Monocytes and Macrophages in Systemic Sclerosis: Profibrotic Functions and Emerging IRF8-Dependent Regulation

Systemic sclerosis (SSc) is a clinically distinct autoimmune connective tissue disease characterized by immune dysregulation, vasculopathy, and excessive fibrosis. Monocytes and macrophages (Mo/Mφ) contribute to these processes through heterogeneous tissue-dependent states that are not sufficiently represented by a binary M1/M2 framework. Human blood and tissue studies, including recent single-cell and spatial analyses, have repeatedly identified hybrid activated monocytes and monocyte-derived macrophages associated with skin or lung involvement. Classical studies have established several Mo/Mφ-linked profibrotic mechanisms in SSc, including the secretion of cytokines, chemokines, and growth factors; organization of macrophage–stromal signaling niches; production and remodeling of the extracellular matrix; monocyte plasticity toward vascular and mesenchymal lineages; and defective efferocytosis and resolution. Upstream of these effector outputs, transcriptional, epigenetic, and metabolic programs are increasingly recognized as key regulators. As one example relevant to Mo/Mφ differentiation, we have focused on interferon regulatory factor 8 (IRF8), showing reduced IRF8 expression in circulating monocytes from diffuse cutaneous SSc associated with skin fibrosis. Experimentally, IRF8 silencing and myeloid-specific Irf8 deletion promote profibrotic features; however, the functional direction of IRF8 across lineages and tissues remains incompletely defined. Several established and emerging SSc therapeutic strategies are thought to act at least in part on the Mo/Mφ compartment, although direct SSc-derived cellular evidence remains limited. This review synthesizes Mo/Mφ diversity and effector functions in SSc and outlines therapeutic implications, highlighting the need for lineage- and tissue-resolved profiling of Mo/Mφ and mechanistic dissection of their upstream programs as a foundation for rational therapeutic strategies in SSc.