Impaired interferon-γ signaling promotes the development of silicosis

Zhouyangfan Peng; Mingwu Duan; Yiting Tang; Jianfeng Wu; Kai Zhao; Yanjun Zhong; Zhihui He; Jie Meng; Fangping Chen; Xianzhong Xiao; Haichao Wang; Timothy R Billiar; Ben Lu; Fang Liang

doi:10.1016/j.isci.2022.104647

Impaired interferon-γ signaling promotes the development of silicosis

iScience. 2022 Jun 19;25(7):104647. doi: 10.1016/j.isci.2022.104647. eCollection 2022 Jul 15.

Authors

Zhouyangfan Peng¹, Mingwu Duan¹, Yiting Tang², Jianfeng Wu³, Kai Zhao¹, Yanjun Zhong⁴, Zhihui He¹, Jie Meng^{5

6}, Fangping Chen¹, Xianzhong Xiao^{7

8}, Haichao Wang⁹, Timothy R Billiar¹⁰, Ben Lu^{1

7

8}, Fang Liang¹

Affiliations

¹ Department of Hematology and Critical Care Medicine, The Third Xiangya Hospital, Central South University, Changsha 410000, P.R. China.
² Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan Province 410000, P.R. China.
³ State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
⁴ ICU Center, The Second Xiangya Hospital, Central South University, Changsha 410000, P.R. China.
⁵ Department of Respiratory Diseases and Critical Care Illness, The 3Road Xiangya Hospital, Central South University, Changsha 410000, P.R. China.
⁶ Hunan Key Laboratory of Organ Fibrosis, Xiangya Hospital, Central South University, Changsha 410000, P.R. China.
⁷ Key Laboratory of Sepsis Translational Medicine of Hunan, Central South University, Changsha, Hunan Province 410000, P.R. China.
⁸ Department of Pathophysiology, School of Basic Medical Science, Central South University, Changsha, Hunan Province 410000, P.R. China.
⁹ The Feinstein Institute for Medical Research, Northwell Health, 350 Community Drive, Manhasset, NY 11030, USA.
¹⁰ Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.

Abstract

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. Single-cell sequencing of bronchoalveolar lavage fluid cells of mine workers with silicosis and their co-workers who did not develop silicosis revealed that the impaired interferon (IFN)-γ signaling in myeloid cells was strongly associated with the occurrence of silicosis. Global or myeloid cell-specific deletion of interferon γ receptor (IFN-γR) markedly enhanced the crystalline silica-induced pulmonary injury in wild-type but not in NLRP3 deficient mice. 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 to resistant crystalline silica-induced lysosomal membrane damage. Thus, these findings provide molecular insights into the intricate mechanisms underlying innate immunity-mediated host responses to environmental irritants.

Keywords: Molecular biology; Molecular physiology; Physiology.