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

  • Cell Mol Immunol. 2025 Jul;22(7):743-759. doi: 10.1038/s41423-025-01293-8.
Peng Xiang  #  1  2 ,  Liwen Wang  #  1  2 ,  Xu Feng  1  2 ,  Qi Guo  1  2 ,  Genqing Xie  3 ,  Langqing Sheng  2  4  5 ,  Linyun Chen  1  2 ,  Jianhui Teng  1  2 ,  Jinlin Yang  1  2 ,  Xuecheng Wu  1  2 ,  Xi Peng  1  2 ,  Renbin Lu  1  2 ,  Xianghang Luo  1  2  6 ,  Jie Wen  7  8 ,  Hai-Yan Zhou  9  10  11
Affiliations
  • 1. Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, 410008, Hunan, China.
  • 2. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital of Central South University, Changsha, 410008, Hunan, China.
  • 3. Department of Endocrinology, The First People's Hospital of Xiangtan City, Xiangtan, Hunan, China.
  • 4. Department of General Surgery, Xiangya Hospital of Central South University, Changsha, China.
  • 5. International Joint Research Center of Minimally Invasive Endoscopic Technology Equipment & Standards, Xiangya Hospital of Central South University, Changsha, China.
  • 6. FuRong Laboratory, Changsha, 410078, Hunan, China.
  • 7. Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, 410008, Hunan, China. [email protected].
  • 8. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital of Central South University, Changsha, 410008, Hunan, China. [email protected].
  • 9. Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, 410008, Hunan, China. [email protected].
  • 10. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital of Central South University, Changsha, 410008, Hunan, China. [email protected].
  • 11. FuRong Laboratory, Changsha, 410078, Hunan, China. [email protected].
  • # Contributed equally.
PMID: 40360692 DOI: 10.1038/s41423-025-01293-8
Abstract

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 immune-regulatory units, which could be targeted to limit Lung Fibrosis.

Keywords
GCA; HTR2C; Pulmonary fibrosis; Sexual dimorphism; Th17 cells.
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