Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025080
Macrophages are key players in the pathology of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Existing studies and our previous studies have documented the role of CD206-positive M2 macrophages in the inflammatory process of AAV. Inflammasome activation is a critical pathway through which macrophages release inflammatory factors. In this study, we investigate the role of the inflammasome in macrophages in AAV and explore the role of CD206 in this process. We recruit newly diagnosed AAV patients and disease controls from our department. The expression and localization of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) and CD206 in the kidney are determined via immunofluorescence experiments. Myeloperoxidase (MPO)-ANCA immunoglobulin G (MPO-ANCA IgG) is purified from new-onset AAV patients with MPO-ANCA and used to treat lipopolysaccharide (LPS)-primed macrophages in vitro. Our findings reveal that NLRP3 expression is significantly elevated in the kidneys of active AAV patients, accompanied by increased cleaved caspase-1 and N-terminal gasdermin-D (GSDMD) levels in peripheral blood mononuclear cells (PBMCs). In vitro, MPO-ANCA IgG induces NLRP3 inflammasome activation and interleukin (IL)-1β production in macrophages, which is associated with increased MPO expression and JNK signaling pathway activation. Immunofluorescence analysis demonstrates partial colocalization of CD206 and NLRP3 in AAV kidneys. Furthermore, silencing of MRC1 gene, which encodes CD206, reduces inflammasome activation induced by MPO-ANCA IgG. In conclusion, our study provides evidence that MPO-ANCA IgG contributes to NLRP3 inflammasome activation and macrophage pyroptosis, with CD206 playing a critical role in this process. These findings elucidate the mechanisms underlying inflammation in AAV and suggest potential therapeutic targets.
Chinese Journal of Tissue Engineering Research•2026•DOI: 10.12307/2026.21307
BACKGROUND: With the acceleration of China's aging population, the number of osteoporosis patients has been increasing significantly. Recent advancements in genome-wide association studies and single-cell transcriptomic sequencing have empowered researchers to identify novel osteoporosis-associated genes through integrative multi-omics analyses. OBJECTIVE: To identify potential therapeutic targets for osteoporosis using summary data-based Mendelian randomization approaches that integrate genome-wide association studies and transcriptomic data from Asian and European populations. METHODS: By integrating cis-expression quantitative trait loci (cis-eQTL) and protein quantitative trait loci (pQTL) datasets from multiple tissues (blood and muscle-bone) with osteoporosis genome-wide association study data (the 2021 European population osteoporosis GWAS data from FinnGen and the 2020 East Asian population GWAS from Biobank Japan), we employed summary data-based Mendelian randomization (SMR) to identify osteoporosis-associated genes. Colocalization analysis, single-cell sequencing, and enrichment analysis were performed for further validation. All data were obtained from published studies or publicly available databases with ethical approval and informed consent. RESULTS AND CONCLUSION: SMR analysis identified 64 genes significantly associated with osteoporosis (after removing duplicates), among which HLA-DQA1, HLA-DQA2, HLA-DQB1, HLA-DQB2, and HLA-DRB5 were validated in both outcome datasets. Colocalization analysis provided evidence for HLA-DQA2 and HLA-DQB1 (posterior probability PPH4 > 0.8). Plasma levels of HLA-DQA2 were associated with reduced osteoporosis risk. Single-cell analysis revealed increased abundance of dendritic cells, B cells, macrophages, and neutrophils in the osteoporotic immune microenvironment. Enrichment analysis showed that identified genes were enriched in MHC class II antigen presentation pathway. This study identified several previously unreported osteoporosis-associated genes through bioinformatics integration of Asian and European GWAS data, warranting further exploration as potential therapeutic targets.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025080
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a life-threatening systemic autoimmune disease characterized by necrotizing small vessel vasculitis, with pauci-immune glomerulonephritis being the most severe manifestation. Macrophages, particularly CD206-positive M2 subsets, are central to AAV pathology, yet the mechanistic link between inflammasome activation and CD206 remains undefined. This study investigates NLRP3 inflammasome activity and pyroptosis in CD206+ macrophages exposed to myeloperoxidase (MPO)-ANCA immunoglobulin G (IgG). Newly diagnosed AAV patients and disease controls were recruited; renal NLRP3 and CD206 expression were assessed by immunofluorescence. MPO-ANCA IgG was purified from new-onset AAV patients and applied to lipopolysaccharide (LPS)-primed macrophages in vitro. Results demonstrate significantly elevated NLRP3 expression in active AAV kidneys, accompanied by increased cleaved caspase-1 and N-terminal gasdermin-D (GSDMD) in peripheral blood mononuclear cells (PBMCs). In vitro, MPO-ANCA IgG induces NLRP3 inflammasome activation and interleukin (IL)-1β production, associated with increased MPO expression and JNK signaling pathway activation. Immunofluorescence reveals partial colocalization of CD206 and NLRP3 in AAV kidneys. Silencing of MRC1, encoding CD206, reduces inflammasome activation induced by MPO-ANCA IgG. These findings establish that MPO-ANCA IgG contributes to NLRP3 inflammasome activation and macrophage pyroptosis, with CD206 playing a critical role. The study elucidates mechanisms underlying AAV inflammation and suggests potential therapeutic targets.