ID: 40546642
Title: Low Secretory Leukocyte Protease Inhibitor (SLPI)-Level Potentiates Alternaria Extract-Induced T-Helper 2 (Th2) Airway Inflammation via the Interleukin-33 (IL-33) Pathway.
Abstract: Introduction Serine proteases play a critical role in the augmented release and cleavage of IL-33, leading to the expansion of group 2 innate lymphoid cells (ILC2s) and T-helper 2 (Th2) airway inflammation. However, the protective regulation of protease-dependent interleukin-33 (IL-33) activation remains poorly understood. Therefore, we investigated the role of secretory leukocyte protease inhibitor (SLPI), as a serine protease inhibitor, in this protective regulation and aimed to clarify its contribution to type 2 immunity. Methods We evaluated the role of SLPI in the Alternaria extract-induced expansion of ILC2s and Th2-type airway inflammation via IL-33, using three models: SLPI-deficient mice, an in vivo SLPI knockdown model with shRNA, and an in vitro model utilizing primary human bronchial epithelial cells (HBECs) exposed to Alternaria extract under various conditions, including plasmid transfection. Results We showed that two mouse models of downregulation of SLPI gene expression augmented Alternaria extract-induced release of IL-33 and the expansion of ILC2s, together with Th2 airway inflammation. Furthermore, two treatment models using SLPI KO mice, administration of a serine protease inhibitor, bovine pancreatic trypsin inhibitor, or anti-IL-33 antibody, attenuated Th2 airway inflammation. In two in vitro experiments, SLPI, as a serine protease inhibitor, prevented both the release of IL-33 from HBECs and the cleavage of full-length IL-33 to shorter mature forms by neutrophil elastase. Discussion These findings suggest that SLPI functions as a key serine protease inhibitor in regulating IL-33-mediated type 2 immune responses. Low SLPI levels may contribute to the pathogenesis of asthma by promoting Th2 inflammation, highlighting SLPI as a potential therapeutic target in patients with low SLPI expression.

ID: 40841361
Title: Piezo1-mediated mechanotransduction regulates the translational activity, function and lung pathogenicity of group 2 innate lymphoid cells.
Abstract: Group 2 innate lymphoid cells (ILC2s) are central effectors of type 2 immune responses in the lung; however, how mechanical cues regulate their function remains unclear. Here, we identified the mechanosensitive ion channel Piezo1 as a key regulator of ILC2 effector function through translational control. Piezo1 is highly expressed in murine and human ILC2s, and its activation by mechanical stress or the Piezo1 agonist, Yoda1 induces calcium influx, triggering mTOR signaling and selectively enhancing IL-13 protein production. Conditional deletion of Piezo1 in ILC2s reduced mTOR activation and puromycin incorporation, leading to impaired protein synthesis and attenuated lung inflammation and fibrosis in the IL-33, Alternaria alternata, and bleomycin models. scRNA-seq and scATAC-seq confirmed that Piezo1-deficient ILC2s retained Il13 transcription and chromatin accessibility but presented translational suppression, as evidenced by protein‒mRNA interactions. Pharmacologic mTOR inhibition phenocopied Piezo1 loss, supporting the functional relevance of the Piezo1-mTOR axis. These findings demonstrate that Piezo1 functions as a mechanosensor that integrates biomechanical cues to regulate cytokine output via mTOR-mediated translation. Targeting Piezo1 signaling or its downstream effectors may provide therapeutic benefits in type 2 inflammation-associated lung diseases.

ID: 41763365
Title: IL-33 enhances responsiveness and mast cell mediator release in isolated human small airways.
Abstract: Concomitant exposure to IL-33, thymic stromal lymphopoietin (TSLP), and IL-25 augments antigen-induced contractions of isolated human small bronchi through enhanced mast cell reactivity. We sought to test the individual contribution of alarmins in antigen-induced airway hyperresponsiveness and hyperosmolarity-induced responses evoked by mannitol, a surrogate model of exercise-induced bronchoconstriction. Intact segments of small airways, isolated from fresh human lung tissue, were incubated with IL-33, TSLP, IL-25, or buffer control for 48 hours. Contractile responses to anti-IgE or mannitol were then assessed using myograph systems. Mast cell degranulation and mediator release were analyzed both from the bronchial segments and from isolated primary human lung mast cells as well as from the human mast cell line LAD2 (Laboratory of Allergic Diseases 2). IL-33 increased contractile force (Emax) to anti-IgE and hyperosmolar mannitol by 62% and 78%, respectively. IL-33 also doubled antigen-IgE-induced prostaglandin D2 release from bronchial segments as well as enhanced degranulation, cysteinyl leukotriene, and prostaglandin D2 release from isolated human lung mast cells stimulated by anti-IgE or mannitol. In contrast, TSLP and IL-25 had no effect on contraction, degranulation, or mediator release in response to either stimulus. IL-33, but not TSLP or IL-25, enhances bronchoconstriction in human small bronchi by amplifying mast cell activation and mediator release in response to both antigen and hyperosmolar challenge.

ID: 41904701
Title: STAT6-IP-dependent inhibition of type 2 innate and Th2 adaptive immunity in the murine lung.
Abstract: Type 2 airway inflammation is one of the main characteristics of allergen-induced asthma. Evidence from animal studies supports a model in which inhalation of allergens triggers epithelial cell release of alarmin cytokines, including IL-33, which activate a number of innate cells in the lung, including group 2 innate lymphoid cells (ILC2s), which produce large amounts of IL-13 and IL-5, to amplify allergic inflammation. Amongst other activities, ILC2-derived IL-13 promotes DC migration to the lung draining mediastinal lymph nodes (MLNs). Our published data indicate that topical administration of an immunomodulatory peptide, STAT6-IP, at the time of antigen priming inhibits T helper 2 adaptive immunity in murine models of asthma, at least in part, through inhibition of dendritic cells (DCs). In this study, we sought to clarify inhibitory activity of STAT6-IP toward DC responses in the lung and the lung draining MLNs induced by IL-33 and ovalbumin (OVA). Our data show that STAT6-IP reduced expansion of total and IL-13-producing ILC2s in OVA/IL-33-treated mice. STAT6-IP also inhibited OVA/IL-33-induced recruitment to and activation of lung DCs, which in turn reduced DC migration and CD4+ Th2 differentiation in the lung MLNs. When challenged several weeks later with OVA, allergic inflammatory responses, including airway hyperresponsiveness, were reduced in STAT6-IP-treated mice. STAT6-IP retained inhibitory activity whether delivered before or after OVA/IL-33 and activity coincided with expansion of IL-13-producing ILC2s. Altogether, our findings provide insight into mechanisms by which STAT6-IP interacts with innate immune cells of the lung to reduce maladaptive type 2 innate and T helper 2 adaptive immunity.

