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. Competing Interest Statement X-D. Sun is an inventor on a patent application covering TR-Ab19 and holds a potential translation interest in its future clinical development; all other authors declare they have no competing interests.