Journal of Innate Immunity最新文献

{"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":"https://doi.org/10.1159/000545139","url":null,"abstract":"<p><strong>Background: </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 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 FHR-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":"1-24"},"PeriodicalIF":4.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Common haplotypes within the chromosome 1q31.3 region determine systemic concentrations of the entire complement factor H protein family.","authors":"Bert R J Veuskens, Mara Van Rossum, Emi Cattenstart, Mieke C Brouwer, Gerard van Mierlo, Judy Geissler, Karin van Leeuwen, Jin Liu, Robert A Anstadt, Burt T Richards, Gregory S Hageman, Taco W Kuijpers, Erik J M Toonen, Richard B Pouw","doi":"10.1159/000545342","DOIUrl":"https://doi.org/10.1159/000545342","url":null,"abstract":"<p><p>The alternative pathway (AP) of complement activation is consistently active, keeping the complement system primed for immediate response. This constant \"tick-over\" mechanism is regulated by the factor H (FH) protein family, which encompasses seven highly related proteins: FH, FHL-1, and five FH-related (FHR-1 to -5) proteins. The current model is that FHR proteins compete with FH and FHL-1 to fine-tune their activities, though their exact role remains unclear. Genetic studies of this complex locus and measurement of individual protein members have revealed distinct haplotypes associating with a wide range of human diseases; highlighting the significant role of this protein family in complement regulation. However, a full assessment of systemic protein concentration of the complete FH protein family, accounting for the known genetic heterogeneity within populations, is still lacking. In this report, utilizing specific FH protein family ELISAs, we demonstrate the impact of common haplotypes within the chromosome 1q31.3 region on the relative abundance of all FH protein family members. These common haplotypes give rise to classifiable protein expression patterns, establishing distinct ratios between FH, FHL-1 and the FHRs. The obtained reference intervals and genetic determinants supports further investigations into this protein family in both health and disease and serves as a benchmark for future studies.</p>","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":" ","pages":"1-26"},"PeriodicalIF":4.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNA Viruses, Toll-Like Receptors, and Cytokines: The Perfect Storm?","authors":"Sophia K Stegeman, Olena Kourko, Heather Amsden, Isabella E Pellizzari Delano, John E Mamatis, Madison Roth, Che C Colpitts, Katrina Gee","doi":"10.1159/000543608","DOIUrl":"10.1159/000543608","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;The interactions between viruses and the host immune response are nuanced and intricate. The cytokine response arguably plays a central role in dictating the outcome of virus infection, balancing inflammation, and healing, which is crucial to resolving infection without destructive immunopathologies.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Summary: &lt;/strong&gt;Early innate immune responses are key to the generation of a beneficial or detrimental immune response. These initial responses are regulated by a plethora of surface bound, endosomal, and cytoplasmic innate immune receptors known as pattern recognition receptors. Of these, the Toll-like receptors (TLRs) play an important role in the induction of cytokines during virus infection. Recognizing pathogen-associated molecular patterns (PAMPs) such as viral proteins and/or nucleotide sequences, the TLRs act as sentinels for the initiation and propagation of immune responses.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Key messages: &lt;/strong&gt;TLRs are important receptors for initiating the innate response to single-stranded RNA (ssRNA) viruses like influenza A virus (IAV), severe acute respiratory syndrome coronavirus-1 (SARS-CoV-1), SARS-CoV-2, Middle East respiratory syndrome coronavirus, dengue virus, and Ebola virus. Infection with these viruses is also associated with aberrant expression of proinflammatory cytokines that contribute to a harmful cytokine storm response. Herein we discuss the connections between these ssRNA viruses, cytokine storm, and the roles of TLRs.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;The interactions between viruses and the host immune response are nuanced and intricate. The cytokine response arguably plays a central role in dictating the outcome of virus infection, balancing inflammation, and healing, which is crucial to resolving infection without destructive immunopathologies.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Summary: &lt;/strong&gt;Early innate immune responses are key to the generation of a beneficial or detrimental immune response. These initial responses are regulated by a plethora of surface bound, endosomal, and cytoplasmic innate immune receptors known as pattern recognition receptors. Of these, the Toll-like receptors (TLRs) play an important role in the induction of cytokines during virus infection. Recognizing pathogen-associated molecular patterns (PAMPs) such as viral proteins and/or nucleotide sequences, the TLRs act as sentinels for the initiation and propagation of immune responses.