ID: 42093293
Title: Targeting Inflammatory Alarmin S100A9 Modulates Activation of Pro-Inflammatory Macrophage to Protect Nasal Epithelial Cells From LPS-Induced Epithelial-Mesenchymal Transition.
Abstract: Chronic rhinosinusitis with nasal polyps (CRSwNP) exhibits pronounced endotypic heterogeneity, with macrophages serving as key drivers of sustained mucosal inflammation. In this study, we identify S100A9 as a macrophage-derived alarmin that is markedly elevated in CRSwNP tissues. Integrative analyses of public bulk transcriptomic datasets and single-cell RNA-sequencing atlases demonstrated that S100A9 expression was predominantly enriched in macrophage clusters, where it showed strong co-expression with canonical M1-associated markers, while exhibiting limited expression in epithelial cell subsets. Spatial and correlation analyses further supported a close association between S100A9⁺ macrophages and epithelial barrier-related gene signatures. Functionally, shRNA-mediated silencing of S100A9 attenuated M1-like macrophage polarization, as evidenced by reduced expression of pro-inflammatory mediators and polarization markers, accompanied by a shift toward a less inflammatory macrophage phenotype. Conditioned media derived from S100A9-deficient macrophages significantly mitigated epithelial injury, leading to restoration of epithelial barrier integrity, as indicated by enhanced expression of tight junction proteins, including occludin and claudins. Importantly, S100A9 knockdown disrupted the pathogenic macrophage-epithelial inflammatory feedback loop, thereby dampening sustained inflammatory signaling and limiting epithelial barrier breakdown that perpetuates tissue damage in CRSwNP. Clinically, elevated S100A9 levels correlated with disease severity indices and effectively distinguished a macrophage-enriched inflammatory endotype of CRSwNP, highlighting S100A9 as both a mechanistic driver and a potential biomarker for disease stratification. Collectively, these findings position S100A9 as a mechanistic mediator and a promising therapeutic target for CRSwNP.

ID: 42121933
Title: Eosinophil-Epithelial Cell Crosstalk at Mucosal Barriers: From Homeostatic Regulation to Disease Pathogenesis.
Abstract: Eosinophils are multifunctional granulocytes that reside constitutively within mucosal tissues, where they engage in bidirectional communication with the epithelial cells lining the respiratory and gastrointestinal (GI) tracts. Once regarded solely as terminal effectors of the type 2 immunity, eosinophils are now recognized as key regulators of epithelial homeostasis and barrier integrity. Epithelial cells initiate crosstalk by releasing the alarm cytokines such as interleukin (IL)-33, thymic stromal lymphopoietin (TSLP), and IL-25, which drive eosinophil recruitment, activation, and tissue retention. Conversely, eosinophils modulate epithelial function through the release of granule proteins, cytokines, and growth factors with both damaging and reparative consequences. In the airway, this crosstalk underpins the pathogenesis of eosinophilic asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), in part via eosinophil-derived mediators that disrupt tight junction integrity and fuel remodeling. In the GI tract, homeostatic eosinophils support villous architecture, epithelial turnover, and goblet cell differentiation through microbiota-driven IL-33 signals and neuropeptide-mediated neuroimmune pathways, whereas dysregulated crosstalk promotes eosinophilic esophagitis (EoE) and inflammatory bowel disease (IBD). This review synthesizes recent research to delineate the molecular mechanisms of eosinophil-epithelial crosstalk across mucosal compartments, highlight tissue-specific differences and shared mechanistic themes, and discuss the implications of these findings for targeted therapy.

ID: 42166932
Title: Air pollutants elicit type 3 immune response in asthma through Ly6C+ monocyte-derived macrophages.
Abstract: Diesel exhaust particles (DEP) have been implicated in reducing lung function and exacerbating asthma. However, precise mechanisms remain unclear. This study aimed to investigate the impact of DEP exposure on airway innate immune cells, focusing on macrophages/monocytes, and their role in asthma exacerbation. Using a murine asthma model, we sensitized and challenged 6-week-old BALB/c mice with ovalbumin (OVA). These mice underwent 10 repeated OVA inhalations over three weeks, with and without concurrent DEP inhalation. Airway hyperresponsiveness and airway inflammation were assessed. We characterized immune cell populations and their crosstalk, focusing on mouse Ly6C+ monocyte-derived macrophages (MoMs) and human CD14+CD16- MoMs. DEP exposure worsened histological scores in the asthmatic lungs and altered the OVA-induced type 2 inflammation profile, leading to increased type 3 inflammation. In terms of lung macrophages, DEP inhalation resulted in the depletion of SiglecF+CD11c+CD11b- resident alveolar macrophages and an increase in SiglecF-CD11b+ MoMs, particularly Ly6C+ MoMs. DEP-exposed Ly6C+ MoMs isolated from the OVA model (DEP-Ly6C+ MoMsOVA) heightened neutrophil chemotaxis and the expression of fibrosis-related genes. DEP-Ly6C+ MoMsOVA also promoted the differentiation of innate lymphoid cells (ILCs) and T helper (Th) cells toward ILC3s and Th17 cells, respectively. Ex vivo DEP-Ly6C+ MoMsOVA transfer also induced significant type 3 inflammation with SiglecF+ neutrophils. In vitro DEP-treated human CD14+CD16- MoMs upregulated neutrophil chemotaxis-related genes and exacerbated non-type 2 inflammation. In conclusion, DEP exposure exacerbates asthma by inducing mixed type 2 and type 3 inflammation in the asthmatic airways through the modulation of Ly6C+ MoMs, which enhance type 3 immunity.

