Journal of Innate Immunity最新文献

{"title":"Acinetobacter baumannii Clinical Isolates Resist Complement-Mediated Lysis by Inhibiting the Complement Cascade and Improperly Depositing MAC.","authors":"Michal Magda, Wendy Boschloo, Serena Bettoni, Derek Fairley, Thomas A Russo, Christian G Giske, Chaitanya Tellapragada, Suzan H M Rooijakkers, Kristian Riesbeck, Anna M Blom","doi":"10.1159/000543664","DOIUrl":"10.1159/000543664","url":null,"abstract":"<p><strong>Introduction: </strong>Acinetobacter baumannii is a gram-negative opportunistic bacterium that causes life-threatening infections in immunocompromised hosts. The complement system is a critical mechanism of innate immunity that protects the human body from bacterial infections. Complement activation leads to the deposition of the membrane attack complex (MAC), which can directly lyse gram-negative bacteria. However, A. baumannii has developed evasion mechanisms to protect itself from complement.</p><p><strong>Methods: </strong>Complement deposition was investigated by flow cytometry and Western blotting. Soluble MAC formation was assessed by ELISA. Bacterial serum resistance was determined by the SYTOX Green Assay. Galleria mellonella was used as an infection model. Genome sequencing revealed virulence genes carried by isolates.</p><p><strong>Results: </strong>We examined clinical isolates of A. baumannii and found 11 isolates with MAC deposition and 5 isolates without deposition. Trypsinization of MAC-positive isolates significantly reduced MAC, indicating incorrect insertion, consistent with a lack of lysis of these strains. MAC-negative isolates inhibited alternative pathway activation and were significantly more serum-resistant. These strains were also more virulent in a G. mellonella infection model. Whole genome sequencing revealed that MAC-negative isolates carried more virulence genes, and both MAC-negative and MAC-positive A. baumannii significantly differed in capsule type. Importantly, a correlation was observed between complement inhibition and capsule type (e.g., capsule locus KL171) of MAC-negative bacteria, while the capsule type (e.g., KL230) of MAC-positive A. baumannii was associated with increased sensitivity to MAC-mediated lysis.</p><p><strong>Conclusion: </strong>Our findings suggest a relationship between capsule type, complement resistance, and host virulence in A. baumannii.</p><p><strong>Introduction: </strong>Acinetobacter baumannii is a gram-negative opportunistic bacterium that causes life-threatening infections in immunocompromised hosts. The complement system is a critical mechanism of innate immunity that protects the human body from bacterial infections. Complement activation leads to the deposition of the membrane attack complex (MAC), which can directly lyse gram-negative bacteria. However, A. baumannii has developed evasion mechanisms to protect itself from complement.</p><p><strong>Methods: </strong>Complement deposition was investigated by flow cytometry and Western blotting. Soluble MAC formation was assessed by ELISA. Bacterial serum resistance was determined by the SYTOX Green Assay. Galleria mellonella was used as an infection model. Genome sequencing revealed virulence genes carried by isolates.</p><p><strong>Results: </strong>We examined clinical isolates of A. baumannii and found 11 isolates with MAC deposition and 5 isolates without deposition. Trypsinization of MAC-positive isolates signif","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":" ","pages":"112-125"},"PeriodicalIF":3.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11845171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143023805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Erratum.","authors":"","doi":"10.1159/000545776","DOIUrl":"10.1159/000545776","url":null,"abstract":"","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":"17 1","pages":"287"},"PeriodicalIF":4.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12158409/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CAPN1 Promotes Pseudomonas aeruginosa-Induced Infection by Interacting with TFEB and Inhibiting Autophagy.","authors":"Yueming Wu, Miaomiao Chen, Hua Chen, Liuhua Pan, Jing Zhao, Shunnan Sun, Ning Zhang, Junlong Xu","doi":"10.1159/000543244","DOIUrl":"10.1159/000543244","url":null,"abstract":"<p><strong>Introduction: </strong>Autophagy-lysosome pathways play a crucial role in the intracellular killing of pathogenic microorganisms. This study aimed to explore the mechanism by which acute lung injury (ALI) of Pseudomonas aeruginosa affects the autophagy-lysosome pathway.