{"title":"C3a-C3aR1-mediated interactions between fibroblast-like synoviocytes and macrophages promote the progression of rheumatoid arthritis.","authors":"Minglong Cai,Zhenyu Li,Xi Wen,Huizhi Jin,Yujing Li,Haibo Wu,Chao Yang,Zhu Chen","doi":"10.1002/art.43319","DOIUrl":null,"url":null,"abstract":"The inflammatory microenvironment in rheumatoid arthritis (RA) synovium is highly complex, comprising functional units known as cellular neighborhoods (CNs). However, how cell interactions within CNs shape the inflammatory microenvironment in RA remains unclear. Here, we utilized imaging mass cytometry (IMC) and single-cell RNA sequencing to dissect the CNs within RA synovium, uncovering critical cell-cell interactions and evaluating whether disrupting interaction signals could alleviate disease severity in collagen-induced arthritis (CIA) mouse model. Our findings revealed that CNs enriched with fibroblast-like synoviocytes (FLS) and immune cells, particularly FLS and macrophages, were more frequent in RA synovium compared to osteoarthritis (OA). Further single-cell RNA sequencing analysis showed that FLS specifically upregulated complement C3 while macrophages displayed high level of C3 receptor, C3aR1. Interestingly, C3a derived from FLS enhanced type I interferon response in macrophages, and blockade of the C3a-C3aR1 signaling reduced secretion of IFN-β in macrophages, thereby affecting FLS activation. Additionally, inhibition of C3a-C3aR1 signaling attenuated the severity of CIA mice with decreased immune cell infiltration, reduced FLS activation, and less bone destruction. Our study suggests that FLS promotes synovial inflammation via interaction with macrophages through a C3a-C3aR1 signaling-mediated positive feedback regulation. Thus, targeting C3a-C3aR1 signaling might provide a new therapeutic strategy for RA.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"93 1","pages":""},"PeriodicalIF":10.9000,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Arthritis & Rheumatology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/art.43319","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"RHEUMATOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
The inflammatory microenvironment in rheumatoid arthritis (RA) synovium is highly complex, comprising functional units known as cellular neighborhoods (CNs). However, how cell interactions within CNs shape the inflammatory microenvironment in RA remains unclear. Here, we utilized imaging mass cytometry (IMC) and single-cell RNA sequencing to dissect the CNs within RA synovium, uncovering critical cell-cell interactions and evaluating whether disrupting interaction signals could alleviate disease severity in collagen-induced arthritis (CIA) mouse model. Our findings revealed that CNs enriched with fibroblast-like synoviocytes (FLS) and immune cells, particularly FLS and macrophages, were more frequent in RA synovium compared to osteoarthritis (OA). Further single-cell RNA sequencing analysis showed that FLS specifically upregulated complement C3 while macrophages displayed high level of C3 receptor, C3aR1. Interestingly, C3a derived from FLS enhanced type I interferon response in macrophages, and blockade of the C3a-C3aR1 signaling reduced secretion of IFN-β in macrophages, thereby affecting FLS activation. Additionally, inhibition of C3a-C3aR1 signaling attenuated the severity of CIA mice with decreased immune cell infiltration, reduced FLS activation, and less bone destruction. Our study suggests that FLS promotes synovial inflammation via interaction with macrophages through a C3a-C3aR1 signaling-mediated positive feedback regulation. Thus, targeting C3a-C3aR1 signaling might provide a new therapeutic strategy for RA.
期刊介绍:
Arthritis & Rheumatology is the official journal of the American College of Rheumatology and focuses on the natural history, pathophysiology, treatment, and outcome of rheumatic diseases. It is a peer-reviewed publication that aims to provide the highest quality basic and clinical research in this field. The journal covers a wide range of investigative areas and also includes review articles, editorials, and educational material for researchers and clinicians. Being recognized as a leading research journal in rheumatology, Arthritis & Rheumatology serves the global community of rheumatology investigators and clinicians.