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Int J Biol Sci 2024; 20(3):968-986. doi:10.7150/ijbs.90808 This issue Cite

Research Paper

SGK1 aggravates idiopathic pulmonary fibrosis by triggering H3k27ac-mediated macrophage reprogramming and disturbing immune homeostasis

Jianzhi Wu^1,#, Liping Gong^3,#, Yijie Li¹, Tiegang Liu^2,5, Rong Sun³, Kexin Jia¹, Runping Liu⁴, Fei Dong^2,5, Xiaohong Gu^2,5,✉, Xiaojiaoyang Li^1,✉

1. School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China.
2. Institute of Chinese Epidemic Disease, Beijing University of Chinese Medicine, Beijing 100029, China.
3. The Second Hospital of Shandong University, Shan Dong University, 247 Bei Yuan Da Jie, Jinan, 250033, China.
4. School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing, 100029, China.
5. School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
^#These authors contributed equally to this work.

✉ Corresponding authors: Xiaojiaoyang Li, Ph.D., School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China; Email: xiaojiaoyang.liedu.cn. Or Xiaohong Gu, MD, Ph.D., Institute of Chinese Epidemic Disease, Beijing University of Chinese Medicine; Email: guxh1003com. More

Abstract

Idiopathic pulmonary fibrosis (IPF) is characterized by fibrotic matrix deposition and irreversible aberrant tissue remodeling. Their mechanisms of action are associated with the activation of macrophages and a disturbed immune environment. We aim to determine how these activated macrophages influenced the pathogenesis of pulmonary fibrosis. We found the fibrotic areas of IPF patients contained more serum and glucocorticoid-induced kinase 1 (SGK1)-positive and M2-type macrophages. Similarly, bleomycin (BLM)+LPS significantly triggered high expression of SGK1 in the IPF mice, accompanied by destroyed lung structure and function, increased fibrosis markers and disturbed immune microenvironment. Mechanistically, SGK1 markedly promoted the reprogramming of M2-type macrophages in fibrotic lungs by triggering glycogen synthase kinase 3beta (GSK3β)-tat-interacting protein 60 (TIP60)- histone-3 lysine-27 acetylation (H3K27ac) signalings, which further released chemokine (C-C motif) ligand 9 (CCL9) to attract Th17 cells and delivered TGF-β to fibroblasts for synergistically destroying immune microenvironment, which was largely reversed by macrophage depletion in mice. We took macrophages as the entry point to deeply analyze IPF pathogenesis and further provided insights for the development of novel drugs represented by SGK1.

Keywords: SGK1, pulmonary fibrosis, macrophage reprogramming, H3K27ac, immune homeostasis

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