摘要
Pulmonary fibrosis(PF)is sexually dimorphic,with a relatively high prevalence and severity in males;however,the mechanism remains unclear.Our study revealed pronounced sexual dimorphism of immune cell genes in the lung,among which grancalcin(GCA)showed profound sex differences.GCA was produced by lung-infiltrating bone marrow macrophages triggered by heightened inflammation in the lung.However,a unique HTR2C+alveolar macrophage population enriched in 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 pathogenic lung infiltration 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 but not in those from female patients.GCA-neutralizing antibodies in combination with pirfenidone,a prescribed medication for treating fibrosis,provided superior effectiveness and survival rates against PF compared with treatment with pirfenidone alone.Overall,our findings reveal that sex-biased lung fibrosis is shaped by lung immuneregulatory units,which could be targeted to limit lung fibrosis.
基金
supported by the National Natural Science Foundation of China(Grant Nos.82170866 and 82422016 to HYZ,82401013 to JW,and 82430028 to XHL)
the Natural Science Foundation of Hunan Province,China(Grant No.2024JJ2095 to HYZ,2025JJ60561 to JW)
the Changsha City Outstanding Innovative Youth Development Program(Grant No.Kq2306007 to HYZ)
the Scientific Research Program of FuRong Laboratory(Grant No.2024PT5104 to XHL).