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Key messages: &lt;/strong&gt;TLRs are important receptors for initiating the innate response to single-stranded RNA (ssRNA) viruses like influenza A virus (IAV), severe acute respiratory syndrome coronavirus-1 (SARS-CoV-1), SARS-CoV-2, Middle East respiratory syndrome coronavirus, dengue virus, and Ebola virus. Infection with these viruses is also associated with aberrant expression of proinflammatory cytokines that contribute to a harmful cytokine storm response. Herein we discuss the connections between these ssRNA vir","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":" ","pages":"126-153"},"PeriodicalIF":4.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11845175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006758","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":"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":"&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;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.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;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.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;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.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;Our findings suggest a relationship between capsule type, complement resistance, and host virulence in A. baumannii.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;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.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;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.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;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":4.7,"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":"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":"&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;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.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;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.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;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.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;CAPN1 promotes PAK-induced ALI by inhibiting the autophagy-lysosome pathway by targeting TFEB.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;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.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;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.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;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":4.7,"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":"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":4.7,"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}

{"title":"Exploring the Role of Macrophages and Their Associated Structures in Rheumatoid Arthritis.","authors":"Xin Tian, Jingjing Chen, Yujie Hong, Yang Cao, Jing Xiao, Yan Zhu","doi":"10.1159/000543444","DOIUrl":"10.1159/000543444","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Rheumatoid arthritis (RA) is a chronic, invasive autoimmune disease characterized by symmetrical polyarthritis involving synovial inflammation. Epidemiological studies indicate that the incidence of RA continues to rise, yet the pathogenesis of this disease remains not fully understood. A significant infiltration of macrophages is observed in the synovium of RA patients. It can be inferred that macrophages likely play a crucial role in the onset and progression of RA.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Summary: &lt;/strong&gt;This review aims to summarize the research progress on the mechanisms by which macrophages and their associated structures contribute to RA, as well as potential therapeutic approaches, aiming to provide new insights into the study of RA pathogenesis and its clinical treatment.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Key messages: &lt;/strong&gt;During the course of RA, besides the inherent roles of macrophages, these cells respond to microenvironmental changes such as pathogen invasion or tissue damage by undergoing polarization, pyroptosis, or forming macrophage extracellular traps (METs), all of which influence inflammatory responses and immune homeostasis, thereby mediating the occurrence and development of RA. Additionally, macrophages secrete exosomes, which participate in intercellular communication and signal transduction processes, thus contributing to the progression of RA. Therefore, it is critical to elucidate how macrophages and their related structures function in RA.