ID: 42189350
Title: Epithelial alarmins TSLP, IL-33, and IL-25 in asthma pathogenesis: mechanistic roles and therapeutic implications.
Abstract: Asthma is a heterogeneous chronic inflammatory airway disease affecting over 300 million people worldwide. The airway epithelium serves as the primary interface with environmental stimuli and responds by releasing epithelial-derived alarmins, thymic stromal lymphopoietin (TSLP), interleukin-33 (IL-33), and interleukin-25 (IL-25), which act as upstream regulators of both innate and adaptive immune responses. Current therapies targeting downstream inflammatory mediators demonstrate limited efficacy in severe and refractory asthma, necessitating novel approaches targeting upstream pathways. This narrative review examines the mechanistic roles of epithelial alarmins TSLP, IL-33, and IL-25 in asthma pathogenesis, covering their regulation, receptor signalling, downstream immune activation, and contributions to airway remodelling. Current and emerging biologic therapies targeting these alarmins are summarised, with key clinical trials tabulated. A comprehensive narrative literature review was conducted. Electronic databases searched included PubMed/MEDLINE, Scopus, Web of Science, and ClinicalTrials.gov, covering publications from January 2015 to March 2025, with seminal earlier studies included where relevant. Search terms used included: "TSLP asthma," "IL-33 asthma," "IL-25 asthma," "epithelial alarmins," "thymic stromal lymphopoietin," "tezepelumab," "itepekimab," "astegolimab," "airway inflammation," "ILC2," "airway remodelling," and "biologic therapy severe asthma." Priority was given to original research articles, randomised controlled trials, and systematic reviews; review articles were included to provide mechanistic context. Studies were selected based on relevance to alarmin biology, immunological pathways, and clinical evidence in asthma. TSLP: Functions as a central amplifier of type-2 and mixed inflammatory responses through transcriptional regulation following epithelial stimulation. Activates dendritic cells, group 2 innate lymphoid cells (ILC2s), and granulocytes via the TSLPR/IL-7Rα complex, driving both eosinophilic and non-eosinophilic inflammation. Tezepelumab, an anti-TSLP monoclonal antibody, has achieved regulatory approval (FDA/EMA) for severe asthma with demonstrated exacerbation reduction across multiple endotypes (40-60% reduction in clinical trials). IL-33: Constitutively stored in epithelial cell nuclei, acts as an immediate danger signal upon cellular injury, triggering rapid innate immune activation through the ST2/IL-1RAcP receptor complex. Mediates acute exacerbations, airway hyperresponsiveness, and steroid-refractory inflammation. Anti-IL-33 agents including itepekimab, astegolimab, and tozorakimab are in Phase 2-3 clinical development with promising early efficacy data. IL-25: Predominantly produced by epithelial tuft cells, sustains chronic type-2 immunity, mucus hypersecretion, and corticosteroid-insensitive disease phenotypes through IL-17RA/IL-17RB receptor engagement. IL-25-targeted approaches demonstrate preclinical efficacy and are advancing toward clinical evaluation. Epithelial alarmins represent critical upstream drivers of asthma pathogenesis, orchestrating diverse inflammatory pathways that determine disease endotypes and severity. Therapeutic targeting of TSLP, IL-33, and IL-25 offers a paradigm shift from downstream cytokine inhibition to source-directed intervention, with potential to reduce exacerbations, prevent airway remodelling, and improve disease control across different asthma phenotypes. The success of anti-TSLP therapy and ongoing clinical development of IL-33 and IL-25 inhibitors validate epithelial alarmins as essential molecular targets for precision medicine approaches in severe and refractory asthma.

ID: 42219146
Title: Monoclonal antibodies targeting inflammatory pathways in chronic obstructive pulmonary disease: Evidence and opportunities.
Abstract: Chronic obstructive pulmonary disease (COPD) is a common and heterogeneous inflammatory lung disease associated with exacerbations that drive morbidity, mortality, and health care utilization worldwide. Although inhaled therapies remain the cornerstone of treatment, many patients continue to experience exacerbations despite optimized therapy, highlighting the need for new targeted approaches. Advances in understanding COPD immunopathology have identified several inflammatory pathways that may be amenable to monoclonal antibody therapies. Traditionally, COPD has been associated with neutrophilic inflammation linked to type-1 and type-3 immune responses. However, clinical trials targeting these pathways, including tumor necrosis factor, interleukin (IL)-1β, and IL-17, have largely failed to demonstrate clinical benefit. In contrast, increasing evidence supports a role for type-2 inflammation and upstream pathways in a subset of patients with COPD, including individuals without a history of asthma. Biomarkers such as blood eosinophils and fractional exhaled nitric oxide can help identify this endotype and guide therapeutic selection. Randomized trials of monoclonal antibodies suppressing inflammatory pathways have demonstrated reductions in exacerbations among carefully selected patients with eosinophilic COPD, leading to the recent recommendation of dupilumab and mepolizumab in international treatment guidelines. Emerging strategies are exploring upstream epithelial mediators, including alarmins such as IL-33, thymic stromal lymphopoietin, and bispecific therapies that suppress multiple inflammatory pathways. A consistent finding is that patients with moderate (nonsevere) COPD and concomitantly elevated blood eosinophils and fractional exhaled nitric oxide derive greater benefit from monoclonal antibodies. These developments suggest that targeted monoclonal antibody therapy may play an expanding role in COPD management, supporting the concept of earlier intervention in high-risk COPD.

