Inflammation Research[JOURNAL]
Sun
200 papers
Pro-resolving Annexin A1-derived peptide Ac2-26 reduces nociception and mitigates joint damage in experimental osteoarthritis.
Bosi PL, Braga AD, Queiroz-Junior CM … +6 more , de Mattos GC, de Oliveira VLS, Galvão I, Kakehasi AM, Teixeira MM, Amaral FA
Inflamm Res · 2026 Mar · PMID 41865182 · Full text
OBJECTIVES: We investigated whether treatment with Annexin A1 (AnxA1) ameliorated joint nociception and tissue damage in an experimental osteoarthritis (OA) model. DESIGN: OA was induced by injection of collagenase into...
OBJECTIVES: We investigated whether treatment with Annexin A1 (AnxA1) ameliorated joint nociception and tissue damage in an experimental osteoarthritis (OA) model. DESIGN: OA was induced by injection of collagenase into the tibiofemoral joint of wild-type (WT) and AnxA1-deficient male Balb/c mice. The control group received saline. Groups of WT mice were treated weekly with Ac2-26, an active peptide corresponding to the N-terminal region of AnxA1, in the affected joint. Mechanical nociception was analyzed weekly, and samples were collected 6 weeks after OA induction to analyze histopathology and markers of joint damage by qPCR and flow cytometry. RESULTS: The expression of Anxa1 is upregulated in the joints at the 1st and 3rd week and returned to the basal level at the 6th week after OA induction. AnxA1-deficient mice had persistent nociception and increased joint inflammation when compared to WT mice, although both groups had comparable cartilage damage. In WT mice, the treatment with Ac2-26 decreased joint nociception, tissue damage, and the expression of metalloproteinase-3 in the joint tissue. The collagenase injection increased the number of FAPCD90 fibroblast-like and CX3CR1macrophage-like synoviocytes expressing RANKL when compared to saline-injected mice. Treatment with Ac2-26 normalized the latter parameters. CONCLUSIONS: AnxA1 and Ac2-26 are promising molecules that regulate key processes in OA, effectively mitigating tissue damage and dysfunction in a model of OA in mice.
Single-cell dissection of pleural and systemic immunity uncovers pathogen-specific immune reprogramming in tuberculosis versus lung adenocarcinoma.
Yu S, Liang Y, Chen J … +6 more , Zhang B, Zhang C, Zhao Y, Yan R, Nie Y, Mao X
Inflamm Res · 2026 Mar · PMID 41865158 · Publisher ↗
To dissect how malignant versus infectious pleural disease reshapes local and systemic immunity, we compared lung adenocarcinoma with tuberculosis using matched pleural effusions and peripheral blood from patients and he...
To dissect how malignant versus infectious pleural disease reshapes local and systemic immunity, we compared lung adenocarcinoma with tuberculosis using matched pleural effusions and peripheral blood from patients and healthy controls using single cell transcriptome analysis and TCR clonotype tracking. Th1/17 polarized pro-inflammation dominating TB effusions, while their precursors, the recently activated CD4 T cells, adopt an antitumor trajectory in LUAD, but their recruitment and clonal expansion were effectively suppressed. In both diseases, CD8⁺ T cells diverged into GZMH⁺ and GZMK⁺ subsets. The former served as the antitumor killer cells but suppressed by multiple anti-inflammatory signals especially from the extracellular matrix in LUAD. The later could serve as stem-like precursors. MAITs and class-switched B cells both exhibited higher levels of activation and expanded in TB. Myeloid cells were mostly recovered from peripheral bloods and showed heightened activation in TB, upregulating TNFRSF14, TNFRSF13B, and pro-inflammatory cytokines (CXCL2, CXCL3, IL1), while LUAD featured immunosuppressive signals including MDK-NCL, FN1-CD44, and THBS1-CD47. Cell-cell communication highlighted LUAD-enriched outgoing interaction strengths by myeloid cells including monocytes and DCs, through IL16 and VISFATIN signaling, which strongly corelated with survivals. In conclusion, both pleural effusions and peripheral blood from TB and LUAD exhibit significant distinct immune landscapes. These results delineate disease-specific molecular mechanisms underlying immune regulation in pleural malignancies and infections.
Regulation of calcium homeostasis by S100A12 drives NETosis in chronic kidney disease.
Zhu H, Chang X, Du Y … +4 more , Zhao X, Juan C, Mao Y, Zhou E
Inflamm Res · 2026 Mar · PMID 41862672 · Publisher ↗
Chronic kidney disease (CKD) is characterized by persistent renal injury and inflammation. Although S100A12 is associated with inflammatory states, its specific role in regulating neutrophil extracellular trap (NET) form...
