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

• Published in: International immunopharmacology 2022-12, Vol.113, p.109339, Article 109339
• Main Authors: Xiong, Jian-Bing, Duan, Jia-Xi, Jiang, Nan, Zhang, Chen-Yu, Zhong, Wen-Jing, Yang, Jin-Tong, Liu, Yu-Biao, Su, Feng, Zhou, Yong, Li, Dai, Yang, Hui-Hui, Guan, Cha-Xiang
• Format: Article
• Language: English
• Subjects: Alveolar epithelial cells; Pulmonary fibrosis; Senescence; TREM-1
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2022.109339

•TREM-1 plays a direct role in BLM-induced PF.•TREM-1 accelerates AEC senescence.•Blockade of TREM-1 inhibits AEC senescence, rescuing PF outcomes. 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.