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Rheumatoid arthritis (RA) is a chronic, invasive autoimmune disease characterized by symmetrical polyarthritis involving synovial inflammation. Epidemiological studies indicate that the incidence of RA continues to rise, yet the pathogenesis of this disease remains not fully understood. A significant infiltration of macrophages is observed in the synovium of RA patients. It can be inferred that macrophages likely play a crucial role in the onset and progression of RA.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Summary: &lt;/strong&gt;This review aims to summarize the research progress on the mechanisms by which macrophages and their associated structures contribute to RA, as well as potential therapeutic approaches, aiming to provide new insights into the study of RA pathogenesis and its clinical treatment.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Key messages: &lt;/strong&gt;During the course of RA, besides the inherent roles of macrophages, these cells respond to microenvironmental changes such as pathogen invasion or tissue damage by undergoing polarization, pyroptosis, or forming macrophage extracellular traps (METs), all of which influence inflammatory responses and immune homeostasis, thereby mediating the occurrence and development of RA. Additionally, macrophages secrete exosomes, which participate in intercellular communication and signal transduction processes, thus contributing to the progression of RA. Therefore, it is critical to elucidate how macrophages and their related structures function ","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":"17 1","pages":"95-111"},"PeriodicalIF":4.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11820663/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143408702","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":"Liver X Receptors and Inflammatory-Induced C/EBPβ Selectively Cooperate to Control CD38 Transcription.","authors":"Estibaliz Glaría, Pol Rodríguez Martínez, Joan Font-Díaz, Juan Vladimir De la Rosa, Antonio Castrillo, Dylan J Crawshaw, Jose Manuel Vidal Taboada, Josep Saura, Jonathan Matalonga, Eduardo Nunes Chini, Carme Caelles, Annabel F Valledor","doi":"10.1159/000543274","DOIUrl":"10.1159/000543274","url":null,"abstract":"<p><strong>Introduction: </strong>Macrophages abundantly express liver X receptors (LXRs), which are ligand-dependent transcription factors and sensors of several cholesterol metabolites. In response to agonists, LXRs promote the expression of key lipid homeostasis regulators. Cross talk between LXRs and inflammatory signals exists in a cell type- and gene-specific manner. A common feature in the macrophage response to inflammatory mediators is the induction of CCAAT/enhancer-binding protein beta (C/EBPβ), a master transcriptional regulator and lineage-determining transcription factor in monocytes/macrophages.</p><p><strong>Methods: </strong>Quantitative real-time PCR in control and C/EBPβ-deficient macrophages was used to explore the role of C/EBPβ in the cross talk between inflammatory mediators and the macrophage response to pharmacological LXR activation. The functional interaction between C/EBPβ and LXRs on selected genomic regions was further characterized by chromatin-immunoprecipitation (ChIP) and gene reporter studies.</p><p><strong>Results: </strong>Whereas inflammatory signaling repressed several LXR-regulated genes involved in lipid metabolism, these effects were conserved after deletion of C/EBPβ. In contrast, inflammatory mediators and LXRs synergistically induced the expression of the multifunctional protein CD38 in a C/EBPβ-dependent manner. C/EBPβ and LXRs bound to several regions with enhancer activity upstream and within the mouse Cd38 gene and their functional cooperation in macrophages required intact binding sites for LXR and C/EBPβ.</p><p><strong>Conclusion: </strong>This study reveals positive cross talk between C/EBPβ and LXRs during the macrophage inflammatory response, which selectively impacts CD38 expression.</p>","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":" ","pages":"56-77"},"PeriodicalIF":4.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11781815/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142864434","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":"Human Blood Non-Classical/Classical Monocyte Cells Are Heterogeneously Presented in Severe COVID-19 and Correlate with Disease Activity.","authors":"Danhong Zhou, Yu Shen, Suxian Jing, Dong Qiu, Yang Wang, Qiuxia Qu, Cheng Chen","doi":"10.1159/000542652","DOIUrl":"10.1159/000542652","url":null,"abstract":"<p><strong>Introduction: </strong>COVID-19 is highly heterogeneous, ranging from cases with mild disease with an almost asymptomatic carrier to severe cases, in which the disease evolves rapidly. A better understanding of monocyte response during SARS-CoV-2 infection would highlight potential biomarkers and establish other possible approaches for severe cases.</p><p><strong>Methods: </strong>The study group consisted of 32 COVID-19 patients and 18 health controls from June 2023 to March 2024. The COVID-19 patients were further classified as mild and severe illnesses based on World Health Organization (WHO) criteria. For flow cytometric analysis, 50 µL of peripheral blood and 1 µL of specific monoclonal antibodies were added to each cytometric tube for surface marker detection.