Chronic kidney disease (CKD) is characterized by persistent renal injury and inflammation. Although S100A12 is associated with inflammatory states, its specific role in regulating neutrophil extracellular trap (NET) formation (NETosis) and contributing to renal pathology in CKD remains poorly understood. This study aimed to identify key diagnostic biomarkers and elucidate the mechanism by which S100A12 mediates NETosis in CKD. METHODS: Integrated bioinformatic analysis was performed on combined datasets (GSE37171, GSE66494, and GSE15072). Differentially expressed genes (DEGs) were screened using WGCNA and three machine learning algorithms (LASSO, SVM-RFE, and Random Forest) to identify hub genes. Immune infiltration was analyzed to assess immune cell proportions. Clinical validation was conducted using peripheral blood samples from 43 CKD patients and 17 healthy controls collected between July 2024 and January 2025. Furthermore, in vitro experiments using dHL-60 cells investigated the impact of S100A12 on NET formation and calcium signaling. RESULTS: We identified 622 DEGs significantly expressed in CKD and enriched in inflammatory regulation. Five hub genes (MMP11, CASR, GATA1, MMP7, and S100A12) were identified, yielding a diagnostic model with high accuracy (AUC = 0.940). Immune infiltration analysis revealed that S100A12 expression was positively correlated with neutrophil infiltration. Experimental validation confirmed significantly elevated levels of S100A12 and NETosis markers (PADI4, MPO, dsDNA, and MPO-DNA complexes) in CKD patients compared to controls. Studies in dHL-60 cells demonstrated that S100A12 overexpression promotes NETosis via calcium overload, a process effectively inhibited by the calcium channel blocker verapamil. CONCLUSIONS: Integrated bioinformatic and experimental analyses identify S100A12 as a robust diagnostic biomarker and a key mediator of NETosis in CKD. Targeting the S100A12-mediated calcium signaling pathway offers a promising future direction for mitigating renal inflammation and injury..
Balancing inflammation and regeneration: immune cell dynamics in nerve repair: a comprehensive review.
Anjum A, Lokanathan Y
Inflamm Res · 2026 Mar · PMID 41862620 · Full text
BACKGROUND: Nerve injuries initiate a complex immune response that is crucial for triggering repairprocesses but can also exacerbate tissue damage if dysregulated. A tightly regulated balancebetween pro-inflammatory and...
BACKGROUND: Nerve injuries initiate a complex immune response that is crucial for triggering repairprocesses but can also exacerbate tissue damage if dysregulated. A tightly regulated balancebetween pro-inflammatory and anti-inflammatory signals is essential for optimal nerveregeneration, as excessive or prolonged inflammation can impede repair, while insufficientimmune activation may delay debris clearance and regeneration. PURPOSE: This review aims to examine the roles of key immune cells, including macrophages,neutrophils, T cells, and B cells exert diverse roles in this process, orchestrating the inflammatoryenvironment and promoting tissue remodeling. Central to their function is metabolicreprogramming, which dictates immune cell activation, phenotype, and regenerative capacity. METHOD: Relevant literature on immune responses and metabolic regulation in nerve injury wasanalyzed to explore how shifts between glycolysis, oxidative phosphorylation, and fatty acidoxidation govern the balance between inflammatory and reparative states. Macrophages displayremarkable functional plasticity, transitioning from pro-inflammatory (M1-like) to proregenerative(M2-like) phenotypes in response to metabolic and microenvironmental cues.Emerging therapeutic strategies aim to harness this immune-metabolic plasticity to improveoutcomes after nerve injury. RESULTS: Evidence suggests that metabolic reprogramming is a critical determinant of immune cellbehavior in nerve repair. Interventions such as small-molecule modulators, metabolicglycoengineering, and targeted delivery systems are being explored to fine-tune immune cellmetabolism and restore inflammatory balance. However, challenges remain in achieving cell-typespecificity, managing the intricacies of the immune milieu, and ensuring safe and effective clinicaltranslation. This review examines the cellular and metabolic mechanisms underlying immunemediatednerve repair, highlights the critical importance of inflammatory balance in determiningregenerative outcomes, and discusses promising metabolic targets and therapeutic approaches. CONCLUSION: Understanding the interplay between immune responses and cellular metabolismoffers promising opportunities to enhance nerve regeneration. Advances in immunometabolismmay facilitate the development of precision therapeutic strategies aimed at optimizinginflammatory balance and improving functional recovery following nerve injury.
Integrative transcriptomic analysis reveals alternative splicing programs in sepsis-induced myocardial injury across dual mouse models.
Zhou S, Liu D, Zong H … +6 more , Nie K, Yan S, Chen Y, Jiang J, Sun M, Peng H
Inflamm Res · 2026 Mar · PMID 41843179 · Publisher ↗
BACKGROUND: Sepsis-induced acute myocardial injury (AMI) is a major contributor to mortality in septic patients, yet its molecular underpinnings remain incompletely understood. While previous studies have largely focused...
BACKGROUND: Sepsis-induced acute myocardial injury (AMI) is a major contributor to mortality in septic patients, yet its molecular underpinnings remain incompletely understood. While previous studies have largely focused on transcriptional changes, the role of alternative splicing (AS) in septic cardiomyopathy has not been systematically explored. METHODS: We employed two widely used murine models of sepsis-cecal ligation and puncture (CLP) and lipopolysaccharide (LPS) injection-to investigate transcriptomic dysregulation in the heart. Through RNA sequencing, we analyzed both differentially expressed genes (DEGs) and differentially alternative splicing events (DAS), followed by bioinformatic enrichment analysis. Key AS events were validated via RT-PCR and qPCR. RESULTS: We identified hundreds of sepsis-induced DAS events, with skipped exon (SE) being the most prominent subtype in both CLP and LPS models. Integration of DEG and DAS datasets revealed 127 overlapping genes involved in inflammatory and stress-related pathways, including MAPK, AMPK, and JAK-STAT signaling. Splicing factors such as Cirbp, Rbm3, Cir1 were dysregulated under septic conditions. Validation experiments confirmed model-specific AS events in genes including Per1, Map3k6, and Septin4, which are implicated in circadian regulation, inflammation, and cytoskeletal remodeling, respectively. CONCLUSION: This study is the first to comprehensively map AS changes in the septic myocardium using dual models. Our integrative approach reveals that alternative splicing represents a critical and underappreciated regulatory layer in septic cardiac injury, supported by both transcript- and protein-level evidence. These findings broaden the understanding of transcriptomic complexity in sepsis and highlight new molecular targets for therapeutic intervention.
