Inflammation最新文献

{"title":"B10 Adoptive Transfer Ameliorates Inflammation and Bone Loss in Experimental Periodontitis Through Promoting Macrophage-Mediated Pro-Resolving Functions.","authors":"Guoqin Cao, Elaheh Dalir Abdolahinia, Takumi Memida, Shengyuan Huang, Sunniva Ruiz, Satoru Shindo, Toshihisa Kawai, Jiang Lin, Xiaozhe Han","doi":"10.1007/s10753-026-02536-0","DOIUrl":"10.1007/s10753-026-02536-0","url":null,"abstract":"<p><p>Immune cell-cell interaction plays a critical role in the regulation of inflammatory responses. IL-10-expressing regulatory B cells (B10) alleviate the periodontal inflammation and bone loss by secreting IL-10, which can stimulate pro-resolving macrophage differentiation. However, little is known about the dynamic B10-macrophage interaction and the specific B10-induced pro-resolving functions in vivo in periodontitis. This study aimed to determine the dynamic local infiltration of B10 and macrophages, and the B10-induced macrophage differentiation and functions in experimental periodontitis. B10 were adoptively transferred via tail vein injection in a mouse model of experimental periodontitis. In some experiments, macrophages were depleted by intraperitoneal injection of clodronate liposomes. Dynamic gingival infiltration of B10 and macrophages were evaluated by in vivo imaging system (IVIS). The level of bone loss was evaluated by Micro-CT and TRAP staining. Cytokine productions, macrophage efferocytosis and autophagy were assessed by immunohistochemical / immunofluorescence analysis. Production of specialized pro-resolving mediators (SPMs) was detected by LC-MS/MS. B10 adoptive transfer inhibited alveolar bone resorption and osteoclast differentiation. B10 adoptive transfer promoted the number of pro-resolving macrophages compared with the control groups. A significant increase in IL-10, Arg-1, and YM-1, ATG5⁺, LC3B⁺, CD68⁺LC3B⁺, CD68⁺ATG5⁺ and CD68⁺Ly6G⁺ cells were detected in gingival tissues following B10 transfer, accompanied by a marked decrease in IL-17 A, TNF-α, and IL-1β expression. However, the B10-mediated suppression of alveolar bone resorption, osteoclast differentiation, TNF-α and IL-1β expression, as well as the upregulation of IL-10, ATG5, and LC3B, was attenuated upon macrophage depletion, whereas IL-17 A expression remained suppressed regardless of the macrophage presence. Notably, B10 adoptive transfer promoted RvD2 release in a macrophage-dependent manner. This study suggested that B10 adoptive transfer inhibited inflammation and bone loss in experimental periodontitis through the induction of macrophage-mediated pro-resolving functions, including RvD2 production, enhanced neutrophil clearance, and induction of macrophage autophagy.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13451254/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148149719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Knockdown of PTEN Inhibits Autophagy-Dependent Ferroptosis to Alleviate LPS-Induced Sepsis-Associated Acute Kidney Injury.","authors":"Dede Lian, Qingling Zhang, Hongjun Li","doi":"10.1007/s10753-026-02529-z","DOIUrl":"10.1007/s10753-026-02529-z","url":null,"abstract":"<p><strong>Purpose: </strong>This research aims to explore the mechanism whereby PTEN modulates autophagy-dependent ferroptosis in sepsis-associated acute kidney injury (SA-AKI).</p><p><strong>Methods: </strong>Bioinformatics analysis was performed using the GSE65682 dataset to screen genes associated with autophagy-dependent ferroptosis. qRT-PCR was performed to validate the expression of key genes. Cell proliferation was determined via the Cell Counting Kit-8 and colony formation assays. Apoptosis, mitochondrial membrane potential, Fe2+ and ROS levels were measured via flow cytometry. Mitochondrial function and autophagy were observed using transmission electron microscopy. Protein analysis was conducted via Western blotting. To verify the role of the key gene PTEN in SA-AKI, an in vivo model of SA-AKI was established via lipopolysaccharide (LPS) induction.</p><p><strong>Results: </strong>PTEN was identified as a key gene, with findings showing that it is highly expressed in SA-AKI. In the LPS-induced in vitro cell model of SA-AKI, PTEN knockdown enhanced cell proliferation, inhibited apoptosis, and reduced intracellular Fe2+ and ROS levels (P < 0.05, P < 0.01). Additionally, LPS-induced mitochondrial swelling and autophagosome accumulation were alleviated by PTEN knockdown, with fewer autophagic structures observed. PTEN knockdown upregulated the expression of Nrf2, SLC7A11, and GPX4, leading to reduced expression of COX2 and 4-HNE, and regulated autophagy-dependent ferroptosis by activating the Nrf2/SLC7A11/GPX4 signaling pathway. Furthermore, PTEN knockdown mitigated LPS-induced renal injury in SA-AKI, demonstrating its protective effect against SA-AKI. Notably, Nrf2 inhibition by ML385 reversed the protective effects of PTEN knockdown.