Stage-dependent activation of the circulating AIM2–caspase-1–GSDMD axis in silicosis: a cross-sectional study

Abstract

Silicosis is a progressive occupational lung disease caused by long-term inhalation of crystalline silica, in which persistent inflammation contributes to lung injury and fibrotic remodeling. Experimental studies suggest that DNA-sensing pathways involving AIM2 may be engaged after silica exposure. We conducted a cross-sectional study of 187 male workers, including unexposed administrative controls (n = 57), dust-exposed workers without silicosis (n = 57), and patients with radiographically confirmed silicosis stage I (n = 37), stage II (n = 20), or stage III (n = 16). Serum cell-free double-stranded DNA (dsDNA) was quantified by fluorometry. AIM2, ASC, caspase-1, and gasdermin D (GSDMD; full-length and cleaved fragment) were assessed in peripheral blood mononuclear cells (PBMCs) by Western blotting in a small subset of participants. Serum IL-1β and IL-18 were measured by ELISA. Nonparametric tests were used for group comparisons, and multivariable regression models were used to evaluate associations with IL-1β. Serum dsDNA increased with silicosis severity and was highest in stage III (median 54.76 ng/mL; P for trend < 0.001). PBMC AIM2 and caspase-1 expression showed a similar stage-related pattern, whereas cleaved GSDMD (GSDMD-N) was mainly elevated in advanced disease. After adjustment for age, smoking status, shift work, educational level, physical exercise, and midday napping, IL-1β remained associated with exposure and disease status. Compared with controls, dust-exposed workers without silicosis had higher IL-1β levels (adjusted GMR = 3.02, 95% CI 1.78–5.12; P < 0.001). IL-1β was markedly elevated in silicosis across stages (adjusted GMR range 11.21–15.93). Circulating markers along the AIM2–caspase-1–GSDMD axis display stage-dependent changes in silicosis, supporting systemic involvement of inflammasome-related inflammatory signaling. These blood-based markers may help capture inflammatory activity across the exposure–disease continuum, although prospective studies are needed to determine their predictive value. Because our measurements were restricted to peripheral blood, confirmation of tissue-level cellular events and mechanisms will require dedicated morphological and functional investigations.