Macrophages in the synovial lining niche initiate neutrophil recruitment and articular inflammation

Using antigen-induced arthritis (AIA) model, Zec et al. show that synovial lining macrophages undergo IRF5-dependent activation and produce CXCL1 as a result of antigen recognition. Consequently, neutrophils are preferentially recruited in the synovial lining niche at the onset of inflammation. The first immune-activating changes within joint resident cells that lead to pathogenic leukocyte recruitment during articular inflammation remain largely unknown. In this study, we employ state-of-the-art confocal microscopy and image analysis in a systemic, whole-organ, and quantitative way to present evidence that synovial inflammation begins with the activation of lining macrophages. We show that lining, but not sublining macrophages phagocytose immune complexes containing the model antigen. Using the antigen-induced arthritis (AIA) model, we demonstrate that on recognition of antigen-antibody complexes, lining macrophages undergo significant activation, which is dependent on interferon regulatory factor 5 (IRF5), and produce chemokines, most notably CXCL1. Consequently, at the onset of inflammation, neutrophils are preferentially recruited in the vicinity of antigen-laden macrophages in the synovial lining niche. As inflammation progresses, neutrophils disperse across the whole synovium and form swarms in synovial sublining during resolution. Our study alters the paradigm of lining macrophages as immunosuppressive cells to important instigators of synovial inflammation.

Automated summary

Using the AIA model, Zec et al. demonstrate that synovial lining macrophages are activated by IRF5 and secrete CXCL1 upon antigen recognition, leading to preferential recruitment of neutrophils in the synovial lining niche at the onset of inflammation. This study utilizes advanced microscopy techniques to reveal that synovial inflammation is initiated by the activation of lining macrophages, challenging the previously held view of these cells as immunosuppressive. The findings highlight the importance of synovial macrophages in instigating synovial inflammation and recruiting immune cells.