</p><p><strong>Conclusions: </strong>This study elucidates that the knockdown of PTEN activates the Nrf2/SLC7A11/GPX4 signaling pathway to modulate autophagy-dependent ferroptosis in SA-AKI.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13433402/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148137751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasminogen Activation System and Fibroblasts: Impact on Tissue Remodeling, Disease, and Organ Homeostasis.","authors":"Fathimath Muneesa Moideen, Yashodhar Prabhakar Bhandary","doi":"10.1007/s10753-026-02533-3","DOIUrl":"10.1007/s10753-026-02533-3","url":null,"abstract":"<p><p>The interplay between fibroblasts and the plasminogen activation system is increasingly recognized as a central driver of fibrosis, thrombosis, and cancer progression. Fibroblasts, as key producers of extracellular matrix (ECM), regulate tissue integrity, repair, and remodeling. Through their interactions with urokinase-type plasminogen activator (uPA), tissue-type plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), and plasmin, fibroblasts influence ECM degradation, cell migration, angiogenesis, and inflammation. Dysregulation of this crosstalk contributes to persistent fibrosis in organs such as lung, liver, kidney, and heart, and facilitates stromal remodeling in cancer. Notably, paradoxical effects are evident-for example, PAI-1 promotes fibroblast survival while inducing apoptosis in alveolar epithelial cells, highlighting context-dependent actions. This review summarizes recent findings across major organs and tissue-specific mechanisms. We also discuss the emerging therapeutic potential of targeting fibroblast-plasminogen interactions, including PAI-1 inhibitors, uPA/uPAR antagonists, and natural compounds, alongside challenges in clinical translation. This review critically integrates mechanistic and organ-specific evidence, including plasminogen receptors as essential mediators of pericellular plasmin generation with uPA/tPA/PAI-1 signaling, across lung, skin, kidney, liver, heart, and cancer contexts. These findings position fibroblasts as central coordinators of fibrinolysis-fibrosis crosstalk and highlight therapeutic opportunities targeting this integrated network.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13408137/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148054332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systemic Inflammation Triggers Motor Axon Degeneration Via Macrophage IL-1β-Mediated P53/SIRT1/Autophagy Pathway.","authors":"Bowen Sun, Jie Li, Xuexin Li, Rui Tu, Xinyu Yao, Fei He, Yun Wang, Li Liu","doi":"10.1007/s10753-026-02530-6","DOIUrl":"10.1007/s10753-026-02530-6","url":null,"abstract":"<p><strong>Background: </strong>Axonal degeneration of motor neurons is a hallmark pathological feature of neurodegenerative diseases, culminating in motor dysfunction in advanced stages. Systemic inflammation exacerbates motor dysfunction, yet the relationship between systemic inflammation and motor axon degeneration remains poorly understood. We investigated whether macrophages impair motor axon morphology during systemic inflammation and the underlying mechanisms.</p><p><strong>Methods: </strong>A zebrafish systemic inflammation model was established using CuSO₄ exposure. In vivo confocal imaging examined spatiotemporal relationships between macrophages and motor axon morphology in transgenic zebrafish. Motor function was assessed using behavioral analysis. RAW264.7 macrophage-like cells stimulated with lipopolysaccharide were co-cultured with NSC-34 motor neurons to investigate molecular mechanisms.</p><p><strong>Results: </strong>CuSO₄ treatment induced elevated inflammatory cytokines and motor dysfunction in zebrafish. Histological analysis revealed increased macrophage infiltration around motor axons with concurrent reductions in axon number, length, and diameter. Macrophage depletion or IL-1Ra pretreatment significantly ameliorated motor axon damage and dysfunction. In vitro, LPS activated the NLRP3 inflammasome in RAW264.7 macrophage-like cells, releasing IL-1β, which was accompanied by disruption of the SIRT1-autophagy axis in motor neurons. Increased IL-1β release from macrophages was accompanied by upregulated P53 expression in motor neurons, which paralleled reduced SIRT1 levels, impaired autophagy, and decreased axon-associated protein expression. Pharmacological inhibition of NLRP3 with MCC950, IL-1Ra treatment, or P53 knockdown restored the SIRT1-autophagy axis and axon protein expression.