Macrophages and the Tissue Repair Circuit: Homeostasis, Autoimmune Diseases, and Resolution-Based Therapeutic Strategies

Tissue repair and regeneration are highly coordinated multicellular processes that rely on the active resolution of inflammation rather than merely its passive cessation. Reciprocal orchestration among stromal, innate, and adaptive immune systems is key to maintaining or restoring tissue homeostasis from pathological perturbations. Macrophages serve as a central nexus of these responses, exhibiting dynamic functional plasticity that extends beyond dichotomous M1/M2 classification. This review explores the evolving, context-dependent roles of macrophages in restoring tissue homeostasis, with a particular focus on efferocytosis and subsequent metabolic rewiring as key drivers of inflammation resolution. Furthermore, we highlight the bi-directional crosstalk between macrophages and heterogeneous fibroblast populations. While these stromal-myeloid interactions are essential for transient matrix remodeling and physiological healing, their sustained activation under inflammatory conditions drives maladaptive repair and fibrotic remodeling. We discuss how the defects and dysregulation of these cellular circuits contribute to the pathogenesis of autoimmune disorders, as exemplified by recent findings in rheumatoid arthritis (RA), systemic sclerosis (SSc), and inflammatory bowel disease (IBD). Finally, we evaluate emerging “resolution therapies” that aim to harness endogenous tissue-reparative programs of macrophages therapeutically to treat autoimmune diseases, including the application of specialized pro-resolving mediators (SPMs) and macrophage reprogramming strategies.