Necroptosis in pulmonary macrophages promotes silica-induced inflammation and interstitial fibrosis in mice.

Silicosis is a disease characterized by extensive lung nodules and fibrosis caused by the prolonged inhalation of silica in occupational settings. However, the molecular mechanism of silicosis development is complex and not fully understood. Furthermore, the role of necroptosis, a death receptor-mediated and caspase-independent mode of inflammatory cell death, is not well understood in silicosis. Here, we demonstrate that the necroptotic signaling pathway of macrophages is significantly activated in the lungs of silicosis mouse models. Meanwhile, increased M1 macrophage infiltration and up-regulation of pro-inflammatory cytokines (TNF-α, IL-6) were observed in our silicosis model. Notably, the expression of the pro-fibrotic factor, TGF-β1, and fibrosis biomarkers α-SMA and collagen I were also unregulated; however, these phenomena were recovered by Nec-1, an inhibitor specific for RIP1 kinase-dependent necroptosis. We conclude that macrophage-mediated necroptosis promotes the progression of silicosis by enhancing lung inflammatory responses and fibrogenesis in a mouse model of silicosis. These findings provide new insights for drug discovery and clinical treatment of silicosis.