TREM2 agonist antibody rebuilds the resident synovial macrophage lining barrier in rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) can be viewed as a disease of barrier failure, in which CX3CR1+/TREM2+ synovial tissue-resident macrophages that form the lining barrier over cartilage and bone become fragmented and disorganized. However, how to therapeutically rebuild this barrier--and how macrophage states transition during repair--remain unclear. We engineered TR-Ab19, a mouse-selective agonistic antibody against TREM2, as a precision tool to initiate and interrogate barrier repair in vivo. TR-Ab19 engages TREM2-linked downstream signaling and redirects synovial macrophages from Clec4d+ inflammatory/proliferative programs toward TREM2+CX3CR1+Aqp1+ barrier-like states, thereby rebuilding the lining barrier. Across collagen-induced arthritis (CIA) and serum-transfer arthritis (STA) models, TR-Ab19 reduces synovitis, preserves cartilage and bone microarchitecture, limits osteoclastogenesis, and attenuates systemic cytokines and B-cell abnormalities. Single-cell RNA-seq with trajectory and cell-cell communication analyses reveal a TREM2-dependent shift toward a barrier-dominant macrophage ecosystem. Together, these findings establish antibody-mediated reprogramming of resident synovial macrophages as a barrier-centered strategy for RA and provide a framework for instructing macrophage niches in chronic inflammation.