ID: 42226044
Title: MyD88 mediates allergic airway inflammation by regulating ILC2s function through inducing the formation of P38/GATA3 complex.
Abstract: Allergic asthma stands as the predominant asthma phenotype propelled by aberrant type 2 immune response. Type-2 innate lymphoid cells (ILC2s) are significant for generating IL-5 and IL-13 cytokines, highlighting their vital role in triggering and escalating the progression of asthma. Myeloid differentiation primary response protein 88 (MyD88) controls innate and adaptive immune responses by orchestrating inflammatory signals. This work focused on investigating the influence of MyD88 in governing ILC2s-driven allergic airway disease alongside its underlying molecular mechanisms. We evaluated the effects of MyD88 in IL-33-induced or allergen-induced airway hyperreactivity (AHR) and airway inflammation. The role and mechanism of MyD88 in regulating ILC2s function were examined in vivo and in vitro by using transcriptome sequencing analysis, flow cytometry, clinical samples, ILC2-specific MyD88 knockout mice, and anti-Thy1.2 antibody against ILC2s in mice. The results showed heightened MyD88 expression in ILC2s sourced from allergic asthmatic patients and asthmatic mice. MyD88 knockout in ILC2s was able to mitigate IL-33-induced airway inflammation, while the MyD88 inhibitor LM8 proves efficacious in attenuating allergen-induced airway inflammation and AHR. After elimination of ILC2s via anti-Thy1.2 antibody, the pharmacological activity of LM8 diminished. Mechanistic studies revealed that MyD88 mediates the activation and proliferation of ILC2s through facilitation of P38-GATA3 complex formation. The research highlights MyD88 as a critical regulator of ILC2s activation, suggesting its potential utility as a therapeutic target for interventions in allergic asthma.

ID: 42302976
Title: Beyond proteostasis: LONP1 as an immunometabolic checkpoint in health and disease.
Abstract: Mitochondrial Lon protease 1 (LONP1) is an ATP-dependent protease involved in mitochondrial protein quality control, mitochondrial DNA (mtDNA) maintenance, and stress adaptation. Beyond this canonical role, accumulating evidence links LONP1 to metabolic rewiring, inflammatory signaling, immune-cell polarization, and disease-associated mitochondrial dysfunction. Recent human LONP1 cryo-electron microscopy (cryo-EM) structures have revealed nucleotide- and substrate-dependent conformational states, including fold-sensing intermediates, pore-loop rearrangements, and catalytic-site organization, providing a structural framework for substrate processing and state-dependent ligandability. Functionally, LONP1 regulates the turnover or stability of metabolic enzymes such as pyruvate dehydrogenase kinase 4 (PDK4), 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), and aconitase 2 (ACO2), thereby influencing carbon flux, epigenetic regulation, and immune-related metabolic programs. LONP1 deficiency or dysfunction can promote mitochondrial stress responses, including mtDNA release and cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING)-dependent inflammation, with implications for aging, pulmonary fibrosis, developmental disorders such as cerebral, ocular, dental, auricular, and skeletal anomalies (CODAS) syndrome, and organ injury. Conversely, increased LONP1 activity or expression has been associated with tumor progression, desmoplastic remodeling, ferroptosis resistance, and viral pathogenesis in selected models, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coxsackievirus B3 (CVB3). Pharmacological studies, including activators, dual-target inhibitors, and bortezomib-bound structural complexes, support the potential ligandability of LONP1 but also highlight unresolved issues in selectivity, target engagement, mitochondrial toxicity, and context-dependent therapeutic windows. This review summarizes current structural, mechanistic, and pharmacological evidence for LONP1 as a context-dependent immunometabolic regulatory node and discusses limitations and open questions that must be addressed before clinical translation.

ID: 42307017
Title: Spatial and Phenotypic Heterogeneity of ILC Subsets in Mouse Lung Under Type 2 Inflammatory Conditions.
Abstract: As key regulators of mucosal immunity, innate lymphoid cells (ILCs) are involved in tissue homeostasis, inflammation, and repair. Studying ILCs within their native microenvironment remains challenging due to the low abundance of these tissue-resident immune cells. Here, we applied cyclic multiplex immunofluorescence, namely multiepitope ligand cartography (MELC), in a systemic IL-33-induced type 2 inflammation model to spatio-temporally characterize ILC phenotype and localization in mouse lungs. Niche analysis with all identified cell types resulted in four distinct niches and an expansion of a mixed B and Plasma cell (BPC)/blood endothelial cell (BEC) niche, while the niche predominated by blood endothelial cells decreased at IL-33 day 3. Spatial neighborhood and coenrichment analyses revealed ILC2 accumulation in myeloid-rich peri-lymphatic niches at early time points of IL-33-mediated inflammation. ILC2s were in direct contact with activated alveolar macrophages and lymphatics. While they expressed ICOS under homeostatic conditions, pronounced expression of MHCII at days 1 and 3 of IL-33 stimulation was observed. Unlike ILC2s, NK cells/ILC1s were coenriched near blood vessels, next to B cells and plasma cells. Our findings demonstrate the utility of spatial multiplex imaging for dissecting rare immune cell localization and phenotypes and uncover dynamic, tissue-specific remodeling of ILC niches during early type 2 inflammation.

ID: 42309230
Title: Common γ-chain cytokines induce an epigenomically plastic precursor-like KIT+ ILC2 state linked to immune disease susceptibility.
Abstract: Group 2 innate lymphoid cells (ILC2s) are key effector cells of type 2 immunity. A subset of ILC2s, which expresses KIT (CD117), display increased phenotypic plasticity and have previously been linked to severe asthma and psoriasis. However, the molecular mechanisms promoting a KIT+ ILC2 state remain poorly understood. We defined the molecular basis for the enhanced plasticity of KIT+ ILC2s and identified signals that induce this phenotype, including links with immune disease susceptibility. We combined bulk as well as single-cell transcriptome (RNA sequencing) and epigenome (assay for transposase-accessible chromatin using sequencing) analysis with in vitro culture assays using primary human KIT+ or KITneg ILC2s and multipotent ILC progenitors. Epigenomic data were integrated with genetic risk variants for major human immune diseases. Multiomic analyses revealed that KIT+ ILC2s maintain a unique hybrid character marked by expression and open chromatin of genes linked to both ILC progenitors and ILC2 biology. KIT+ ILC2s showed extensive epigenomic priming at gene loci related to naive lymphocyte biology, tissue homing, and ILC3 effector functions, including IL17 and IL23R-explaining why KIT+ ILC2s are poised to adopt an ILC3-like phenotype. Genetic risk variants for asthma and autoimmunity are enriched in the poised epigenome of KIT+ ILC2s. Common γ-chain cytokines IL-2/IL-7 induced and maintained a KIT+ phenotype in KITneg ILC2s through STAT5 activation. Our study defines KIT+ ILC2s as existing in a developmentally immature state and carrying a precursor-like epigenome that promotes phenotypic plasticity and is linked to immune disease susceptibility. Importantly, we identify STAT5-mediated cytokine signals as candidates for therapeutic targeting of KIT+ ILC2s.