CD169 macrophages promote periodontal bone repair via pathogen clearance and IL10 secretion.
Xiong Z, Lu J, Wu X … +2 more , Yang H, Luo L
Inflamm Res · 2026 Mar · PMID 41843164 · Publisher ↗
OBJECTIVE: Periodontal bone regeneration remains a major challenge in in the treatment of periodontitis. This study we aimed to investigate whether there are CD169⁺ macrophages in periodontal tissues and the functions of...
OBJECTIVE: Periodontal bone regeneration remains a major challenge in in the treatment of periodontitis. This study we aimed to investigate whether there are CD169⁺ macrophages in periodontal tissues and the functions of these cells in the progressive and resolving phases of periodontitis. METHODS: Immunofluorescence staining was performed to localize CD169⁺ macrophages in human and murine periodontal tissues. Subsequently, CD169⁺ macrophages from mature bone marrow-derived macrophages (BMDMs) were isolated. To characterize their functional properties, we assessed the phagocytic capacity of CD169⁺ macrophages in vitro. Furthermore, CD169⁺ macrophages were co-cultured to evaluate their osteogenic-promoting effects by qPCR, alkaline phosphatase (ALP) staining, and alizarin red staining (ARS). For in vivo validation, ligature-induced periodontitis (LIP) mice were established and local bacterial inoculated to investigate phagocytic function of CD169⁺ macrophages. Anti-interferon-alpha/beta receptor (Anti-IFNAR1) was injected locally to inhibit the signaling of IFN Is. Bone repair was assessed using micro-computed tomography (micro-CT) and histological staining. RESULTS: CD169 was primarily expressed on macrophages in periodontal tissues. In vitro CD169⁺ macrophages were positively induced by IFN Is. CD169⁺ macrophages exhibited robust phagocytic activity in clearing Porphyromonas gingivalis (P. gingivalis). Moreover, CD169⁺ macrophages promoted the osteogenic differentiation of BMSCs through the secretion of interleukin 10 (IL10), as evidenced by upregulated expression of osteogenesis-related genes (including Alpl, Sp7, Ibsp and Bglap), enhanced activity of ALP, and increased formation of mineralized nodules. In vivo results further demonstrated that CD169⁺ macrophages exhibited a high phagocytic capacity against P. gingivalis compared. During the resolving phase of periodontitis, a decrease in the number of CD169⁺ macrophages resulting from Anti-IFNAR1 application not only impaired alveolar bone repair, but also reduced expression of IL10 and osteogenesis-related proteins, such as OSX(Sp7) and OCN(Bglap). CONCLUSIONS: CD169⁺ macrophages play a critical role in periodontitis by clearing of P. gingivalis during the progressive phase of periodontitis, and promoting bone repair via the secretion of IL10 during the resolving phase.
Macrophage RNA polymerase II subunit 5-mediating protein deficiency exacerbates kidney inflammation and fibrosis.
Nie J, Liu B, Xiong H … +5 more , Gao Y, Li S, Chen S, Yu W, Liang H
Inflamm Res · 2026 Mar · PMID 41843157 · Publisher ↗
BACKGROUND: Chronic kidney disease is closely associated with kidney inflammation and fibrosis. Macrophage plays a critical role in the pathogenesis of kidney inflammation and fibrosis. However, the molecular mechanisms...
BACKGROUND: Chronic kidney disease is closely associated with kidney inflammation and fibrosis. Macrophage plays a critical role in the pathogenesis of kidney inflammation and fibrosis. However, the molecular mechanisms underlying macrophage activation remain poorly elucidated. In this work, we examined the role of macrophage RNA polymerase II subunit 5 -mediating protein (RMP) in kidney inflammation and fibrosis. METHODS: The mouse model of kidney fibrosis was induced by folic acid administration or unilateral ureteral obstruction . Macrophage-specific RMP knockout mice and wild-type controls were subjected to folic acid or obstructive injury. Macrophages derived from wild-type or RMP deficiency mice were exposed to TGF-β1 stimuli. Kidney collagen deposition, extracellular matrix protein expression, macrophage to myofibroblast transition, and inflammatory cytokines were assessed using histological staining, Western blot, immunofluorescence, and RT-PCR. RESULTS: The RMP expression in macrophages was markedly elevated in the kidneys of mice following folic acid administration or unilateral ureteral obstruction. Compared with wild-type mice subjected to folic acid stress or obstruction injury, macrophage-specific RMP knockout considerably aggravated collagen deposition and extracellular matrix protein production in injured kidneys. Moreover, loss of RMP in macrophages promoted proinflammatory cytokines release in the folic acid-injured or obstructed kidneys. Furthermore, macrophage RMP deficiency contributed to macrophages to myofibroblasts transition and increased myofibroblasts accumulation in folic acid or obstructive nephropathy. In cultured macrophages, the absence of RMP upregulated the expression of α-smooth muscle actin and enhanced the transition of macrophages to myofibroblasts. CONCLUSIONS: Our study reveals RMP as an important regulator of macrophage activation and kidney fibrosis progression. Hence, RMP may represent a promising therapeutic target for chronic kidney disease.