</p><p><strong>Methods: </strong>ALI mouse models were induced by lipopolysaccharide and P. aeruginosa strain K (PAK). Lung tissue sections were stained with hematoxylin-eosin for observation. Flow cytometry was used to analyze bacteria and inflammatory cell infiltration. ELISA was performed to measure inflammatory factor levels. Transmission electron microscopy evaluated autolysosome quantity. Western blot detected levels of related proteins. Immunofluorescence evaluated LC3 expression, and the localization of TFEB in cells was observed. Co-immunoprecipitation and pull-down experiments confirmed the interaction between CAPN1 and TFEB. qRT-PCR measured capn1 and tfeb expression.</p><p><strong>Results: </strong>Mouse experiments revealed that PAK infection led to the suppression of autolysosomes in mouse lung tissue, along with increased CAPN1 expression and decreased TFEB in the lung tissue of PAK-induced pneumonia mice. CAPN1-deficient mice could reverse the impact of PAK infection on autolysosomes in mouse lung tissue. These findings were further verified by cell experiments. At a mechanistic level, CAPN1 can interact with TFEB after PAK infection and prevent its entry into the nucleus, thereby inhibiting the autophagolysosomal pathway.</p><p><strong>Conclusion: </strong>CAPN1 promotes PAK-induced ALI by inhibiting the autophagy-lysosome pathway by targeting TFEB.</p><p><strong>Introduction: </strong>Autophagy-lysosome pathways play a crucial role in the intracellular killing of pathogenic microorganisms. This study aimed to explore the mechanism by which acute lung injury (ALI) of Pseudomonas aeruginosa affects the autophagy-lysosome pathway.</p><p><strong>Methods: </strong>ALI mouse models were induced by lipopolysaccharide and P. aeruginosa strain K (PAK). Lung tissue sections were stained with hematoxylin-eosin for observation. Flow cytometry was used to analyze bacteria and inflammatory cell infiltration. ELISA was performed to measure inflammatory factor levels. Transmission electron microscopy evaluated autolysosome quantity. Western blot detected levels of related proteins. Immunofluorescence evaluated LC3 expression, and the localization of TFEB in cells was observed. Co-immunoprecipitation and pull-down experiments confirmed the interaction between CAPN1 and TFEB. qRT-PCR measured capn1 and tfeb expression.</p><p><strong>Results: </strong>Mouse experiments revealed that PAK infection led to the suppression of autolysosomes in mouse lung tissue, along with increased CAPN1 expression and decreased TFEB in the lung tissue of PAK-induced pneumonia mice. CAPN1-deficient mice could reverse the impact of PAK infection on autolysosomes in mouse lung tissue. These fin","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":"17 1","pages":"176-197"},"PeriodicalIF":3.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11906175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and Characterization of Novel ELISAs for the Specific Quantification of the Factor H-Related Proteins 2, 3, 4, and 5.","authors":"Mara van Rossum, Bert R J Veuskens, Mieke C Brouwer, Gerard van Mierlo, Laura Lucientes-Continente, Elena Goicoechea de Jorge, Barbara Uzonyi, Alexandra T Matola, Mihály Józsi, Günter Müller, Anita M Meter-Arkema, Felix Poppelaars, Diana Pauly, Richard B Pouw, Erik J M Toonen","doi":"10.1159/000545139","DOIUrl":"10.1159/000545139","url":null,"abstract":"<p><strong>Introduction: </strong>The complement system's alternative pathway relies on factor H (FH) for immune homeostasis. Next to FH, a group of highly similar proteins was described known as the FH-related (FHR) proteins. The FH protein family includes FH, factor H-like protein 1, and five FHR proteins (FHR-1 to -5). The exact function of the FHRs is still unknown, necessitating further research. However, the lack of highly specific assays has hindered studying their role in health and disease. This study aimed to develop novel ELISAs for reliably and specifically quantifying levels of the FHRs in human blood.</p><p><strong>Methods: </strong>Novel FHR-specific antibodies were generated. Positive hybridoma clones were taken to monoclonality, verified for target specificity via ELISA and Western blot, and antibody pairs were selected for further ELISA development. During development, ELISAs were characterized and validated for specificity, stability, accuracy, and reproducibility, among others.</p><p><strong>Results: </strong>Monoclonal antibodies specific for FHR-2, -3, -4, or -5 were generated. Using these antibodies, four ELISAs were developed capable of quantifying FHR levels in an accurate and robust manner. Each assay showed high target specificity, good analyte recovery and strong reproducibility between replicates, test runs, and test laboratories.</p><p><strong>Conclusions: </strong>These assays enable specific and accurate quantification of FHR-2, -3, -4, and -5 in human blood. They facilitate large-scale screening of patient cohorts in a standardized manner and contribute to understanding the role of the FHRs in health and disease.</p>","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":" ","pages":"226-243"},"PeriodicalIF":3.