</p><p><strong>Conclusions: </strong>Systemic inflammation activates macrophage NLRP3 inflammasome and promotes the release of inflammatory mediators including IL-1β, with findings suggestive of a model in which elevated IL-1β paralleled increased motor neuronal P53 expression and disruption of the SIRT1-autophagy balance, potentially contributing to motor axon morphological damage and dysfunction.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13391795/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148029781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The CEBPB-AP-1 (JunB/Fos) Axis Drives Neuroinflammation and Microglial Dysfunction Via TNF Signaling in Ischemic Stroke.","authors":"Kun Liang, Shuangshuang Lu, Weihao Shi, Weijian Fan, Yijun Huang, Jianwei Chen, Lei Zhu","doi":"10.1007/s10753-026-02525-3","DOIUrl":"10.1007/s10753-026-02525-3","url":null,"abstract":"<p><p>Ischemic stroke triggers a strong neuroinflammatory response, with microglia playing dual roles in both exacerbating tissue damage and promoting repair. The molecular mechanisms regulating microglial activation and polarization remain inadequately defined. In this study, we demonstrate that the transcription factor CEBPB is a key upstream regulator of the AP-1 (JunB-Fos) complex, driving pro-inflammatory transcriptional programs in microglia following transient focal cerebral ischemia (tFCI). Transcriptomic profiling of microglia from tFCI mice revealed significant gene expression changes, particularly enrichment in inflammatory, immune, and cytokine production pathways, and identified Cebpb, Junb, Fos, and Tnf as key hub genes. Mechanistically, CEBPB is upregulated in post-ischemic microglia and directly binds to the Fos promoter to activate AP-1, inducing downstream inflammatory mediators, including IL-1β and TNF-α. Inhibition of AP-1 with the selective inhibitor T-5224 shifted microglia from a pro-inflammatory to an anti-inflammatory phenotype in vitro, decreasing pro-inflammatory cytokine production and enhancing anti-inflammatory mediator release. In vivo, T-5224 treatment in tFCI mice suppressed neuroinflammation, reduced neuronal apoptosis in the striatum and cortex, promoted a restorative microglial phenotype, and improved long-term sensorimotor and cognitive function. These findings establish the CEBPB/AP-1 axis as a critical driver of neuroinflammation in ischemic stroke and highlight it as a promising therapeutic target.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13402266/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148029853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GBP5 Aggravates Acute Lung Injury Via NLRP3 Inflammasome Activation While Inducing a HIF-1α-CD73-adenosine Feedback Loop.","authors":"Jia Zhang, Linshu Xie, Xinyu Yang, Qianqian Liu, Xiaoju Zhang","doi":"10.1007/s10753-026-02528-0","DOIUrl":"10.1007/s10753-026-02528-0","url":null,"abstract":"<p><p>Guanylate-binding protein 5 (GBP5) is an interferon-inducible GTPase that promotes NLRP3 inflammasome activation. However, its role in acute lung injury (ALI) and its relationship with compensatory anti-inflammatory pathways remain poorly defined. Methods: We employed an LPS-induced ALI mouse model with AAV-mediated intratracheal GBP5 knockdown, transcriptomic profiling (RNA-seq), and in vitro studies in THP-1 macrophages. GBP5 overexpression and CD73 overexpression were used to dissect the GBP5-HIF-1α-CD73-adenosine axis. RNA-seq analysis of LPS-induced lung injury revealed upregulation of GBP family members (particularly GBP5) and multiple adenosine metabolism genes. AAV-mediated GBP5 knockdown in male C57BL/6 mice (6-8 weeks, n = 10/group) attenuated LPS-induced lung injury, reduced NLRP3 inflammasome activation (NLRP3, ASC, cleaved caspase-1), and decreased inflammatory cytokine levels (IL-1β, IL-6, TNF-α). In parallel, GBP5 knockdown suppressed CD73 and ADORA2A expression, whereas GBP5 overexpression in THP-1 macrophages enhanced CD73 expression via HIF-1α-dependent transcriptional activation confirmed by dual-luciferase reporter assays. CD73 overexpression in turn elevated cAMP/p-CREB signaling and suppressed NLRP3 inflammasome activity. GBP5 exacerbates ALI through NLRP3 inflammasome activation while simultaneously driving a compensatory HIF-1α-CD73-adenosine-cAMP-CREB feedback loop that restrains excessive inflammation. Targeting this dual pathway may offer novel therapeutic strategies for ALI and ARDS.