Macrophages coordinated with IL-18 receptor expressing pathogenic innate lymphoid cells drive silicosis progression
Yichuan You1, Zhuozhang Yin1, Chenhao Sun1
1Department of Occupational and Environmental Health, School of Public Health, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China; Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention (China Medical University), Ministry of Education, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China.
Abstract:
Prolonged exposure to crystalline silica (CS) induces silicosis characterized as pulmonary fibrosis. Innate and adaptive immune responses are orchestrated in silicosis pathogenesis. Herein, we delineated the specific role of innate immunity, utilizing recombination-activating gene 1 (Rag1)-knockout mice, which are deficient in adaptive immunity. Unexpectedly, CS-exposure drove more severe lung fibrosis in the Rag1-/- mice than wild-type counterparts, due to a hyperactive NLRP3/Caspase-1 signaling in lung macrophages and a concomitant expansion of lung innate lymphoid cells (ILCs). Specifically, group 1 ILCs (ILC1s) and group 3 ILCs (ILC3s) expanded, and the ILC3s/ILC1s ratio lifted with silicosis progression. Depleting experiment confirmed that ILCs drive silicosis in Rag1-/- mice. Specifically, interleukin-18 receptor α (IL-18Rα) marked pathogenic ILCs with the characteristics of multi-cytokine productions, high proliferation, and potent activation status. Lung macrophages regulated the pathogenic function of IL-18Rα+ ILCs, promoting silicosis in Rag1-/- mice. NLRP3 and IL-18 exerted distinct effects on IL-18Rα+ ILCs that both NLRP3 and IL-18 similarly modulated ILC1s, whereas IL-18 affected cytokine production by ILC3s without influencing their emergence in the lungs. Our study extended the knowledge about how the innate immune response drives CS-induced fibrosis and provided intervention targets for silicosis.
