothelial cells, with elevated expression of Vegfa. GO/KEGG analysis exhibit characteristics associated with reducing inflammatory responses, inhibiting oxidative stress, promoting angiogenesis and tissue remodeling. The IL-10 Ab intervention led to a deterioration in neurological outcomes in young TBI. SCENIC analysis demonstrated that the transcription factor NR2C2 regulates the distinct neutrophils. Transplantation experiments using GFP+ mouse bone marrow indicated that it could be a source of skull bone marrow. Transcriptome sequencing confirmed that phenotypic changes in dHL-60 cells, following NR2C2 overexpression, activate signaling pathways involved in Complement and coagulation cascades Immune, Hematopoietic cell lineage Immune, Jak STAT and Toll like receptor. The regulation of NR2C2 was achieved through siRNA knockdown technology to mitigate the effects of NO-prednisolone. NR2C2 overexpression, induced by NO-prednisolone, leads to the production of IL-10+VEGF-α+neutrophils in the brain tissue of aged mice with TBI, resulting in improved blood-brain barrier integrity, reduced pathological changes in brain tissue injury, inhibition of neuroinflammation, and significant enhancement of neurobehavioral function. CONCLUSION: This study explored the role of a specific subset of skull-derived IL-10+VEGF-α+neutrophils in TBI, with an emphasis on age-related immune cell heterogeneity. The findings indicate that these neutrophils exhibit anti-inflammatory and reparative properties, and are associated with the transcription factor NR2C2 and the potential therapeutic agent NO-prednisolone. This research provides potential interventions for treating TBI in the aging population.

ID: 42183275
Title: Neutrophil efferocytosis in chronic inflammatory gastrointestinal diseases: mechanistic insights and therapeutic potential.
Abstract: Efferocytosis-the phagocytic clearance of apoptotic cells-is central to tissue homeostasis and the active resolution of inflammation. Although its mechanistic basis and disease relevance have been studied in isolation, no review has comprehensively integrated neutrophil efferocytosis mechanisms, their pathophysiological roles across major chronic inflammatory gastrointestinal diseases, and natural product-based therapeutic strategies-a gap this work addresses. We systematically describe the efferocytic recognition cascade, encompassing find-me signals, eat-me signals (including phosphatidylserine and the underappreciated plasminogen/M6P-IGF2R axis), and don't-eat-me checkpoints (CD47-SIRPα). We clarify that efferocytosis is not restricted to M2-polarized macrophages-M0 and M1 macrophages also participate-but that polarization state critically determines the pro-resolving coupling of downstream signaling. We analyze shared and disease-specific efferocytic defect mechanisms in inflammatory bowel disease, chronic gastritis, NAFLD/NASH, and pancreatitis, identifying IL-10R signaling failure, receptor shedding, CD47 upregulation, and SPM deficiency as convergent pathological nodes. Against this backdrop, we critically evaluate natural product strategies-flavonoids, polyphenols, alkaloids, terpenoids, polysaccharides, and omega-3 fatty acids-targeting these nodes, with explicit grading of evidence levels. Translational challenges and the potential of single-cell sequencing, spatial transcriptomics, and patient-derived organoid co-culture systems are also discussed. Restoring efferocytosis represents a mechanistically grounded therapeutic frontier for chronic gastrointestinal disease.