Evaluation of ATP12A and NFKBIZ as potential markers of inflammatory status in cystic fibrosis airway epithelial cells.
Allegretta C, Guidone D, Boscia S … +12 more , Pisano L, Ricci S, Azzari C, Fevola C, De Santis M, Ciciriello F, Montemitro E, Dolce D, Cabrini G, Galietta LJV, Terlizzi V, Laselva O
Inflamm Res · 2026 Mar · PMID 41843147 · Full text
BACKGROUND: People with Cystic Fibrosis (pwCF) are prone to bacterial lung infections with P. aeruginosa, which have been linked to chronic inflammation in the lung. Although the highly effective CFTR modulator therapy (...
BACKGROUND: People with Cystic Fibrosis (pwCF) are prone to bacterial lung infections with P. aeruginosa, which have been linked to chronic inflammation in the lung. Although the highly effective CFTR modulator therapy (Elexacaftor-Tezacaftor-Ivacaftor, ETI) has dramatically improved respiratory outcomes in pwCF, airway inflammation and bacterial colonization persist in the upper and lower respiratory tracts. METHODS: We investigated the effect of ETI in both plasma and fresh primary nasal epithelial (HNE) cells obtained from pwCF pre- and post-three months of ETI treatment. Given that inflammation has been shown to upregulate NFKBIZ and the ATP12A proton pump, we measured their levels in fresh HNE cells and in cultured HNE cells exposed to clinical exoproducts (EXO) of P. aeruginosa or other inflammatory stimuli. RESULTS: ELISA analysis revealed a significant reduction of IL-6, IL-8, and IL-17C in both plasma and HNE cells after ETI treatment. NFKBIZ and ATP12A expression was increased after infection and inflammatory stimuli in CF bronchial epithelial (CFBE) and HNE cells, and this increase was reduced by Dimethyl-Fumarate, an anti-inflammatory drug. CONCLUSIONS: These preclinical studies, using patient-derived tissues, suggest that NFKBIZ and ATP12A may play a relevant role in the pathophysiology and inflammatory response of the CF airway epithelium.
Targeting CEBPA/ALOX15B attenuates postmenopausal osteoporosis by inhibiting ferroptosis through the AMPK/mTOR signaling pathway.
Wang T, Li J, Li C … +6 more , Wang Z, Zhang L, Han C, Qi G, Xu L, Zheng L
Inflamm Res · 2026 Mar · PMID 41843143 · Publisher ↗
OBJECTIVE: Postmenopausal osteoporosis (PMOP) is characterized by bone loss attributed to estrogen deficiency; however, the involvement of ferroptosis in its pathogenesis has yet to be fully elucidated. The objective of...
OBJECTIVE: Postmenopausal osteoporosis (PMOP) is characterized by bone loss attributed to estrogen deficiency; however, the involvement of ferroptosis in its pathogenesis has yet to be fully elucidated. The objective of this study was to explore the regulatory mechanism of the CEBPA/ALOX15B axis in PMOP, with a focus on modulating ferroptosis. METHODS: Four gene expression datasets (GSE56116, GSE56814, GSE56815, GSE230665) were analyzed to identify differentially expressed genes (DEGs) and ferroptosis-related genes (FRGs) in PMOP. In vitro experimental approaches, including cell viability, apoptosis, ferroptosis marker detection, and osteogenic differentiation assays, were conducted in hFOB 1.19 cells with ALOX15B/CEBPA knockdown/overexpression. The AMPK/mTOR pathway was validated using Western blot and pharmacological inhibitors. In vivo, ALOX15B knockout mice were subjected to ovariectomy (OVX) to establish a PMOP model, and bone mineral density (BMD), micro-CT, and histopathological analyses were performed. RESULTS: ALOX15B was significantly upregulated in PMOP patients, negatively correlating with estrogen levels. ALOX15B knockdown in hFOB 1.19 cells suppressed ferroptosis (reduced Fe²⁺, MDA, ROS, and PTGS2; increased GSH/GSSG and GPX4) and promoted osteoblast differentiation (elevated ALP, RUNX2, OCN). Mechanistically, CEBPA directly bound to the ALOX15B promoter to transcriptionally activate it. CEBPA/ALOX15B regulated ferroptosis and osteogenesis via the AMPK/mTOR axis. In OVX mice, ALOX15B knockout ameliorated bone loss (increased BMD, BV/TV, Tb.Th; reduced Tb.Sp) and ferroptosis (decreased iron deposition, 4-HNE; increased GPX4). CONCLUSION: The CEBPA/ALOX15B axis promotes osteoblast ferroptosis in PMOP by inhibiting the AMPK/mTOR pathway, providing a novel therapeutic target for PMOP treatment.
ML364 ameliorates NLRP3-induced inflammatory response.
Zhu M, Yu J, Wang Y … +8 more , Yin F, Wang Y, Ye R, Zhang Q, Xu C, Liang J, Peng X, Yang D
Inflamm Res · 2026 Mar · PMID 41843135 · Publisher ↗
BACKGROUND: The NLRP3 inflammasome is a critical mediator of innate immune responses and inflammatory diseases, and its activation is tightly regulated by post-translational modifications such as ubiquitination. While se...