</p><p><strong>Results: </strong>Here, the promising finding was that the blood non-classical/classical monocyte (NC/CL) subset was skewed toward NChighCLlow and NClowCLhigh clusters among the severe COVID-19 patients. The NChighCLlow cluster in severe COVID-19 displayed a distinct clinical phenotype, implying a higher 7-day disease progression rate (p = 0.019) and a worse 28-day survival (p = 0.026). Moreover, the secretion of IL-1β and IFN-γ was primarily attributed to CL subset in monocytes, while IL-6 was secreted mainly by NC subset.</p><p><strong>Conclusion: </strong>As supported, regarding cytokine profile in context of SARS-CoV-2 infection, it was identified that circulating NC cells are proinflammatory cells most related to regulatory cells, while CL subset displayed an effective capacity to virus. These findings have implications toward optimizing evaluation in severe COVID-19, and developing strategies that target altered balance of NC/CL cell subsets.</p>","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":" ","pages":"1-9"},"PeriodicalIF":4.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11666265/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142716142","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":"Streptococcus pyogenes Activates Human Platelets via Streptolysin S-Mediated Calcium Ion Influx.","authors":"Anna Riegner, Kristin Jahn, Jan Wesche, Thomas Thiele, Nikolai Siemens","doi":"10.1159/000544951","DOIUrl":"10.1159/000544951","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;Streptococcus pyogenes (group A streptococcus, GAS) is an exclusively human pathogen. It causes a wide spectrum of diseases, ranging from mild infections such as pharyngitis to severe life-threatening conditions such as streptococcal toxic shock syndrome (STSS). Thrombocytopenia is a common feature of STSS and is associated with severe outcome. GAS produce a plethora of virulence factors, including streptolysin S (SLS), which has lytic as well as immunomodulatory properties. However, its role in platelet activation remains unclear.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Washed human platelets were infected with GAS wild-type and SLS-deficient mutant (ΔsagA) strains. Platelet activation was assessed by measuring degranulation (CD62P expression). The role of calcium influx and the involvement of purinergic type 2 receptors (P2R) in platelet activation by GAS were assessed using chemical antagonists and calcium chelators.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;GAS activate human platelets via SLS-mediated calcium influx, marked by increased surface expression of CD62P. IVIG treatment improved platelet viability in wild-type infections but failed to prevent SLS-mediated activation. Blocking of P2 receptors via suramin or NF449 as well as the use of calcium chelators reduced SLS-mediated platelet activation.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;This study identified SLS as an M-protein and consequently a serotype-independent activator of human platelets. While IVIG partially improved platelet viability in GAS infections, its inability to prevent excessive platelet activation underscores the need for additional treatment options in severe GAS infections.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;Streptococcus pyogenes (group A streptococcus, GAS) is an exclusively human pathogen. It causes a wide spectrum of diseases, ranging from mild infections such as pharyngitis to severe life-threatening conditions such as streptococcal toxic shock syndrome (STSS). Thrombocytopenia is a common feature of STSS and is associated with severe outcome. GAS produce a plethora of virulence factors, including streptolysin S (SLS), which has lytic as well as immunomodulatory properties. However, its role in platelet activation remains unclear.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Washed human platelets were infected with GAS wild-type and SLS-deficient mutant (ΔsagA) strains. Platelet activation was assessed by measuring degranulation (CD62P expression). The role of calcium influx and the involvement of purinergic type 2 receptors (P2R) in platelet activation by GAS were assessed using chemical antagonists and calcium chelators.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;GAS activate human platelets via SLS-mediated calcium influx, marked by increased surface expression of CD62P. IVIG treatment improved platelet viability in wild-type infections but failed to prevent SLS-mediated activation. Blocking of P2 receptors via suramin or NF449 as well as the use of calcium chelators","PeriodicalId":16113,"journal":{"name":"Journal of Innate Immunity","volume":" ","pages":"198-210"},"PeriodicalIF":4.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11952823/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542285","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}