ID: 42323248
Title: How to monitor response to biologics in children with severe asthma.
Abstract: Severe paediatric asthma imposes a substantial health and financial burden. Biologics-monoclonal antibodies targeting specific asthma inflammatory pathways, are transforming severe asthma management. Currently approved biologics for paediatric use (≥6 or ≥12 years of age) include anti-immunoglobulin E (omalizumab), anti-interleukin (IL)-5 (mepolizumab), ultra-long acting anti-IL5 (depemokimab), anti-IL-5 receptor (benralizumab), anti-IL4/IL-13 (dupilumab), and anti-thymic stromal lymphopoietin (TSLP) (tezepelumab). While clinical trials have shown promising results, real-world data on long-term efficacy and safety in children and adolescents remain limited. Moreover, guidelines for initiating, monitoring biologics and assessing treatment response varies across countries lacking consensus. This is the second in a series of narrative reviews on biologics in severe paediatric asthma. The first review summarised key clinical trials findings and offered practical guidance for initiating therapy. In this review, we focus on strategies for monitoring treatment response, the role of asthma biomarkers and the potential of emerging therapies. We also highlight current research gaps and future directions to optimise biologics use in children and adolescents with severe asthma.

ID: 42361797
Title: Iron drives protease-independent cleavage of gasdermin D in allergic airway diseases.
Abstract: Gasdermin D (GSDMD)-mediated interleukin (IL)-33 secretion by lung epithelial cells initiates airway inflammation upon allergen challenge. How environmental allergens activate GSDMD remains elusive. Here, we demonstrate that exposing epithelial cells to allergens triggers protease-activated receptor 1 (PAR1)-dependent ferritinophagy, elevating intracellular labile iron. This iron pool is essential for noncanonical, protease-independent GSDMD activation. The iron chaperone poly(rC)-binding protein 2 (PCBP2) delivers iron directly to GSDMD, initiating a highly localized Fenton reaction. This generates constrained hydroxyl radicals that cleave GSDMD, releasing the active N-terminal p40 fragment to form pores for IL-33 release. Blocking any step of this iron-GSDMD pathway, via iron chelation or genetic ablation, abolishes IL-33 secretion, prevents group 2 innate lymphoid cell (ILC2) activation, and mitigates allergic airway inflammation and tissue damage in mice. Our findings reveal an unconventional, iron-catalyzed, and protease-independent mechanism for GSDMD activation, offering potential new therapeutic targets for allergic inflammatory diseases.

ID: 42381636
Title: Serotonin Degradation and Lipid Metabolism Regulate Human Tc2 Cell Effector Functions.
Abstract: Cytotoxic type 2 T cells (Tc2) are increasingly recognized as contributors to type 2 inflammation, including asthma, yet the metabolic programs that support their function remain poorly defined. We aimed to define the metabolic requirements of Tc2 cells, identify pathways that regulate their effector function, and assess whether serotonin-modifying therapies are associated with altered Tc2 responses and allergic sensitization in humans. Tc2 cells from human peripheral blood and lung tissue were analyzed using Seahorse metabolic assays, Mitotracker staining, flow cytometry, and RNA sequencing. Effector functions were evaluated following inhibition of glycolysis, fatty acid metabolism, and monoamine oxidase A (MAOA) inhibition. In parallel, anti-depressant prescription data were analyzed in the population-based BAMSE cohort to assess associations with allergic sensitization. Peripheral blood mononuclear cells from individuals prescribed selective serotonin reuptake inhibitors (SSRIs) and matched controls were stimulated ex vivo to assess cytokine production. Tc2 cells exhibited a distinct metabolic profile characterized by increased mitochondrial respiration, glycolytic activity, and elevated expression of GLUT1 and CD36. Type 2 cytokine production (IL-4, IL-5, IL-13) was enhanced by alarmins and significantly reduced following inhibition of glycolysis, fatty acid metabolism, or PPARγ activity. RNA sequencing identified high MAOA expression in Tc2 cells, and pharmacological inhibition of MAOA selectively reduced type 2 cytokine production without affecting IFN-γ. In the BAMSE cohort, dispensing of prescribed anti-depressive drugs was associated with reduced IgE sensitization. Consistent with these findings, individuals prescribed SSRIs exhibited reduced IL-5+ and IL-13+ expressing Tc2 cells and increased IFN-γ-producing Tc2 cells following ex vivo stimulation. Tc2 cells rely on coordinated lipid metabolism and serotonin catabolism to sustain type 2 cytokine production. Serotonin-modifying therapies were associated with reduced allergic sensitization and altered Tc2 function in humans, consistent with a link between serotonin signaling and type 2 immunity.

