Perivascular RELM⍺-positive synovial macrophages recruit monocytes at the onset of inflammatory arthritis

Barbora Schonfeldova ^1* Marah Chibwana ¹ Rebecca Gentek ² Kristina Zec ¹ Irina A Udalova ^1*

• ¹ Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom
• ² MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, Scotland, United Kingdom

Macrophages, monocytes and neutrophils are major types of myeloid cells involved in inflammatory diseases, such as rheumatoid arthritis (RA). Recent scRNA-seq studies identified a remarkable diversity of synovial macrophages but, with the exception of lining macrophages, their geographical location and specific roles remain largely unexplored. Here, we localised the RELM⍺-positive macrophages, predicted to produce high levels of monocyte-recruiting chemokines, to the synovial interstitium and more specifically, to the vicinity of interstitial blood vessels. Using complementary reporter mouse models, CCL2 mCherry to label CCL2-producing cells, and CCR2 CRE/mKate2 marking CCR2 expressing monocytes, we demonstrated that RELM⍺-positive perivascular macrophages secrete CCL2 assisting in the recruitment of monocytes predominantly to the synovial interstitium at the onset of antigen-induced arthritis. The inflamed synovial environment guides the differentiation of the recruited monocytes into tissue-resident macrophages, including but not limited to macrophages expressing VSIG4, a characteristic marker of lining macrophages. Thus, RELMa-positive macrophages orchestrate monocyte recruitment to the synovium during articular inflammation, contributing to a local replenishment of synovial lining macrophages.