BACKGROUND: The NLRP3 inflammasome is a critical mediator of innate immune responses and inflammatory diseases, and its activation is tightly regulated by post-translational modifications such as ubiquitination. While several E3 ligases have been shown to modulate NLRP3 activity, deubiquitinases are increasingly recognized as key regulators that control NLRP3 stability and activation. However, the identification of additional deubiquitinases and pharmacological inhibitors remains essential for a comprehensive understanding of NLRP3 inflammasome regulation. This study investigated the role of the deubiquitinase USP2 in NLRP3 inflammasome activation and evaluated the therapeutic potential of its inhibitor ML364 in inflammasome-driven inflammatory diseases. MATERIALS AND METHODS: Murine macrophage cell lines (J774A.1), HEK293 cells, and bone marrow-derived macrophages (BMDMs) were used to assess inflammasome activation through genetic knockdown, overexpression, and pharmacological inhibition of USP2. Protein interactions, ubiquitination status, ASC speck formation, caspase-1 activation, and IL-1β secretion were evaluated using immunoprecipitation, immunoblotting, microscopy, and ELISA. In vivo efficacy of the USP2 inhibitor ML364 was examined in mouse models of monosodium urate (MSU)-induced peritonitis and dextran sulfate sodium (DSS)-induced colitis by assessing inflammatory cell recruitment, cytokine production, disease activity, and histopathology. RESULTS: USP2 was required for optimal NLRP3 inflammasome activation, as its knockdown or pharmacological inhibition significantly reduced caspase-1 activation, IL-1β release, and pyroptotic responses. Mechanistically, USP2 directly interacted with the NACHT domain of NLRP3 and promoted its stability by removing ubiquitin chains, whereas a catalytically inactive USP2 mutant failed to support inflammasome activation. USP2 deficiency increased NLRP3 ubiquitination and reduced protein abundance in macrophages. Importantly, ML364 effectively suppressed NLRP3 inflammasome activation in vitro and alleviated inflammatory responses in vivo, reducing neutrophil recruitment, IL-1β production, and tissue injury in MSU-induced peritonitis and DSS-induced colitis models. CONCLUSION: USP2 acts as a critical deubiquitinase that promotes NLRP3 inflammasome activation by stabilizing NLRP3 through deubiquitination of its NACHT domain. Pharmacological inhibition of USP2 with ML364 effectively suppresses inflammasome activation and ameliorates inflammatory pathology in vivo. These findings identify USP2 as an important regulator of NLRP3 signaling and highlight ML364 as a potential therapeutic strategy for NLRP3 inflammasome-associated diseases.
Endotheliopathy within the thromboinflammatory network of sepsis-induced coagulopathy.
Iba T, Maier CL, Ferrer R … +2 more , Nagakari K, Levy JH
Inflamm Res · 2026 Mar · PMID 41843129 · Publisher ↗
BACKGROUND: Sepsis represents a life-threatening syndrome driven by dysregulated host responses in which inflammation, coagulation, and endothelial dysfunction intersect. Increasing evidence suggests that endotheliopathy...
BACKGROUND: Sepsis represents a life-threatening syndrome driven by dysregulated host responses in which inflammation, coagulation, and endothelial dysfunction intersect. Increasing evidence suggests that endotheliopathy is a dynamically interacting component linking systemic inflammation, immunothrombosis, and microvascular dysfunction. Rather than acting as a singular upstream trigger, endothelial dysfunction evolves in parallel with platelet, neutrophil, and monocyte activation, forming a self-amplifying thromboinflammatory network that drives organ failure. MAIN TEXT: The vascular endothelium maintains hemostatic balance through anticoagulant pathways mediated by thrombomodulin, endothelial protein C receptor (EPCR), and antithrombin, supported by a protective glycocalyx layer. During sepsis, pathogen- and damage-associated molecular patterns (PAMPs and DAMPs) trigger the degradation of the glycocalyx, deactivation of the vascular stabilizing regulator Tie2, and shedding of thrombomodulin and EPCR, ultimately leading to capillary leakage and a procoagulant endothelial phenotype. Concurrently, excessive immunothrombosis, characterized by tissue factor expression, platelet activation, and neutrophil extracellular trap (NET) formation, amplifies endothelial injury and impairs microcirculation. Sepsis occurs across a spectrum of clinical states, with sepsis-induced coagulopathy (SIC) representing an early, potentially reversible stage marked by thrombin generation and suppressed fibrinolysis, whereas progression to overt disseminated intravascular coagulation (DIC) entails consumptive coagulopathy and organ failure. Biomarker-based phenotyping using syndecan-1, soluble thrombomodulin, angiopoietin-2, and NET-related markers enables mechanistic stratification and therapeutic targeting. CONCLUSIONS: Recognition of endotheliopathy as an interacting component of SIC provides a unifying framework for understanding disease progression and identifying temporally appropriate therapeutic targets. Emerging endothelial-directed therapies, including heparanase inhibitors, Tie2 agonists, antithrombin and thrombomodulin supplementation, and NET-targeted interventions, represent a paradigm shift toward precision medicine in managing sepsis. Integrating endothelial biomarkers and immunothrombotic phenotyping into adaptive trial designs will be critical to advancing approaches for personalized vascular and immune modulation. Recognition of endotheliopathy as the central driver of sepsis-induced coagulopathy provides a unifying framework for understanding the mechanisms involved and driving therapeutic innovation.
A novel small molecule KMU-11361 attenuates rheumatoid arthritis by mechanistic inhibition of the TAK1-NF-κB-NLRP3 axis.
