Deciphering Complement-Dependent Macrophage Phenotypes in Human Autoimmune Arthritis

University Of Colorado Denver, Aurora CO

Investigators

Abstract

Project Summary Despite advances in the treatment of rheumatoid arthritis (RA) with biologic therapies, a substantial number of patients do not have adequate disease control and specifically fail commonly used treatments. This suggests an unmet need for new and personalized therapies for RA. Current studies have found that tissue macrophages in the synovium of patients with RA can interact with complement factors, a complex innate immune system that plays critical roles in rheumatic diseases by promoting inflammation and disrupting tissue homeostasis. Specifically, our recent work has revealed that the MERTK+ tissue macrophages are expanded in lymphocyte- low synovial RA tissues and display multiple complement factors, including the receptors C5AR1 and C3AR1. In particular, we observed that a new MERTK+ macrophage subtype we refer to as the MERTK+HBEGF+ tissue macrophage is marked by high C5AR1, TNF, and CXCL2 and CXCL3 expression. Through experimental validation, we further found that the addition of an inhibitor of C5aR1 suppressed the inflammatory and interferon response pathways while upregulated tissue protective phagocytic programs. Thus, we hypothesize that modulating specific complement pathways in the MERTK+ tissue macrophages could improve homeostatic synovial macrophage function in this apparently dysregulated subtype, and further relieve deleterious pro- inflammatory cytokine and other mediator signals propagated by neighboring synovial fibroblasts. Herein, we propose to determine the complement component signatures and responses for the MERTK+HBEGF+ tissue macrophages (Aim 1), define how complement pathway crosstalk impacts synovial macrophages and fibroblasts (Aim 2), and evaluate how macrophage phagocytic function is enhance by complement pathway modulation (Aim 3). Together with our established synovial RA tissue cohort, developed single-cell omics integrative methods, and ex vivo and in vivo experimental assay and macrophage-fibroblast co-cultured system in place, these aims will provide novel insights into a new complement pathway-modulated macrophage target population that upon rewiring may restore tissue homeostasis and suppress tissue inflammation (Significance). Our proposed work will also generate new computational-experimental integrative methods and single-cell spatial transcriptomic approaches that are urgently needed for translational research toward personalized treatments of RA and other autoimmune diseases that are revealed through emerging single-cell technologies (Innovation).