Pulmonary osteoclast-like cells in silica induced pulmonary fibrosis

Abstract

The pathophysiology of silicosis is poorly understood, limiting development of therapies for those who have been exposed to the respirable particle. We explored the mechanisms of silica-induced pulmonary fibrosis in a mouse model using multiple modalities including whole-lung single-nucleus RNA sequencing. These analyses revealed that in addition to pulmonary inflammation and fibrosis, intratracheal silica challenge induced osteoclast-like differentiation of alveolar macrophages and recruited monocytes, driven by induction of the osteoclastogenic cytokine, receptor activator of nuclear factor-κΒ ligand (RANKL) in pulmonary lymphocytes and alveolar type II cells. Furthermore, anti-RANKL monoclonal antibody treatment suppressed silica-induced osteoclast-like differentiation in the lung and attenuated silica-induced pulmonary fibrosis. We conclude that silica induces osteoclast-like differentiation of distinct recruited and tissue resident monocyte populations, leading to progressive lung injury, likely due to sustained elaboration of bone resorbing proteases and hydrochloric acid. Interrupting osteoclast-like differentiation may therefore constitute a promising avenue for moderating lung damage in silicosis.

Comparative transcriptomic analyses of peripheral blood mononuclear cells of patients with non-pneumonia and severe pneumonia at 1 year-Long-COVID-19

“…In a murine model study, silica-induced pulmonary fibrosis was observed to stimulate osteoclast-like differentiation, leading to the recruitment of monocytes to the tissue. This process of osteoclast-like differentiation of alveolar macrophages is mediated by the osteoclastogenic cytokine RANKL, which is released from pulmonary lymphocytes and type II alveolar epithelial cells [49]. Collectively, these studies suggest the potential involvement of this mechanism in the persistent effects observed post-viral infection.…”