ID: 42393712
Title: The mitochondrial protease, LonP1, is a potential cardioprotective target for attenuating doxorubicin-induced cardiomyocyte death.
Abstract: Doxorubicin (DOX), a first-line chemotherapeutic agent, has been linked to severe off-target cardiotoxicity in the clinic. Previous works suggest that mitochondria are key mediators of this cardiotoxicity. Leakage of mitochondrial contents after DOX treatment, including mitochondrial DNA (mtDNA), is thought to activate apoptotic and inflammatory signaling pathways implicated in cardiomyocyte cell death. Whether the master mitochondrial protease, LonP1, can dampen these pathways and improve cardiomyocyte viability following DOX treatment remains unknown. Human cardiac cells (AC-16) and primary (1°) human cardiomyocytes were subjected to DOX treatment, followed by bulk RNA-Seq, RT-qPCR, qPCR, and immunoblotting to assess apoptotic signaling, inflammatory signaling, mtDNA release, and LonP1 expression, respectively. Lentivirus transduction of AC-16 cells was used to generate both knockdown (KD) and overexpression (OE) LonP1 cell lines to determine the effects of altered LonP1 levels on DOX-induced apoptosis and mtDNA release. Further, levels of mitochondrial DNA (mtDNA) were measured using qPCR from serum samples obtained from patients undergoing DOX treatment to assess the clinical relevance of released mtDNA as a potential biomarker for the development of DOX cardiotoxicity. DOX treatment of AC-16 cells, as well as 1° human cardiomyocytes, upregulated both apoptotic and inflammatory signaling in both cell models. Increased LonP1 levels were also observed under DOX treatment in AC-16 cells and 1° human cardiomyocytes. Likewise, DOX increased mtDNA release from both cell lines, both prior to, and as a sequel to cell death. Decreasing LonP1 levels exacerbated DOX-mediated apoptotic signaling and mtDNA release, whereas overexpression of LonP1 attenuated these effects. Furthermore, DOX treatment in cancer patients increases plasma mtDNA levels. These findings suggest LonP1 plays a protective role in the heart following DOX treatment, supporting LonP1 as a potential novel therapeutic target for prevention of DOX cardiotoxicity. Patterns of mtDNA release within patients undergoing DOX treatment also highlight the potential of mtDNA as a potential biomarker and target for prevention of DOX cardiotoxicity, justifying the need for more extensive, prospectively monitored cohort studies to expand upon these findings and statistically model mtDNA release patterns.

ID: 42397368
Title: [First experience of using tezepelumab for the treatment of chronic rhinosinusitis with nasal polyps in the Moscow region].
Abstract: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammatory disease of the nasal mucosa and paranasal sinuses associated with severe nasal congestion, olfactory impairment, decreased quality of life, the need for repeated surgical interventions, and the use of systemic glucocorticosteroids. Real-world data on the use of tezepelumab in patients with severe relapsing CRSwNP remain limited. To describe the initial experience of tezepelumab application in real-world setting in patients with recurrent rhinosinusitis with nasal polyps and to evaluate early improvement of symptoms, quality of life, and tolerability of therapy based on available clinical data. We describe clinical observations of 8 patients with recurrent CRSwNP who received tezepelumab 210 mg subcutaneously every 4 weeks for 2 months. Patients were treated in a multidisciplinary day hospital. The total severity of symptoms was assessed using the visual analogue scale (VAS), quality of life - using the SNOT-22 questionnaire, the initial endoscopic picture - using the Lund-Kennedy score. In addition, peripheral blood eosinophils, treatment history, comorbidity and tolerability of therapy were evaluated. The primary assessment was performed at the baseline visit and approximately 2 months after the start of treatment. The analysis was descriptive. The series included 8 patients, 6 of whom were women; the mean age was 54.2±9.0 years. All patients had recurrent CRSwNP and a history of surgical interventions. Bronchial asthma was described in 5 of 8 patients, and intolerance to nonsteroidal anti-inflammatory drugs or Samster's triad - in 4 of 8. Initially, the average score for VAS was 30.2±1.7, for SNOT-22 - 63.8±3.9. After 2 months, the mean VAS score decreased to 11.0±1.2, the average absolute change amounted to 19.2±1.5 points. The mean SNOT-22 score decreased to 30.1±5.8, with an average absolute change of -33.6±5.9 points. Improvement in VAS and SNOT-22 scores was observed in all 8 patients. The course of treatment was continued for all patients due to clinical improvement. In this small case series, tezepelumab was associated with an early reduction in symptom burden and improved quality of life in patients with severe recurrent rhinosinusitis with nasal polyps. The obtained observation results are preliminary. Confirmation in larger, systematically assembled cohorts with longer follow-up and standardized assessment of endoscopic, radiographic symptoms and safety indicators is needed. Хронический риносинусит с назальными полипами (ПРС) представляет собой хроническое воспалительное заболевание слизистой оболочки носа и околоносовых пазух, ассоциированное с выраженной заложенностью носа, нарушением обоняния, снижением качества жизни, необходимостью повторных хирургических вмешательств и применением системных глюкокортикостероидов. Данные реальной клинической практики о применении тезепелумаба у пациентов с тяжелым рецидивирующим ПРС остаются ограниченными. Описать первый опыт применения тезепелумаба в реальной клинической практике у пациентов с рецидивирующим риносинуситом с назальными полипами, оценить раннюю динамику симптомов, качества жизни и переносимость терапии на основании доступных клинических данных. Приведено описание клинических наблюдений 8 пациентов с рецидивирующим ПРС, получавших тезепелумаб 210 мг подкожно каждые 4 нед в течение 2 мес. Пациенты проходили лечение в условиях многопрофильного дневного стационара. Оценивали суммарную выраженность симптомов по визуальной аналоговой шкале (ВАШ), качество жизни по опроснику SNOT-22, исходную эндоскопическую картину по шкале Лунда–Кеннеди, эозинофилы периферической крови, анамнез лечения, коморбидность и переносимость терапии. Основную оценку проводили во время исходного визита и приблизительно через 2 мес после начала лечения. Анализ был описательным. В серию вошло 8 пациентов, из них 6 женщин; средний возраст составил 54,2±9,0 года. У всех пациентов выявлено рецидивирующее течение ПРС и отмечены хирургические вмешательства в анамнезе. Бронхиальная астма описана у 5 из 8 пациентов, непереносимость нестероидных противовоспалительных препаратов или аспириновая триада — у 4 из 8. Исходно средняя сумма баллов по ВАШ составляла 30,2±1,7, по SNOT-22 — 63,8±3,9. Через 2 мес средняя сумма баллов по ВАШ снизилась до 11,0±1,2, среднее абсолютное изменение составило –19,2±1,5 балла. Средняя оценка по SNOT-22 снизилась до 30,1±5,8, среднее абсолютное изменение составило –33,6±5,9 балла. Улучшение оценок по ВАШ и SNOT-22 наблюдалось у всех 8 пациентов. Курс лечения продолжен всем пациентам в связи с положительной клинической динамикой. В данной небольшой серии случаев применение тезепелумаба ассоциировано с ранним уменьшением симптоматической нагрузки и улучшением качества жизни у пациентов с тяжелым рецидивирующим риносинуситом с назальными полипами. Полученные результаты наблюдения являются предварительными. Необходимо подтверждение в более крупных систематически собранных когортах с более длительным наблюдением и стандартизированной оценкой эндоскопических, рентгенологических симптомов и показателей безопасности.