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12048131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Qilian Jiechang Ning Alleviates TNBS-Induced Ulcerative Colitis in Mice and Segatella copri Outer Membrane Vesicle-Triggered Inflammation in Colon Epithelial Cells via the Caspase-1/11-GSDMD Pathways.","authors":"Jinyang Hu, Junjie Niu, Shisheng Jiang, Yuhua Wu","doi":"10.1159/000545394","DOIUrl":"10.1159/000545394","url":null,"abstract":"<p><strong>Introduction: </strong>Qilian Jiechang Ning (QJN), a traditional Chinese herbal formula, has demonstrated potential therapeutic effects in the treatment of ulcerative colitis (UC). This study aims to investigate the mechanism of QJN in the outer membrane vesicles (OMVs) of Segatella copri (S. copri)-induced colon epithelial cells and UC mice.</p><p><strong>Methods: </strong>Transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA) were utilized to assess the morphology and size of OMVs. Inflammation markers and tight junction protein levels in HCoEpiCs induced by OMVs were monitored using ELISA and western blot. QJN was administered to intervene in HCoEpiCs treated with S. copri OMVs. Additionally, trinitrobenzene sulfonic acid (TNBS)-induced mouse models were conducted to evaluate the therapeutic effects of QJN on UC.</p><p><strong>Results: </strong>S. copri OMVs treated with QJN demonstrated a significant reduction in particle size, protein concentration, and LPS content. In HCoEpiCs, QJN effectively decreased the expression of inflammation-inducing cytokines (IL-1β, IL-18, IL-6, TNF-α) and proinflammatory proteins (GSDMD-N, NLRP3, ASC, cleaved Caspase-1, cleaved Caspase-4) triggered by S. copri OMVs, while enhancing the expression of tight junction proteins (ZO-1 and Occludin). In the UC mouse models, QJN significantly reduced the Disease Activity Index (DAI), improved colon length, lowered LPS levels, ameliorated colonic tissue damage, and inhibited Caspase-1- and Caspase-11-dependent inflammatory responses.</p><p><strong>Conclusion: </strong>QJN can alleviate S. copri-OMV-induced inflammatory response in colonic epithelial cells and reduce symptoms of UC in mouse models by modulating the Caspase-1 and Caspase-11 pathways.</p>","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":"17 1","pages":"262-276"},"PeriodicalIF":3.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12077867/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TLR9 Downregulation in Breast Cancer: Its Role in Tumor Immunity, Inflammatory Response, and Cellular Senescence.","authors":"Emily Sible, Gregory Weitsman, Salome Amouyal, Guillaume Roblot, Marie Marotel, Rémi Pescarmona, Nathalie Bendriss-Vermare, Cheryl Gillett, Amie Ceesay, Alexia Gazeu, Marie Cecile Michallet, Christophe Caux, Francois-Loic Cosset, Umaima Al Alem, Tony Ng, Uzma Ayesha Hasan","doi":"10.1159/000545527","DOIUrl":"10.1159/000545527","url":null,"abstract":"<p><strong>Introduction: </strong>Toll-like receptor 9 (TLR9) is primarily expressed in human dendritic and B cells and recognizes double-stranded DNA motifs from pathogens to initiate an inflammatory response. Recent studies have revealed TLR9s' involvement beyond its conventional role in the immune response, notably during the tumorigenesis of various cancers such as head and neck, cervical, and ovarian cancers.</p><p><strong>Methods: </strong>In this study patient biopsies of breast cancer tumors and normal breast epithelium were analyzed by immunohistochemistry to examine TLR9 expression. The study also investigated downregulation in transformed breast cancer cell lines compared to untransformed breast epithelial cells by analyzing gene or protein expression, including TLR9, IL-6, CCL2, CXCL1, and GM-CSF. MDA-MB-361 cells were engineered to express exogenous TLR9, and the effects on colony growth and senescence were assessed using colony formation assays, senescence staining, cytokine analysis, and flow cytometry.</p><p><strong>Results: </strong>TLR9 levels in breast cancer tumors were significantly reduced compared to normal breast tissue epithelium. This downregulation was also observed in several transformed breast cancer cell lines compared to untransformed breast epithelial cell lines. Furthermore, MDA-MB-361 breast cancer cells expressing exogenous TLR9 exhibited reduced colony growth and an increase in the senescence marker IL-6, pro-inflammatory cytokine CCL2, CXCL1 chemokine; and growth factor GM-CSF.</p><p><strong>Conclusion: </strong>These findings support TLR9's regulatory role in mitigating breast cancer and highlight its critical connection between the innate immunity and tumor cell growth.</p>","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":" ","pages":"354-368"},"PeriodicalIF":3.