Macrophages in Systemic Sclerosis: Novel Insights and Therapeutic Implications.

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.

Mycophenolate Mofetil Treatment of Systemic Sclerosis Reduces Myeloid Cell Numbers and Attenuates the Inflammatory Gene Signature in Skin.

Fewer than half of patients with systemic sclerosis demonstrate modified Rodnan skin score improvement during mycophenolate mofetil (MMF) treatment. To understand the molecular basis for this observation, we extended our prior studies and characterized molecular and cellular changes in skin biopsies from subjects with systemic sclerosis treated with MMF. Eleven subjects completed ≥24 months of MMF therapy. Two distinct skin gene expression trajectories were observed across six of these subjects. Three of the six subjects showed attenuation of the inflammatory signature by 24 months, paralleling reductions in CCL2 mRNA expression in skin and reduced numbers of macrophages and myeloid dendritic cells in skin biopsies. MMF cessation at 24 months resulted in an increased inflammatory score, increased CCL2 mRNA and protein levels, modified Rodnan skin score rebound, and increased numbers of skin myeloid cells in these subjects. In contrast, three other subjects remained on MMF >24 months and showed a persistent decrease in inflammatory score, decreasing or stable modified Rodnan skin score, CCL2 mRNA reductions, sera CCL2 protein levels trending downward, reduction in monocyte migration, and no increase in skin myeloid cell numbers. These data summarize molecular changes during MMF therapy that suggest reduction of innate immune cell numbers, possibly by attenuating expression of chemokines, including CCL2.