ID: 42289901
Title: p120-catenin enhances macrophage efferocytosis and facilitates resolution of lung inflammatory injury.
Abstract: Defective resolution of inflammation following sepsis contributes to persistent immune dysfunction and increased morbidity and mortality worldwide. Efficient clearance of apoptotic polymorphonuclear neutrophils (PMNs) by macrophages, a process known as efferocytosis, is essential for resolving inflammation, promoting tissue repair, and restoring immune homeostasis; however, the molecular mechanisms governing this process remain poorly understood. Here, we identify p120-catenin (p120) as a critical regulator of efferocytosis that promotes the resolution of inflammatory lung injury. In alveolar macrophage-depleted mice challenged with endotoxin, intratracheal instillation of p120-deficient macrophages delayed the resolution of PMN infiltration, protein exudation, and lung edema and injury compared with control macrophages. These changes were accompanied by increased levels of TNF-α and IL-6, decreased levels of TGF-β and IL-10, and a reduced number of macrophages containing apoptotic PMNs in bronchoalveolar lavage fluid. p120 depletion also markedly reduced the phagocytosis of apoptotic PMNs by cultured macrophages. Mechanistically, p120 deficiency decreased the expression of the efferocytic receptors CD36 and Axl and shifted macrophage polarization toward a pro-inflammatory M1 phenotype. Furthermore, apoptotic cells induced the association and co-localization of p120 with peroxisome proliferator-activated receptor-γ (PPARγ), whereas p120 deletion markedly reduced PPARγ activity in response to apoptotic PMNs. Pharmacologic inhibition of PPARγ abolished p120-mediated macrophage efferocytosis and the resolution of lung inflammation. Collectively, these findings establish a central role for p120 in macrophage efferocytosis and inflammatory resolution and suggest that targeting macrophage p120 may represent a novel therapeutic strategy to promote recovery from inflammatory lung injury.

ID: 42340550
Title: Neutrophil extracellular traps in osteoporosis: mechanistic links to bone remodeling imbalance and therapeutic perspectives.
Abstract: Osteoporosis (OP) is increasingly recognized as a disorder driven not only by endocrine and metabolic abnormalities but also by chronic low-grade inflammation and aging-related immune dysregulation. Neutrophil extracellular traps (NETs), web-like extracellular DNA-protein structures released by activated neutrophils, can act as structural inflammatory scaffolds that sustain sterile inflammation, oxidative injury, and microenvironmental imbalance. However, the mechanistic contribution and translational significance of NETs in osteoporosis remain incompletely integrated. This review aims to summarize the current evidence linking NET formation to bone remodeling imbalance in osteoporosis, with particular emphasis on osteoclast activation, osteoblast dysfunction, inflammaging, oxidative stress, ferroptosis, metabolic reprogramming, and potential NET-targeted therapeutic strategies. We reviewed recent studies concerning NET biology, osteoimmunology, inflammaging, and inflammation-associated osteoporosis. Based on these findings, we constructed an integrated "NETs-inflammation-bone remodeling imbalance" framework to explain how persistent NET accumulation may promote osteoclastogenesis, impair osteogenic differentiation, amplify inflammatory feedback loops, and reshape the bone microenvironment. We also discussed the potential clinical relevance of neutrophil-related inflammatory indicators and NET-specific biomarkers. Persistent NET formation and insufficient NET clearance under inflammaging conditions may contribute to a self-sustaining inflammatory-oxidative network in the bone microenvironment. NET-derived extracellular DNA, histones, neutrophil elastase, myeloperoxidase, and citrullinated proteins may activate pattern-recognition receptor pathways, including TLR4/NF-κB and potentially TLR9- and TLR2-related signaling, thereby enhancing RANKL-mediated osteoclastogenesis and suppressing osteoblast differentiation and survival. In parallel, NETs may amplify oxidative stress, disturb iron homeostasis, promote ferroptosis susceptibility, and induce metabolic reprogramming, collectively shifting bone remodeling toward bone resorption. Targeting NET formation, promoting NET degradation, or blocking NET-related inflammatory and oxidative signaling may provide new therapeutic opportunities for inflammation-driven osteoporosis. Nevertheless, the NETs-ferroptosis-metabolic reprogramming axis in osteoporosis should currently be regarded as a promising mechanistic framework that requires further experimental and clinical validation.