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12310192/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144475641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interaction between Group 3 Innate Lymphoid Cells, Microbiota, and Intestinal Diseases: Mechanisms and Therapeutic Potential.","authors":"Lijie Hao, Yi Ge, Zhuo Chen, Duo Yuan, Xiaoyan Zhang, Huihong Zhai, Ziyu Liu","doi":"10.1159/000546972","DOIUrl":"10.1159/000546972","url":null,"abstract":"<p><strong>Background: </strong>The incidence of intestinal diseases is increasing every year, placing a heavy burden on the world's health and economy. The interaction of immune, microbial, and environmental factors leading to chronic inflammation and immune dysfunction has gradually become a focus of research on the pathogenesis of intestinal diseases. Among them, type 3 innate lymphoid cells (ILC3s) have attracted much attention due to their unique features.</p><p><strong>Summary: </strong>This paper has been carefully reviewed to provide a comprehensive overview of the roles of ILC3s in maintaining the homeostasis of intestinal flora. Initially, the effects of various intestinal microbiota, including bacteria, fungi, viruses, and pathogenic bacteria, on the function of ILC3s were introduced in detail. Subsequently, it summarizes how ILC3 imbalance disrupts the intestinal barrier and leads to digestive diseases, including infectious diseases, colorectal cancer, inflammatory bowel disease, and irritable bowel syndrome.</p><p><strong>Key messages: </strong>By reviewing the role of ILC3s in maintaining the homeostasis of the intestinal flora and the current research status of ILC3s imbalance disrupting the intestinal barrier and leading to digestive tract diseases, this review provides potential immunotherapy targets for the future and offers a basis for the construction of future animal models and the conduct of clinical trials.</p>","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":" ","pages":"341-353"},"PeriodicalIF":4.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12270470/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144325982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging Advancements in Metabolic Properties of Macrophages within Disease Microenvironment for Immune Therapy.","authors":"Feng Zhao, Zhongyu Yue, Lijiaqi Zhang, Yujie Qi, Yunting Sun, Shuling Wang, Qingchang Tian","doi":"10.1159/000546476","DOIUrl":"10.1159/000546476","url":null,"abstract":"<p><strong>Background: </strong>As sentinel cells of innate immunity, macrophages exhibit microenvironment-driven functional plasticity critical for immune regulation and tissue homeostasis, yet maladaptive metabolic reprogramming-induced polarization dysregulation exacerbates disease progression by manifesting immune dysfunction.</p><p><strong>Summary: </strong>This review systematically deciphers the metabolic signatures governing macrophage polarization - spanning amino acid metabolism, glycolytic flux, lipid dynamics, and iron homeostasis - while dissecting how pathological microenvironments (encompassing tumor niches, atherosclerotic plaques, and obese adipose tissue) co-opt these pathways to drive pathogenesis. Crucially, this analysis demonstrates that cellular metabolism dictates macrophage phenotypic/functional states across disease contexts, with comprehensive decoding of their metabolic networks emerging as imperative for developing next-generation immunotherapies.</p><p><strong>Key messages: </strong>Therapeutically, pathogenic polarization may be reversed through strategic interventions targeting metabolite-sensing receptors, pharmacologically blocking metabolic checkpoints, and reprogramming core metabolic modalities to restore immunoregulatory competence.</p>","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":" ","pages":"320-340"},"PeriodicalIF":4.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12252386/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxidative Stress and Chronic Inflammation as Partners in Crime in Interstitial Cystitis/Bladder Pain Syndrome.","authors":"Aleksandar Janev, Daša Zupančič, Peter Veranič, Tadeja Kuret","doi":"10.1159/000546901","DOIUrl":"10.1159/000546901","url":null,"abstract":"<p><strong>Background: </strong>Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic inflammatory disease of the urinary bladder, characterized by chronic pain, increased urinary frequency, urgency, and nocturia. Currently, no therapeutic option consistently provides long-term relief for all IC/BPS patients, likely due to the largely unknown mechanisms underlying the disease's development and progression. IC/BPS is considered a multifactorial disorder with a complex pathobiology that ultimately leads to unresolved inflammation, bladder dysfunction, and pain.</p><p><strong>Summary: </strong>Recent research has highlighted chronic inflammation and oxidative stress, resulting from either increased production of reactive oxygen species or their inadequate elimination, as a significant feature of IC/BPS. The frequent co-occurrence of IC/BPS with other chronic diseases characterized by prolonged oxidative stress and subtle chronic inflammation, such as autoimmune diseases, chronic psychological stress, fibromyalgia, and irritable bowel syndrome, suggests a common underlying pathogenic pathway.