Baek HS, Yoon D, Hong VS … +12 more , Lee SJ, Lee SI, Lee JY, Lee HW, Jeong S, Jung H, Kang H, Kim SH, Son CN, Lee H, Lee J, Kim S
Inflamm Res · 2026 Mar · PMID 41843120 · Publisher ↗
BACKGROUND: Rheumatoid arthritis (RA) is characterized by chronic inflammation and joint destructioncaused by dysregulated immune signaling. Despite the development of various protein kinaseinhibitors to treat inflammato...
BACKGROUND: Rheumatoid arthritis (RA) is characterized by chronic inflammation and joint destructioncaused by dysregulated immune signaling. Despite the development of various protein kinaseinhibitors to treat inflammatory diseases such as RA, the results achieved are still notsatisfactory. PURPOSE: This study aimed to investigate the therapeutic potential and biological mechanisms of KMU-11361, an innovative multi-protein kinase inhibitor which modulates the inflammatorypathways involved in the pathophysiology of RA, using both in vitro and in vivo models ofarthritis. METHODS: We investigated the effects of KMU-11361 on lipopolysaccharide (LPS)-inducedinflammation, receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation,and osteoblast differentiation, using various assays in human rheumatoid arthritis (RA)-fibroblast-like synoviocytes (RA-FLS), THP-1 cells, RAW264.7 cells, T cells, and MC-3T3-E1 cells. Furthermore, we evaluated the toxicity and efficacy of KMU-11361 in a zebrafishmodel and a K/BxN serum transfer-induced arthritis mouse model. In addition, we performedkinase profiling and conducted molecular docking simulations to examine whether KMU-11361 interacts with MAPK1 and TAK1 involved in TLR4 signaling. RESULTS: Kinase profiling and molecular docking analyses revealed that KMU-11361 interacts with MAPK1 and TAK1, key regulators of TLR4 signaling. KMU-11361 markedly suppressedTLR4-mediated inflammatory signaling by reducing LPS-induced pro-inflammatory cytokineproduction, phosphorylation of TAK1 and MAPKs, NF-κB activation, and NLRP3 expressionin RA-FLS and THP-1 cells. Additionally, KMU-11361 inhibited RANKL-inducedosteoclastogenesis in RAW264.7 cells and attenuated T-cell activation-associated signalingpathways. Notably, KMU-11361 promoted osteoblastic differentiation in MC3T3-E1 cells. Inthe K/BxN serum transfer-induced arthritis mouse model, KMU-11361 significantly reducedankle swelling and IL-6 levels. CONCLUSION: KMU-11361 exhibits potent anti-inflammatory and bone-protective properties by targeting keykinases involved in TLR4-mediated signaling and osteoclast differentiation. These findingsprovide mechanistic insight into its biological activity and highlight its therapeutic potential inboth in vitro and in vivo models of arthritis.
Biomarkers of endothelial glycocalyx dysfunction in pregnancy: a systematic review of clinical relevance and detection techniques.
Fogacci F, Yahya D, Roeters Van Lennep J … +6 more , Öörni K, Di Micoli V, De Seta F, Scollo C, Borghi C, Cicero AFG
Inflamm Res · 2026 Mar · PMID 41843118 · Full text
OBJECTIVE AND DESIGN: The endothelial glycocalyx (EG) is a key regulator of vascular homeostasis, acting as a dynamic barrier between the bloodstream and the endothelium. In pregnancy, structural and functional alteratio...
OBJECTIVE AND DESIGN: The endothelial glycocalyx (EG) is a key regulator of vascular homeostasis, acting as a dynamic barrier between the bloodstream and the endothelium. In pregnancy, structural and functional alterations of the EG have been increasingly implicated in the pathogenesis of endothelial dysfunction, particularly in preeclampsia and other vascular complications. This systematic review critically examines current evidence on circulating biomarkers of EG degradation and their clinical relevance in hypertensive and metabolic disorders of pregnancy. METHODS: We explore the mechanistic role of the glycocalyx in maintaining vascular integrity, evaluate state-of-the-art detection methods-including sidestream dark field (SDF) imaging and biochemical assays-and summarize data on key circulating components such as syndecan-1, hyaluronic acid, heparan sulfate, and adhesion molecules. RESULTS: Particular attention is given to distinguishing early- from late-onset preeclampsia and to other high-risk obstetric conditions, including gestational diabetes, fetal growth restriction, and infection-related complications. Despite heterogeneity across studies, most findings support a consistent association between EG disruption and adverse maternal-fetal outcomes. CONCLUSIONS: This review highlights the potential of glycocalyx-derived biomarkers and imaging tools as non-invasive indicators of microvascular injury. Their integration into existing surveillance models could enhance early risk stratification and open new avenues for targeted clinical interventions in cardio-obstetric care.
The characterization of RUNX1-mediated macrophage polarization requires a multidimensional perspective beyond the M1/M2 binary.
Chen L, Hong C, Xie Y
Inflamm Res · 2026 Mar · PMID 41843115 · Publisher ↗
We comment on the recent study by He et al. reporting that RUNX1 promotes non-small cell lung cancer (NSCLC) progression by driving a pro-tumoral macrophage program via the ACP5/β-catenin/SMAD3 axis, interpreted as "M2"...
