Impaired interferon-γ signaling promotes the development of silicosis

Silicosis is caused by inhalation of crystalline silica dust particles and known as one of the most serious occupational diseases worldwide. However, little is known about intrinsic factors leading to disease susceptibility. Using single-cell sequencing of bronchoalveolar lavage fluid (BALF) of mine workers with silicosis and their co-workers who did not develop silicosis, we found that the impaired interferon (IFN)-γ signaling in myeloid cells was strongly associated with the occurrence of silicosis. In a murine model of silicosis, global or myeloid cell-specific deletion of interferon γ receptor (IFN-γR) markedly enhanced the silica crystals-induced pulmonary interstitial fibrosis and respiratory dysfunction in wild-type but not in mutant mice deficient in NOD-like receptor family pyrin domain-containing 3 (NLRP3). In vitro, IFN-γ priming of macrophages suppressed the crystalline silica-induced NLRP3 inflammasome activation partly by inducing the formation of spacious phagosomes with relatively reduced ratio of crystalline silica/phagosomal areas/volumes through the RAB20-dependent membrane trafficking pathway. RAB20 deficiency was associated with the elevated susceptibility to silicosis as well as the elevated NLRP3 inflammasome activation in a manner similar to the impaired IFN-γ signaling. Thus, these findings provide novel molecular insights into the intricate mechanisms underlying innate immunity-mediated host responses to environmental irritants, and shed light on the future development of novel therapies for the prevention of silicosis. Bronchoalveolar lavage fluid cells from 2 exposure and 3 silicosis patients were counted and loaded onto the 10x device (10x Genomics). Cells were processed the manufacturer’s protocol and sequenced on Illumina NextSeq sequencer. Sample demultiplexing, barcode processing, alignment, filtering, UMI counting, and aggregation of sequencing runs were performed using the Cell Ranger analysis pipeline (V4.1). >>>Submitter states that raw data are unavailable due to patient privacy concerns.<<<