Macrophages in Systemic Sclerosis: Novel Insights and Therapeutic Implications

Abstract

Purpose of review: Macrophages play key roles in tissue homeostasis and immune surveillance, mobilizing immune activation in response to microbial invasion and promoting wound healing to repair damaged tissue. However, failure to resolve macrophage activation can lead to chronic inflammation and fibrosis, and ultimately to pathology. Activated macrophages have been implicated in the pathogenesis of systemic sclerosis (SSc), although the triggers that induce immune activation in SSc and the signaling pathways that underlie aberrant macrophage activation remain unknown.

Recent findings: Macrophages are implicated in fibrotic activation in SSc. Targeted therapeutic interventions directed against SSc macrophages may ameliorate inflammation and fibrosis. While current studies have begun to elucidate the role of macrophages in disease initiation and progression, further work is needed to address macrophage subset heterogeneity within and among SSc end-target tissues to determine the disparate functions mediated by these subsets and to identify additional targets for therapeutic intervention.

Keywords: Fibrosis; Innate immunity; Macrophages; Monocytes; Scleroderma; Systemic sclerosis.

Fig. 1

Model of SSc pathogenesis, highlighting monocyte/macrophage involvement and therapeutic interventions. (1) Genetic susceptibility combined with an environmental insult provides a signal to initiate SSc pathogenesis. (2) This triggers innate immune and inflammatory activation, downstream Wnt, JAK/STAT, and Hedgehog signaling activation, leading to the increased expression of fibrotic mediators, including TGF-β and IL-6. (3) Monocytes are recruited to the end-target tissue, resulting in pro-fibrotic macrophage activation. (4) Activated macrophages release pro-fibrotic cytokines, growth factors, and inflammatory mediators, resulting (5) in the differentiation of fibroblasts from adipocytes, fibroblast activation, and activation/recruitment of myofibroblasts. Persistent activation and inflammation cause sustained fibrosis, which is exacerbated by TGF-β-mediated stimulation of pro-fibrotic PDGF production. (6) Continued proliferation leads to collagen deposition, extracellular matrix production, and chronic fibrosis. Therapies that modulate fibrosis and macrophage activation include as follows: pirfenidone (PFD), an anti-fibrotic therapy that inhibits hedgehog signaling and TGF-β; C-82, a topical inhibitor of β-catenin signaling; mycophenolate mofetil (MMF), which inhibits lymphocyte proliferation; fresolimumab, an anti-TGF-β antibody that inhibits all three isoforms of TGF-β; and nintedanib (NTD), a small-molecule tyrosine kinase inhibitor that targets angiogenic factor receptors