ID: 42347208
Title: Incorporating WGCNA and Machine Learning to Identify ADAP2 as a Critical Efferocytosis-Related Gene in Sepsis.
Abstract: Sepsis, a life-threatening organ dysfunction caused by dysregulated host responses to infection, frequently involves impaired macrophage efferocytosis that leads to apoptotic cell accumulation, secondary necrosis, and persistent inflammation. Early prognostic stratification remains challenging, as current biomarkers lack sufficient specificity and sensitivity, underscoring the urgent need for novel prognosis-related indicators. We integrated bulk transcriptomic data from a discovery cohort (GSE205672) and an independent validation cohort (GSE133822) with single-cell RNA-seq profiles of early- and late-stage sepsis (GSE167363, GSE175453). WGCNA and five consensus machine-learning algorithms were combined to screen core efferocytosis-associated genes, and expression was validated via qPCR in PBMCs from sepsis patients and CLP-induced septic mice. ADAP2 was identified as the core gene achieving strict consensus across all five algorithms, with early upregulation and late depletion in sepsis, predominant expression in monocytes/macrophages-particularly M1-like and IFN-responsive subsets-and a significant correlation with efferocytosis scores and immune cell infiltration. Its expression was negatively correlated with sepsis severity (SOFA score) and showed a trend toward worse survival in patients with low ADAP2 levels. This multi-dimensional transcriptomic study establishes ADAP2 as a candidate biomarker with potential prognostic value in sepsis, closely linked to macrophage efferocytosis. These findings may aid early risk stratification and inform macrophage-directed immunotherapies, although prospective validation and functional studies are required.

ID: 42352073
Title: Myeloid DRP1 Sulfenylation Drives Reparative Macrophage Polarization and Neovascularization in Ischemic Muscle.
Abstract: Reparative macrophage polarization and macrophage-derived reactive oxygen species (ROS) are required for ischemia-induced revascularization in peripheral artery disease (PAD). Our previous study showed that mitochondrial fission protein dynamin-related protein 1 (DRP1) promotes reparative polarization and metabolic reprogramming in macrophages and post-ischemic neovascularization. However, the redox-dependent mechanism governing DRP1 activation in this context remains elusive. Here, using a mouse hindlimb ischemia (HLI) model of PAD, we identify cysteine sulfenylation (CysOH) of DRP1 as a critical redox modification induced in ischemic bone marrow (BM)-derived cells. BM chimeric mice reconstituted with CRISPR/Cas9-generated "redox-dead" DRP1-C631A knock-in mutant (Drp1C/A) BM exhibited markedly reduced limb perfusion recovery and CD31+ capillary density in ischemic muscles following HLI. These defects were associated with enhanced Ly6G+ neutrophil accumulation, pro-inflammatory F4/80+CD80+ M1-like macrophages and reduced anti-inflammatory F4/80+CD206+ M2-like macrophages in ischemic muscle. Mechanistically, using an in vitro PAD model, hypoxia serum starvation (HSS) rapidly induced NADPH oxidase 2-dependent cytosolic ROS production and DRP1-CysOH formation in wild-type macrophages. In contrast, Drp1C/A macrophages failed to undergo DRP1-CysOH-dependent mitochondrial fission under HSS, resulting in aberrant metabolic reprogramming characterized by enhanced glycolysis and mitochondrial ROS, pro-inflammatory p-NF-κB and M1-genes, and suppressed anti-inflammatory p-AMPK, efferocytosis and M2-genes. Thus, our findings establish DRP1 sulfenylation as a previously unrecognized redox-sensing mechanism that links ischemia-induced ROS to reparative macrophage reprogramming and revascularization, identifying a novel therapeutic target for PAD.