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13375705/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148005310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ID2 Regulates Macrophage Polarization and Mediates Methotrexate Responsiveness in Rheumatoid Arthritis.","authors":"Lu Ye, Xiaomei Wang, Huaxiang Wu, Weihong Xu","doi":"10.1007/s10753-026-02527-1","DOIUrl":"https://doi.org/10.1007/s10753-026-02527-1","url":null,"abstract":"<p><p>Methotrexate (MTX) is the first-line treatment for rheumatoid arthritis (RA), but patient responses are highly variable. Macrophages are central drivers of RA inflammation, yet how monocyte/macrophage heterogeneity and transcriptional programs influence MTX responsiveness remains unclear. Single-cell RNA sequencing was performed on peripheral blood mononuclear cells from MTX-responsive and MTX-unresponsive RA patients to define immune composition and macrophage-like monocyte subsets. Polarization states were assessed using gene-signature scoring and pseudotime analysis. The role of inhibitor of differentiation 2 (ID2) was examined in LPS-stimulated RA patient-derived macrophages using gain- and loss-of-function approaches, cytokine assays and chromatin immunoprecipitation assays. Although overall immune cell distributions were similar between groups, macrophage-like monocytes from MTX-unresponsive patients exhibited higher M1 polarization scores. PLBD1⁺ and CDKN1A⁺ macrophage-like monocytes were enriched in MTX-unresponsive patients, whereas RLIM⁺ macrophage-like monocytes were reduced. Integrative analyses identified ID2 as a regulator associated with MTX resistance. ID2 expression was elevated in macrophage-like monocytes from MTX-unresponsive patients and positively correlated with M1 polarization. In vitro, MTX suppressed ID2 expression and inflammatory activation. ID2 knockdown reduced pro-inflammatory responses, whereas overexpression attenuated the inhibitory effects of MTX. ID2 was found to regulate EEF1A1 transcription. ID2 promotes pro-inflammatory macrophage polarization and may contribute to MTX resistance in RA.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147987137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CXCL10-LACTC1/C2 Expressing Mesenchymal Stem Cell Conditioned Medium Attenuates TNF-α-Induced Gene Expressions and Cell Viability in HUVECs.","authors":"Kaya Molo, Ruken Ege, Kübra Ati̇k, Elif Çıtak, Orçun Çulcuoğlu, Hakan Darıcı, Emel Ordu","doi":"10.1007/s10753-026-02518-2","DOIUrl":"10.1007/s10753-026-02518-2","url":null,"abstract":"<p><p>Infectious diseases exacerbate atherosclerosis-associated morbidity and mortality by inducing sustained inflammatory responses characterized by elevated IL-6, TNF-α, IFN-γ, and CXCL10. Persistent CXCL10-driven recruitment of CXCR3⁺ immune cells promotes endothelial dysfunction and atherosclerotic progression. Although mesenchymal stem cells (MSCs) respond to inflammatory cues and secrete CXCL10, the contribution of CXCL10/CXCR3 signaling to intrinsic MSC immunomodulatory programming remains poorly understood. The objective of this study is to investigate whether CXCL10 signaling can modulate MSC-mediated immunoregulation. To address this, Wharton's jelly-derived MSCs (WJ-MSCs) were genetically engineered to express a membrane-anchored CXCL10-Lactadherin C1/C2 fusion protein (CXCL10-LACTC1/C2). This strategy was designed to recapitulate physiological, localized, and sustained CXCL10 signaling, enabling spatially restricted chemokine presentation that more closely mimics cell-associated CXCL10 in inflammatory microenvironments compared with soluble CXCL10. The Lactadherin C1/C2 domain was selected to achieve stable, physiological membrane anchoring without introducing artificial transmembrane domains or compromising CXCL10 bioactivity. CXCL10-LACTC1/C2-expressing MSCs exhibited increased expression of key immunoregulatory mediators, including IDO1, TGF-β1, and IL4I1. Furthermore, conditioned medium derived from these MSCs attenuated TNF-α-induced inflammatory responses in human umbilical vein endothelial cells (HUVECs), as indicated by the modulation of endothelial activation and homeostasis markers (ICAM-1, PECAM-1, KDR, vWF, and NRF2) and improvement of cell viability. Collectively, these findings provide mechanistic insight into CXCL10-mediated MSC immunoregulation and support further investigation of MSC-based and cell-free therapeutic strategies aimed at mitigating CXCL10-driven endothelial inflammation in infection-associated vascular injury and atherosclerotic disease progression.