ZC3H4 regulates infiltrating monocytes, attenuating pulmonary fibrosis through IL-10.

Silicosis is a pulmonary fibrosis-associated disease caused by the inhalation of large amounts of free silicon dioxide (SiO2) that mainly manifests as early inflammation and late pulmonary fibrosis. As macrophage precursors, monocytes accumulate in the lung during early inflammation, but their role in the development of silicosis is unclear. Single-cell sequencing (cell numbers = 25,002), Western blotting, quantitative real-time PCR, ELISA and cell functional experiments were used to explore the specific effects of monocytes on fibroblasts. The CRISPR/Cas9 system was used to specifically knock down ZC3H4, a novel member of the CCCH zinc finger protein family, and was combined with pharmacological methods to explore the mechanism by which ZC3H4 affects chemokine and cytokine secretion. The results indicated that (1) SiO2 induced an infiltrating phenotype in monocytes; (2) infiltrating monocytes inhibited the activation, viability and migration of fibroblasts by regulating IL-10 but not IL-8; and (3) SiO2 downregulated IL-10 via ZC3H4-induced autophagy. This study revealed that ZC3H4 regulated the secretion function of monocytes, which, in turn, inhibited fibroblast function in early inflammation through autophagy signaling, thereby reducing pulmonary fibrosis. These findings provide a new idea for the clinical treatment of silicosis.