We comment on the recent study by He et al. reporting that RUNX1 promotes non-small cell lung cancer (NSCLC) progression by driving a pro-tumoral macrophage program via the ACP5/β-catenin/SMAD3 axis, interpreted as "M2" polarization. While the M1/M2 framework (e.g., CD86 vs. CD206/Arg1) remains widely used, accumulating single-cell and spatial profiling data indicate that tumor-associated macrophages (TAMs) in vivo occupy a multidimensional continuum and may co-express canonical inflammatory and anti-inflammatory markers, challenging binary labeling. We propose that RUNX1 may induce a more specific TAM transcriptional program than a generic "M2" state and encourage future studies to apply high-resolution subtype annotations (e.g., SPP1 or C1QC TAM signatures) to define RUNX1-associated macrophage states more precisely. In addition, validating the RUNX1 axis in immunocompetent models (beyond NOD/SCID settings) and identifying tumor-derived upstream inducers (e.g., cytokines or exosomal cargos) would strengthen mechanistic completeness and translational relevance.
Retraction Note: Tetraspanin 1 inhibits TNFα-induced apoptosis via NF-κB signaling pathway in alveolar epithelial cells.
Yang L, Wang Y, Pan Z … +6 more , Gao S, Zou B, Lin Z, Feng D, HuangFu C, Liu G
Inflamm Res · 2026 Mar · PMID 41843076 · Publisher ↗
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The crosstalk between iron metabolism and immune tolerance in autoimmunity.
Tavassoli Razavi F, Yazdanpanah E, Shadab A … +2 more , Emami A, Haghmorad D
Inflamm Res · 2026 Mar · PMID 41843072 · Publisher ↗
BACKGROUND: Iron metabolism has emerged as a critical regulator of immune homeostasis, influencing both innate and adaptive immune responses. Dysregulation of iron balance is increasingly recognized as a key driver of au...
BACKGROUND: Iron metabolism has emerged as a critical regulator of immune homeostasis, influencing both innate and adaptive immune responses. Dysregulation of iron balance is increasingly recognized as a key driver of autoimmunity, contributing to oxidative stress, ferroptosis, immune cell dysfunction, and the breakdown of immune tolerance. FINDINGS: This review explores the complex interplay between iron metabolism and autoimmune diseases, including multiple sclerosis (MS), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). We highlight how iron overload and deficiency impact immune cell differentiation, macrophage polarization, Treg/Th17 balance, and B cell activation, thereby promoting chronic inflammation and tissue damage. Moreover, we discuss disease-specific mechanisms such as iron accumulation in the CNS in MS, synovial iron overload in RA, and hepcidin-driven anemia and ferroptosis in SLE. CONCLUSIONS: Emerging therapeutic approaches, including iron chelation, hepcidin modulation, ferroptosis inhibition, and microbiome-targeted interventions, are examined as potential strategies to restore immune tolerance and mitigate autoimmune pathology. Finally, we emphasize the need for precise iron-targeted therapies, integration with immunomodulatory treatments, and the development of reliable iron-related biomarkers to optimize clinical management of autoimmunity.
Inflammatory bowel disease and extracellular matrix: when victim becomes double agent.
Sferra R, Vetuschi A, Latella G … +2 more , Cappariello A, Pompili S
Inflamm Res · 2026 Mar · PMID 41843067 · Full text
BACKGROUND: The extracellular matrix (ECM) represents an intricate network of proteins present in all organs, with specific physical and biochemical functions. ECM is composed of two distinct but connected entities: the...
BACKGROUND: The extracellular matrix (ECM) represents an intricate network of proteins present in all organs, with specific physical and biochemical functions. ECM is composed of two distinct but connected entities: the basement membrane, located beneath the epithelium, and the interstitial matrix, present in the mucosa and submucosa. Physiologically, ECM modulates several functions, including epithelium turnover, intercellular communications, cell adhesion, differentiation, proliferation, apoptosis, and tissue remodeling. FINDINGS: After an injury, the epithelial barrier fails, affecting the ECM structure and functions. The normal gut structure and functions depend on ECM, which is regulated by ECM-producing cells/ECM-degrading enzymes. Intestinal injury can lead to epithelial barrier disruption and then to acute mucosal inflammation that can heal or become chronic. The ECM is directly involved in mucosal healing, while the key mechanisms leading to the chronicity of intestinal inflammation are unknown. Inflammatory cells release countless cytokines, chemokines, and growth factors, which, by interacting with specific components of the ECM, induce an overactivation of the immune system. In this context, ECM represents an important player in inflammatory diseases, including the inflammatory bowel diseases (IBD) and related complications such as intestinal fibrosis. In the last years, progressive advancements in the knowledge of IBD pathogenesis have provided crucial information for the discovery of new treatments. Nevertheless, few studies investigate the ECM's multiple roles in the sustenance and the exacerbation of the immune reaction. CONCLUSION: This review aims to emphasize the dynamic aspects of the ECM, giving an overview of its direct involvement in intestinal inflammatory diseases and the related intestinal fibrosis.
Comprehensive immunological and molecular analysis revealed inflammation-related diagnostic signatures in chronic rhinosinusitis.
Yu C, Xu Z, Zhao X … +2 more , Gu S, Kan X
Inflamm Res · 2026 Mar · PMID 41843019 · Publisher ↗
OBJECTIVE AND DESIGN: This study aimed to identify robust diagnostic biomarkers and characterize molecular subtypes of chronic rhinosinusitis (CRS) by integrating multi-omics data with machine learning, utilizing a case–...