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13369754/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147987333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hepatocyte-Derived S100A4/A6/A10/A11 Proteins Promote Liver Fibrosis by Direct and Indirect Activation of HSCs.","authors":"He Tong, Yingxue Zhang, Haiting Pan, Sarina Wang, Yan Zhao, Zhuoya Zhao, Yulong Bao, Li Wang","doi":"10.1007/s10753-026-02524-4","DOIUrl":"10.1007/s10753-026-02524-4","url":null,"abstract":"<p><p>Liver fibrosis is a chronic disease caused by various etiologies, including dysregulated interactions among hepatocytes, KCs, and HSCs. Studies have shown that the S100 protein family plays an important role in liver fibrosis, especially the S100A4/A6/A10/A11 proteins; however, the effects of hepatocyte-derived S100A4/A6/A10/A11 proteins on the crosstalk between KCs and HSCs in liver fibrosis are unknown. The aim of this study was to investigate how hepatocyte-derived S100A4/A6/A10/A11 proteins modulate KC and HSC activation during liver fibrosis. Fibrotic, HCC and ICC human liver paraffin-embedded block samples were obtained. A CCl₄-induced liver fibrosis model was established, and in this model, S100A4/A6/A10/A11 proteins were blocked using specific antibodies. AML-12 mouse hepatocytes, KCs, and HSCs were used in vitro. During liver fibrosis, S100A4/A6/A10/A11 proteins are released by hepatocytes and function as DAMPs that activate KCs via the p38 and JNK signaling pathways. This activation triggers the release of inflammatory cytokines, which in turn promote HSC activation and collagen deposition through a TGF-β/SMAD2-dependent mechanism. Moreover, S100A4/A6/A10/A11 proteins can directly stimulate HSC activation and collagen deposition via the TGF-β/SMAD2 pathway. Blocking S100A4/A6/A10/A11 proteins significantly attenuated the release of inflammatory cytokines and reduced collagen deposition. Clinical evidence further indicates that the expression of S100A4/A6/A10/A11 proteins is significantly upregulated in liver tissues from patients with HCC and ICC. This study reveals a dual regulatory mechanism in liver fibrosis: S100A4/A6/A10/A11 proteins derived from hepatocytes not only indirectly promote HSC activation by stimulating KCs to release pro-inflammatory factors but also directly activate HSCs. These findings highlight the potential of this group of S100 proteins as a promising therapeutic target for liver fibrosis.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13375748/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147987084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of MyD88 in Tubular Epithelial Cells Alleviates the Cellular Senescence in Sepsis-Associated Acute Kidney Injury.","authors":"Yan Zhang, Yali Wang, Yingxin Zhao, Congcong Yao, Yuxin Dong, Keke Sun, Massimo Attanasio, Songtao Shou, Heng Jin","doi":"10.1007/s10753-026-02526-2","DOIUrl":"10.1007/s10753-026-02526-2","url":null,"abstract":"<p><p>Cellular senescence has emerged as an important contributor to acute kidney injury (AKI); however, its role in sepsis-associated acute kidney injury (SA-AKI) remains insufficiently characterized. This study aimed to investigate the involvement of cellular senescence in SA-AKI and to determine the contribution of the Toll-like receptor (TLR)/MyD88 signaling pathway. A cecal ligation and puncture (CLP) mouse model was established to induce SA-AKI. Cellular senescence markers and inflammatory indices were evaluated at 24, 48, and 72 h after injury using senescence-associated β-galactosidase (SA-β-Gal) staining, immunofluorescence, and quantitative real-time PCR (qPCR). Integrated transcriptomic and proteomic analyses were performed to identify candidate hub genes involved in SA-AKI. Human Kidney-2 (HK-2) cells were used to assess the role of MyD88 in tubular epithelial cell senescence, and mice with tubular epithelial cell-specific deletion of Myd88 were subsequently used to investigate the in vivo role of MyD88 in SA-AKI. At 72 h after CLP, SA-AKI was associated with a marked increase in SA-β-Gal activity, p21 expression, DNA damage, and inflammatory cytokine production, together with decreased lamin B1 (LAMNB1) expression and reduced proliferative activity, indicating the induction of cellular senescence. Inflammatory cell infiltration was also evident at this time point. Integrated omics analysis identified MyD88 as a key candidate molecule. In HK-2 cells, pharmacological inhibition of MyD88 attenuated lipopolysaccharide-induced cellular senescence and inflammatory responses. Consistently, tubular epithelial cell-specific deletion of Myd88 significantly reduced cellular senescence, inflammatory infiltration, and renal injury following SA-AKI. These findings indicate that cellular senescence in SA-AKI is mediated, at least in part, by the TLR/MyD88 signaling pathway. Targeting this pathway may represent a potential therapeutic strategy for attenuating SA-AKI progression and improving renal outcomes.</p>","PeriodicalId":13524,"journal":{"name":"Inflammation","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13364797/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147972230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}