ID: 42413666
Title: Inhibiting VDAC1 oligomerization attenuated cerebral ischemia-reperfusion injury by promoting mitophagy via reduced LONP1 interaction.
Abstract: Increasing evidence highlights the protective role of mitophagy in eliminating damaged mitochondria during ischemic stroke. As a mitochondrial gatekeeper, voltage-dependent anion channel 1 (VDAC1) mediates the elimination of damaged mitochondria through mitophagy. However, whether VDAC1 contributes to cerebral ischemia-reperfusion (I/R) injury and the underlying mechanisms remain unexplored. In this study, we demonstrated that inhibiting VDAC1 oligomerization reduced infarct volume and improved neurological function following cerebral I/R. We further confirmed that inhibiting VDAC1 oligomerization promoted mitophagy, thereby exerting neuroprotective effects. Additionally, VDAC1 knockdown restored mitochondrial membrane potential and decreased mitochondrial reactive oxygen species generation, thereby alleviating mitochondria damage in neurons subjected to oxygen-glucose deprivation /reoxygenation (OGD/R). Mechanistically, we identified the interaction between VDAC1 oligomers and Lon protease 1 (LONP1) as a critical regulator of mitophagy during cerebral I/R injury. Taken together, our findings provide novel insights into the regulation of mitophagy in cerebral I/R injury and suggest that VDAC1 represents a promising therapeutic target for ischemic stroke.

ID: 42416079
Title: The role of mitochondrial proteases in inflammation and immunity.
Abstract: The global rise in chronic inflammatory and autoimmune disorders has intensified research to understand cellular stress response pathways that drive immune dysregulation. Mitochondria have emerged not only as central hubs of cellular metabolism but also as active modulators of immunity and inflammation. Mitochondrial proteases are essential regulators of mitochondrial protein quality control, dynamics, and stress responses. By selectively degrading misfolded or damaged proteins, they maintain mitochondrial function and bioenergetic capacity. Beyond housekeeping roles, mitochondrial proteases also influence immune signaling by modulating mitochondrial stress pathways, reactive oxygen species production, and the release of mitochondrial-derived danger signals. Dysregulation of these proteases has been linked to chronic inflammation and contributes to the pathogenesis of inflammatory diseases. This review summarizes current knowledge on the role of mitochondrial proteases CLPXP, LONP1, i-AAA, m-AAA, as well as processing peptidase OMA1, in immune cells and inflammatory pathologies. We explore the molecular mechanisms by which these mitochondrial proteases regulate immune signaling, integrating the results from immune cells as well as other non-immune cell types, including those involved in cancer, neurodegeneration, renal injury, and other inflammatory pathologies. We explore mitochondrial proteases function as context-dependent regulators of immunometabolic signaling, with effects shaped by cell type, metabolic state, and stress conditions. Finally, we discuss emerging small molecules and drugs targeting mitochondrial proteases to highlight their potential therapeutic role in modulating inflammation. By situating mitochondrial proteases at the crossroads of immunometabolism and therapeutic intervention, this review underscores their untapped potential in the development of innovative anti-inflammatory strategies.

ID: 42421742
Title: Mitochondrial transcription factor A: linking mtDNA maintenance, mitochondrial stress responses, and inflammaging.
Abstract: Mitochondrial transcription factor A (TFAM) is a nuclear-encoded mitochondrial protein that directly binds mitochondrial DNA (mtDNA) and contributes to mitochondrial genome maintenance. Beyond its established roles in mitochondrial transcription, mtDNA packaging, nucleoid organization, replication support, and copy number control, TFAM is increasingly recognized as a potential regulator of aging-related mitochondrial stress responses. Because mtDNA instability, respiratory dysfunction, reactive oxygen species imbalance, impaired autophagy, cellular senescence, and chronic inflammation are closely interconnected during aging, TFAM may occupy a proximal position linking mitochondrial genome homeostasis to broader aging biology. However, TFAM should not be viewed as a uniformly protective factor. Its effects appear to depend on TFAM abundance, TFAM-to-mtDNA stoichiometry, tissue type, metabolic state, mitochondrial import, LONP1-mediated turnover, and mitochondrial quality-control capacity. TFAM deficiency may compromise mtDNA maintenance, impair oxidative phosphorylation, increase mitochondrial ROS production, and promote mtDNA-driven innate immune activation. Conversely, excessive or dysregulated TFAM accumulation may lead to mtDNA hypercompaction, reduce mtDNA accessibility, and potentially produce maladaptive effects in specific disease contexts. In this review, we discuss the structural basis of TFAM-mtDNA interaction, the role of TFAM in mtDNA transcription, copy number control, genome protection, damage handling, inflammatory signaling, cellular senescence, systemic aging, and age-related diseases. We also highlight therapeutic opportunities, limitations, and unresolved questions, emphasizing that future strategies should aim to restore TFAM homeostasis rather than simply increase TFAM expression.