OBJECTIVE AND DESIGN: This study aimed to identify robust diagnostic biomarkers and characterize molecular subtypes of chronic rhinosinusitis (CRS) by integrating multi-omics data with machine learning, utilizing a case–control design with patient samples. MATERIAL OR SUBJECTS: The analysis incorporated gene expression data from bulk and single-cell RNA sequencing datasets; validation experiments used clinical samples from human CRS patients and control subjects. TREATMENT: Not applicable. METHODS: We analyzed differentially expressed genes and immune cell infiltration from transcriptomic data, employed machine learning algorithms to select diagnostic genes and build a predictive model, and validated key targets using quantitative real-time PCR and dual-fluorescence immunohistochemical staining. RESULTS: Machine learning identified six inflammation-related genes (SPI1, IFITM3, ITGAM, BCL2A1, HLA-DPB1, PLA2G7) as a diagnostic signature, with predictive models demonstrating strong diagnostic performance. Validation confirmed significant differential expression of BCL2A1 and PLA2G7 in CRS patient samples compared to controls. CONCLUSIONS: This integrative analysis highlights the utility of computational approaches for discovering CRS biomarkers and subtypes, implicating specific genes in inflammation-associated pathways and paving the way for precision diagnostics and targeted therapies.
COX5A induces M2 macrophage polarization in chronic rhinosinusitis with nasal polyps through ROS generation.
Wang J, Chen Y, Chen X … +7 more , Xiong P, Zheng B, Gu Y, Guan D, Shen Y, Lu T, Yang Y
Inflamm Res · 2026 Mar · PMID 41842984 · Full text
BACKGROUND: Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) is characterized by persistent mucosal inflammation and tissue remodeling, driven by the crosstalk between epithelial and immune cells. Emerging evidence indi...
BACKGROUND: Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) is characterized by persistent mucosal inflammation and tissue remodeling, driven by the crosstalk between epithelial and immune cells. Emerging evidence indicates that, in addition to IL-13, TSLP, and IL-33, other mediators also significantly contribute to the crosstalk. In this study, we investigate the mechanism by which epithelial cell mitochondrial dysfunction drives immune dysregulation in CRSwNP, aiming to uncover novel therapeutic targets. METHODS: We analyzed transcriptomic data from three GEO datasets (GSE194282, GSE72713, GSE36830) to identify Differentially Expressed Genes (DEGs). By integrating mitochondrial-associated genes (MitoCarta3.0), we performed functional enrichment (GO/KEGG) and PPI network analyses to identify hub genes. In vitro experiments, including western blotting, flow cytometry, and immunofluorescence, were applied to elucidated the role of COX5A in mediating M2 macrophage polarization via ROS production. A murine nasal polyp (NP) model further confirmed key findings. RESULTS: We identified 110 mitochondrial-related DEGs (80 upregulated, 30 downregulated), prominently enriched in immune regulation and mitochondrial respiratory chain. Immune infiltration analysis revealed significant upregulation of M2 macrophages and resting memory CD4T cells in CRSwNP tissues. Strikingly, IL-13-stimulated epithelial cells (ECs) drove M2 polarization via COX5A-mediated ROS production-an effect abolished by COX5A knockdown or ROS scavengers. Furthermore, a murine nasal polyps model confirmed elevated COX5A and M2 marker expression, reinforcing the clinical relevance of our findings. CONCLUSION: Our research highlights the crucial role of mitochondrial dysfunction, particularly through COX5A-mediated reactive oxygen species (ROS) generation, in promoting the polarization of M2 macrophages and the progression of CRSwNP. These findings emphasize the potential for targeting mitochondrial-immune crosstalk as an effective therapeutic strategy, thereby opening new avenues for addressing CRSwNP.
Glucosamine as a regulator of O-GlcNAc signaling: linking metabolism to disease pathogenesis.
Kim SM, Lee C, Kim DY … +1 more , Han IO
Inflamm Res · 2026 Mar · PMID 41842977 · Publisher ↗
BACKGROUND: Glucosamine, a naturally occurring amino sugar abundant in cartilage, has long been utilized as a dietary supplement to alleviate osteoarthritis (OA) and joint pain. Beyond its structural role in maintaining...
BACKGROUND: Glucosamine, a naturally occurring amino sugar abundant in cartilage, has long been utilized as a dietary supplement to alleviate osteoarthritis (OA) and joint pain. Beyond its structural role in maintaining joint integrity, glucosamine is metabolized through the hexosamine biosynthetic pathway (HBP) to generate UDP-N-acetylglucosamine (UDP-GlcNAc), the indispensable donor substrate for protein O-linked N-acetylglucosamine (O-GlcNAc) modification. FINDINGS: Accumulating evidence indicates that glucosamine-driven modulation of HBP flux and the consequent alteration of O-GlcNAcylation exert profound effects on cellular signaling, metabolic regulation, and inflammatory responses. These mechanisms extend far beyond musculoskeletal health, influencing the pathogenesis of diverse conditions such as rheumatoid arthritis (RA), diabetes, obesity, neuroinflammation, neurodegenerative disorders, sepsis, and cancer. Despite glucosamine's long-standing clinical use, its potential role as a metabolic regulator of O-GlcNAc cycling remains underexplored. CONCLUSION: This review integrates current insights into the molecular basis of glucosamine-enhanced O-GlcNAcylation, highlighting its implications for disease onset and progression, and proposing a broader therapeutic framework that positions glucosamine as a promising modulator of inflammation and systemic pathology.
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