Sexual dimorphism of lung immune-regulatory units imprint biased pulmonary fibrosis

Pulmonary fibrosis (PF) exhibits sexual dimorphism with a higher prevalence and severity in males, whereas the mechanism remains unclear. Our study uncovered pronounced sexual dimorphism of immune cell genes in the lung, among which grancalcin (GCA) showed profound gender differences. The production of GCA was owed to the lung-infiltrating bone-marrow macrophages triggered by heightened inflammation in the lung. However, a unique HTR2C+ alveolar macrophage population enriched in the female lungs metabolically reprogramed bone marrow-derived macrophages and constrained local GCA amplification. As a novel chemokine, GCA bound to Protein Tyrosine Phosphatase Receptor Type T (PTPRT) in Th17 cells and facilitated their pathogenic lung infiltrating by activating the ROCK1-MLC pathway, thus aggravating lung fibrosis. Notably, both GCA and Th17 cells abundantly accumulated in lung biopsies from male PF patients rather than females. GCA neutralizing antibody in combination with pirfenidone, a prescribed medication for treating fibrosis, provided superior effectiveness and survival rates against PF than treatment with pirfenidone alone. Overall, our findings revealed that sex-biased lung fibrosis is shaped by lung immune-regulatory units, which could be targeted to limit lung fibrosis.