Abstract
Systemic sclerosis (SSc) is a chronic, multisystem orphan disease with a highly variable clinical course, high mortality rate, and a poorly understood complex pathogenesis. We have identified an important role for a subpopulation of monocytes and macrophages characterized by surface expression of the scavenger receptor macrophage receptor with collagenous structure (MARCO) in chronic inflammation and fibrosis in SSc and in preclinical disease models. We show that MARCO+ monocytes and macrophages accumulate in lesional skin and lung in topographic proximity to activated myofibroblasts in patients with SSc and in the bleomycin-induced mouse model of SSc. Short-term treatment of mice with a potentially novel nanoparticle, poly(lactic-co-glycolic) acid (PLG), which is composed of a carboxylated, FDA-approved, biodegradable polymer and modulates activation and trafficking of MARCO+ inflammatory monocytes, markedly attenuated bleomycin-induced skin and lung inflammation and fibrosis. Mechanistically, in isolated cells in culture, PLG nanoparticles inhibited TGF-dependent fibrotic responses in vitro. Thus, MARCO+ monocytes are potent effector cells of skin and lung fibrosis and can be therapeutically targeted in SSc using PLG nanoparticles.
Highlights
Systemic sclerosis (SSc) is a chronic disease with a poorly understood pathogenesis associated with inflammatory and fibrotic processes in the skin, lungs, and other organs [1–3]
macrophage receptor with collagenous structure (MARCO)+ monocytes and macrophages are enriched in the fibrotic skin and lungs of patients with SSc and mice with BLM-induced systemic fibrosis
In light of recent studies in which researchers have suggested a pathogenic role of persistently activated macrophages and monocytes in SSc [11], we first evaluated the expression of genes related to macrophage and monocyte activation by querying a publicly available single-cell transcriptome data set [25]
Summary
Systemic sclerosis (SSc) is a chronic disease with a poorly understood pathogenesis associated with inflammatory and fibrotic processes in the skin, lungs, and other organs [1–3]. GWAS have identified SSc-associated susceptibility loci [6–8], with the majority of genes involved in inflammation and innate immune responses, including TLR signaling and monocyte and macrophage activation and polarization [9, 10]. In the skin and lung, they play vital roles in wound healing and response to injury, and their dysregulated activation results in chronic inflammatory and fibrotic pathologies [14, 15]. In cooperation with TLRs, MARCO plays an important role in innate defenses against microbial pathogens and is implicated in persistent inflammation [17, 18]. To our knowledge, nothing was known regarding the role of MARCO+ inflammatory monocytes and macrophages in SSc
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