</p><p><strong>Key messages: </strong>In this review, we summarize key findings suggesting that oxidative stress and chronic inflammation play a part in the onset and progression of IC/BPS. We explore how oxidative stress contributes to IC/BPS through various mechanisms, including damage to bladder urothelial cells and mitochondria, the activation of innate immune signaling pathways, which together create a self-perpetuating cycle of inflammation. Additionally, we discuss potential therapeutic options and novel drug candidates with anti-inflammatory and antioxidant properties, which could modulate regulatory pathways involved in disease development and provide long-term efficacy in IC/BPS.</p>","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":" ","pages":"369-396"},"PeriodicalIF":3.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12334152/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144505962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"5-Methoxytryptophan Protects against Toll-Like Receptor 2-Mediated Renal Tissue Inflammation and Fibrosis in a Murine Unilateral Ureteral Obstruction Model.","authors":"Jing-Yiing Wu, Guan-Lin Lee, Yu-Fan Chueh, Cheng-Chin Kuo, Yu-Juei Hsu, Kenneth K Wu","doi":"10.1159/000543275","DOIUrl":"10.1159/000543275","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;5-Methoxytryptophan (5-MTP) is a cellular metabolite with anti-inflammatory properties. Several recent reports indicate that 5-MTP protects against post-injury tissue fibrosis. It was unclear how 5-MTP controls tissue fibrosis. We postulated that 5-MTP attenuates renal interstitial fibrosis by blocking toll-like receptor 2 (TLR2) and transforming growth factor β (TGFβ) signaling pathways.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;In vivo experiments were carried out in a well-established unilateral ureteral obstruction (UUO) model in wild-type (WT) and tlr2-/- mice. The effect of 5-MTP on renal fibrosis was evaluated by pretreatment of WT UUO mice with intraperitoneal administration of 5-MTP. To determine whether 5-MTP attenuates fibrosis by inhibiting TLR2 and TGFβ signaling pathways, we evaluated the effect of 5-MTP on TLR2-induced fibroblast phenotypic switch in NRK-49F fibroblasts and TLR2 and TGFβ signaling pathways in human proximal tubular epithelial cells (HPTECs) and RAW264.7 macrophages stimulated with Pam3CSK4 (Pam3) or TGFβ1.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;UUO-induced renal fibrosis was abrogated in tlr2-/- mice consistent with a crucial role of TLR2 in UUO-induced renal fibrosis. UUO-induced macrophage infiltration and pro-fibrotic cytokine production in renal tissues were suppressed by tlr2 knockout. 5-MTP administration attenuated renal tissue fibrosis accompanied by reduction of macrophage infiltration and IL-6 and TGFβ levels. 5-MTP inhibits TLR2 upregulation and blocks TLR2-MyD88-TRAF6 signaling pathway in macrophages. Furthermore, 5-MTP blocked Pam3- and TGFβ1-induced phenotypic switch of NRK-49F to myofibroblasts and inhibited Pam3- and TGFβ1-induced signaling pathways in HPTECs and RAW264.7 cells.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;5-MTP is effective in protecting against UUO-induced renal interstitial fibrosis by blocking TLR2 and TGFβ signaling pathways.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;5-Methoxytryptophan (5-MTP) is a cellular metabolite with anti-inflammatory properties. Several recent reports indicate that 5-MTP protects against post-injury tissue fibrosis. It was unclear how 5-MTP controls tissue fibrosis. We postulated that 5-MTP attenuates renal interstitial fibrosis by blocking toll-like receptor 2 (TLR2) and transforming growth factor β (TGFβ) signaling pathways.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;In vivo experiments were carried out in a well-established unilateral ureteral obstruction (UUO) model in wild-type (WT) and tlr2-/- mice. The effect of 5-MTP on renal fibrosis was evaluated by pretreatment of WT UUO mice with intraperitoneal administration of 5-MTP. To determine whether 5-MTP attenuates fibrosis by inhibiting TLR2 and TGFβ signaling pathways, we evaluated the effect of 5-MTP on TLR2-induced fibroblast phenotypic switch in NRK-49F fibroblasts and TLR2 and TGFβ signaling pathways in human proximal tubular epithelial cells (HPTECs) and RAW264.7 macrophages stimulated with Pam3CSK4 (","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":" ","pages":"78-94"},"PeriodicalIF":3.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11801855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142949968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}