TREM-1 exacerbates bleomycin-induced pulmonary fibrosis by aggravating alveolar epithelial cell senescence in mice

Jian-Bing Xiong; Jia-Xi Duan; Nan Jiang; Chen-Yu Zhang; Wen-Jing Zhong; Jin-Tong Yang; Yu-Biao Liu; Feng Su; Yong Zhou; Dai Li; Hui-Hui Yang; Cha-Xiang Guan

doi:10.1016/j.intimp.2022.109339

TREM-1 exacerbates bleomycin-induced pulmonary fibrosis by aggravating alveolar epithelial cell senescence in mice

Int Immunopharmacol. 2022 Dec;113(Pt A):109339. doi: 10.1016/j.intimp.2022.109339. Epub 2022 Oct 27.

Authors

Jian-Bing Xiong¹, Jia-Xi Duan², Nan Jiang³, Chen-Yu Zhang³, Wen-Jing Zhong³, Jin-Tong Yang³, Yu-Biao Liu³, Feng Su⁴, Yong Zhou³, Dai Li⁵, Hui-Hui Yang⁶, Cha-Xiang Guan⁷

Affiliations

¹ Department of Emergency, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China; Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China; National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China.
² National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China; Department of Geriatrics, Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China.
³ Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China.
⁴ Department of Emergency, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China; National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China.
⁵ Phase I Clinical Trial Center, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China.
⁶ Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China. Electronic address: yanghuihui126@csu.edu.cn.
⁷ Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China. Electronic address: guanchaxiang@csu.edu.cn.

PMID: 36330909
DOI: 10.1016/j.intimp.2022.109339

Abstract

Our previous study showed that triggering receptors expressed on myeloid cell-1 (TREM-1) was upregulated in bleomycin (BLM)-induced pulmonary fibrosis (PF) mouse model. However, the role of TREM-1 in the development of PF and its underlying mechanism remain unclear. Herein, we report that the prophylactical blockade of TREM-1 using a decoy peptide dodecapeptide (LR12) exerted protective effects against BLM-induced PF in mice, with a higher survival rate, attenuated tissue injury, and less extracellular matrix deposition. Interestingly, therapeutic blockade of TREM-1 at the early stage of fibrosis also attenuated BLM-induced PF, suggesting a non-inflammatory effect. More importantly, we observed that TREM-1 blockade with LR12 significantly reduced the expression of the senescence-relative protein, including p16, p21, p53, and γ-H2AX in the lungs of PF mice. Notably, TREM-1 was upregulated in alveolar epithelial cells (AECs) and correlated with the levels of senescence markers in BLM-treated mice. In vitro, activating TREM-1 with an agonistic antibody exacerbated BLM-induced senescence in MLE12 cells, a murine AEC cell line. Furthermore, prophylactic or therapeutic blockade of TREM-1 protected MLE12 cells from senescence induced by BLM or H₂O₂. In conclusion, our findings elucidate a pro-fibrotic effect of TREM-1 by inducing AECs senescence in PF, providing a potential strategy for fibrotic disease treatment.

Keywords: Alveolar epithelial cells; Pulmonary fibrosis; Senescence; TREM-1.

MeSH terms

Alveolar Epithelial Cells* / pathology
Animals
Bleomycin / toxicity
Hydrogen Peroxide / metabolism
Mice
Myeloid Cells
Pulmonary Fibrosis* / metabolism
Pulmonary Fibrosis* / physiopathology
Triggering Receptor Expressed on Myeloid Cells-1* / metabolism

Substances

Bleomycin
Hydrogen Peroxide
Triggering Receptor Expressed on Myeloid Cells-1
TREM1 protein, mouse