2. Academic Validation
  3. Sexual dimorphism of lung immune-regulatory units imprint biased pulmonary fibrosis

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

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. 22023248@csu.edu.cn.
  • 8 National Clinical Research Center for Geriatric Disorders, Xiangya Hospital of Central South University, Changsha, 410008, Hunan, China. 22023248@csu.edu.cn.
  • 9 Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, 410008, Hunan, China. hyzhou02@csu.edu.cn.
  • 10 National Clinical Research Center for Geriatric Disorders, Xiangya Hospital of Central South University, Changsha, 410008, Hunan, China. hyzhou02@csu.edu.cn.
  • 11 FuRong Laboratory, Changsha, 410078, Hunan, China. hyzhou02@csu.edu.cn.
  • # 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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