ID: 42404908
Title: Circadian control of immune homeostasis in cardiovascular health and disease.
Abstract: The circadian system is an important regulator of cardiovascular immune homeostasis. Emerging evidence suggests that daily timing of immune responses may influence cardiovascular disease progression by coordinating leukocyte trafficking, inflammatory thresholds, metabolic adaptation, and tissue repair across the 24-hour cycle. This review examines how core and auxiliary circadian regulators, including BMAL1, CLOCK, PER/CRY complexes, REV-ERBs, RORs, and systemic timing cues, shape immune-cell activation through transcriptional, epigenetic, metabolic, and neuroendocrine mechanisms. We further synthesize evidence on circadian coordination of leukocyte trafficking, particularly the CXCL12/CXCR4 axis, and discuss how disrupted timing may promote inappropriate leukocyte recruitment into the vascular wall. At the cellular level, circadian misalignment has been associated with altered macrophage polarization, inflammasome activation, and inflammatory injury, processes that may modulate atherosclerosis, myocardial ischemia-reperfusion injury, and post-infarction remodeling. Finally, we evaluate the translational potential and current limitations of chronopharmacology, emphasizing that time-of-day treatment strategies require careful consideration of clinical evidence, circadian phase assessment, chronotype, sex, age, comorbidities, and treatment feasibility. This evidence-weighted chrono-immunological perspective may help refine future research on cardiovascular inflammation and inform the development of more individualized prevention and therapeutic strategies.

ID: 42429815
Title: Neuronal Guidance Proteins in the Fundamental Biology of Inflammation Resolution.
Abstract: The initiation and resolution of acute inflammatory responses rely on highly orchestrated biochemical and cellular programs, in which a finely tuned repertoire of mediators regulates the dynamics, migration, and effector functions of immune cells in space and time. Persistent, incompletely resolved inflammatory reactions disrupt this delicate homeostatic equilibrium and foster the development of severe acute and chronic diseases. Central mediators that terminate inflammatory responses and actively transition them into resolution are therefore of paramount importance. These include not only specialized pro-resolving lipid mediators but also peptide and protein mediators, cytokines with context-dependent pro-resolving function, stromal and neuronal signals, as well as cell-intrinsic resolution mechanisms such as efferocytosis, metabolic reprogramming, and tissue-repair programs. Innate and adaptive immune cells integrate these signals and, as major sources and effectors of pro-resolving mediators, drive clearance of harmful stimuli and dying cells and foster tissue repair. Within this broader network of pro-resolving pathways, neuronal guidance proteins (NGPs) are increasingly recognized as critical regulators of immune cell positioning and function that act far beyond their classical roles in axon guidance and are now regarded as integral components of the active inflammation-resolution program. This chapter interrogates the fundamental biology of selected NGPs-including Netrin-1, repulsive guidance molecule A (RGM-A), Semaphorin 7A (Sema7A), Neogenin (Neo1), and Plexin C1 (PLXC1)-and delineates their dual roles within inflammatory and resolution programs, with particular emphasis on how these cues sculpt leukocyte trafficking, promote cellular clearance, and drive immune cell reprogramming along the temporal axis from the early phase of acute inflammation to the restoration of tissue homeostasis.

ID: 42459689
Title: Neutrophil death pathways in myocardial infarction: the balance between injury and repair.
Abstract: Following acute myocardial infarction (AMI), neutrophils rush to the damaged heart tissue. Their presence is critical, and how they die influences whether the heart heals or suffers further injury. This outcome depends on specific cell death pathways of neutrophils, including NETosis, apoptosis, and autophagy. NETosis can be harmful when neutrophils release sticky, web-like structures (NETs) filled with toxic enzymes, particularly during early thromboinflammatory amplification. These webs trap platelets and trigger clotting, which blocks blood vessels and worsens heart damage. In contrast, timely neutrophil apoptosis is a quiet, controlled death that signals cleanup cells (macrophages) to remove debris and start tissue repair, although apoptotic signaling in other cardiac cell types or inappropriate time windows may be detrimental. Autophagy acts as a regulator, helping determine which of these paths the cell takes. Furthermore, platelets could modulate these specific cell death pathways by releasing soluble mediators (e.g., P-selectin, HMGB1, polyP, CXCL4), promoting NETosis while suppressing apoptosis to exacerbate ischemic myocardial injury. Some anti-inflammatory strategies could fail if broad immune suppression inadvertently disrupts reparative neutrophil apoptosis and efferocytosis. Future therapies could aim to precisely block pathological NETosis or support timely neutrophil apoptosis to limit injury and improve heart recovery.

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.