ID: 42421946
Title: Innate airway immune response to fungal allergens.
Abstract: Fungi are ubiquitous in our environment, and inhaled exposure of their spores is associated with the development of upper and lower respiratory airway diseases including asthma and chronic rhinosinusitis (CRS). CRS and asthma associated with fungal sensitization also tend to be more severe compared with other endotypes. Alternaria and Aspergillus species have specifically been recognized as the primary fungal allergens that stimulate a robust innate immune response, potentially leading to allergic sensitization and type 2 inflammation. Other fungi, such as Cladosporium, Penicillium, and Candida, are also associated with airway inflammatory disease. Fungal proteases disrupt airway mucosal barriers and activate protease-activated receptors (PARs), leading to a release of alarmin cytokines, including IL-25, IL-33, and thymic stromal lymphopoietin (TSLP), that drive innate type 2 inflammatory responses. Recent studies have also shown that protease allergens can cleave the protease-sensing domain of IL-33, generating a more active form. Alarmins activate innate immune cells including group 2 innate lymphoid cells (ILC2s), dendritic cells, mast cells, and eosinophils which contribute to epithelial mucus production, airway hyperresponsiveness, and tissue remodeling. This review aims to detail mechanisms of fungal allergen-induced airway inflammation and identify gaps in understanding and therapeutic opportunities.

ID: 42438767
Title: Evidence Update for Tezepelumab to Treat Severe Uncontrolled Asthma, Corticosteroid-dependent Asthma, Chronic Rhinosinusitis With Nasal Polyposis, and Chronic Obstructive Pulmonary Disease. 2nd Barcelona Respiratory Network report.
Abstract: Tezepelumab is a human monoclonal antibody directed against thymic stromal lymphopoietin that inhibits initiation of the type 2 inflammatory cascade. Several pivotal studies demonstrating tezepelumab effectiveness and leading to regulatory and marketing authorization have since been complemented by further evidence, most notably from the following studies: (a) for severe uncontrolled asthma, the PASSAGE phase 4 clinical trial, conducted in a routine clinical practice setting, found that tezepelumab significantly reduced exacerbations, including in underrepresented populations (African-Americans, adolescents, smokers, individuals with chronic obstructive pulmonary disease), and improved lung function, disease control, and quality of life. (b) For corticosteroid-dependent asthma, the WAYFINDER phase 3b clinical trial reported tezepelumab's effectiveness in reducing both dependency and the number of exacerbations as well as clinical remission in around a quarter of patients. (c) For chronic rhinosinusitis with nasal polyps, the WAYPOINT phase 3 clinical trial found that tezepelumab, after therapeutic optimization, decreased nasal polyp size and nasal congestion, improved clinical impact and sense of smell, and reduced the need for surgery. (d) For moderate-to-very severe chronic obstructive pulmonary disease, the COURSE phase 2a clinical trial reported a non-significant reduction in exacerbations, but also that reductions were greater for the type 2 phenotype (eosinophils ≥150 cells/μL). In conclusion, up-to-date evidence confirms tezepelumab safety and efficacy in treating severe uncontrolled asthma in routine clinical practice and in managing corticosteroid-dependent asthma and chronic rhinosinusitis with nasal polyps. Tezepelumab es un anticuerpo monoclonal humano dirigido frente a la linfopoyetina del estroma tímico, inhibiendo el inicio de la cascada inflamatoria tipo 2. Tras la publicación de los estudios pivotales que demostraron su eficacia y la posterior aprobación por las agencias reguladoras y su comercialización, diversos estudios han complementado la información disponible. Entre éstos destaca: a) en asma grave no controlada, el estudio PASSAGE de fase 4 (práctica clínica habitual) confirmó la reducción significativa de las exacerbaciones, incluso en poblaciones habitualmente infrarrepresentadas en los ensayos (afroamericanos, adolescentes, fumadores, EPOC), además de mejorar la función pulmonar, el control y la calidad de vida; b) en asma dependiente de la cortisona, el estudio WAYFINDER demostró la eficacia de tezepelumab en la reducción de cortisona y del número de exacerbaciones, además de conseguir que hasta un 23,4% alcanzase la remisión clínica; c) en rinosinusitis crónica con poliposis nasal, el ensayo clínico de fase 3 WAYPOINT, demostró que el tratamiento con tezepelumab disminuyó el tamaño de los pólipos nasales y la congestión nasal, además de mejorar el impacto clínico, el olfato y la necesidad de polipectomía; y d) en pacientes con la enfermedad pulmonar obstructiva crónica de moderada a muy grave, el ensayo clínico COURSE constató una reducción no significativa de las exacerbaciones, que resultó mayor en el subgrupo de pacientes con fenotipo T2 (eosinófilos ≥150 células/μL). En conclusión, la nueva evidencia disponible de tezepelumab constata su eficacia y seguridad en asma grave en situación de práctica clínica habitual, en el asma dependiente de cortisona y en la rinosinusitis crónica con poliposis nasal.

ID: 42450179
Title: Contribution of Interleukin-22 Binding Protein to the Development of Allergen-Induced Airway Hyperresponsiveness.
Abstract: Interleukin-22 binding protein (IL-22BP) is a soluble decoy receptor that competitively inhibits IL-22 by preventing its interaction with the IL-22 receptor. Although the IL-22 receptor is primarily expressed on non-hematopoietic cells, such as airway epithelial cells, the role of IL-22BP in the pathogenesis of asthma remains uncertain. We observed that IL-22BP was upregulated in the airways of wild-type (WT) mice intranasally sensitized and challenged with house dust mite (HDM) extract. To directly elucidate the function of IL-22BP in allergic airway responses, IL-22BP-deficient (IL-22BP-/-) and WT mice were sensitized and challenged with HDM, and airway responses were systematically assessed. IL-22BP-/- mice exhibited significantly lower airway hyperresponsiveness (AHR) compared to WT mice following sensitization and challenge with HDM. In contrast, eosinophil counts in bronchoalveolar lavage (BAL) fluid did not differ significantly between the two groups. Similarly, levels of interleukin (IL)-4, IL-5, IL-6, IL-13, IL-17A, and keratinocyte chemoattractant (KC) in BAL fluid were comparable between WT and IL-22BP-/- mice. Notably, IL-22 levels in lung homogenates were significantly higher in IL-22BP-/- mice than in WT mice after sensitization and challenge with HDM. These findings suggest that inhibition of IL-22BP attenuates the development of allergen-induced AHR, an effect likely mediated through enhanced IL-22 activity rather than alterations in airway inflammation or type 2 cytokine production.