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. 2025 Apr 16;163(1):45.
doi: 10.1007/s00418-025-02374-5.

Blocking triggering receptors expressed on myeloid cell-1 alleviates alveolar epithelial cell senescence by inhibiting oxidative stress in pulmonary fibrosis

Wen-Jing Zhong #  1 , Jian-Bing Xiong #  2   3 , Chen-Yu Zhang  1 , Ling Jin  1 , Nan-Shi-Yu Yang  1 , Han-Xi Sha  1 , Yu-Biao Liu  1 , Jia-Xi Duan  4   3 , Cha-Xiang Guan  1 , Yong Zhou  1 , Feng Su  5   6
Affiliations

Blocking triggering receptors expressed on myeloid cell-1 alleviates alveolar epithelial cell senescence by inhibiting oxidative stress in pulmonary fibrosis

Wen-Jing Zhong et al. Histochem Cell Biol. .

Abstract

Pulmonary fibrosis (PF) is an insidious, progressive, and fatal age-associated disease that occurs primarily in older adults and has a poor prognosis. Alveolar epithelial cell (AEC) senescence is the critical pathological mechanism of PF. The accumulation of oxygen radicals, commonly referred to as reactive oxygen species (ROS), strongly contributes to cellular senescence. The triggering receptor expressed on myeloid cells-1 (TREM-1) is a pattern recognition receptor. Triggering via TREM-1 results in ROS, leading to the amplification of inflammation. However, whether TREM-1 is involved in PF by inducing oxidative stress to exacerbate AEC senescence remains unclear. We first observed that blockade of TREM-1 during the fibrotic phase attenuated bleomycin (BLM)-induced PF in mice, with decreased expression of senescence-related proteins, including p16, p21, p53, and γ-H2AX, in the lung tissue. Moreover, TREM-1 blockade during the fibrosis stage restored antioxidant levels by increasing the percentage of Nrf2- and HO-1-positive cells in mice with PF. Notably, TREM-1 was highly expressed in surfactant-associated protein (SPC)-positive AECs in mice with PF. In vitro, blocking TREM-1 activated Nrf2 antioxidant signaling, thereby decreasing intracellular ROS levels and diminishing BLM-induced senescence in AECs. Furthermore, inhibition of Nrf2/HO-1 partially counteracted the anti-senescence effect of blocking TREM-1 in BLM-treated AECs. In this study, we reported that TREM-1 stimulated the senescence of AECs, induced ROS and exacerbated PF. We also provide compelling evidence suggesting that the Nrf2/HO-1 signaling pathway underpins TREM-1-triggered senescence. Therefore, our findings provide new insights into the molecular mechanisms associated with TREM-1 and AEC senescence in the pathogenesis of PF.

Keywords: Alveolar epithelial cell; Nrf2; Pulmonary fibrosis; Senescence; TREM-1.

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Conflict of interest statement

Declarations. Conflict of interest: The authors declare no competing interests. Ethical approval: All animal experiments adhered strictly to institutional guidelines and were approved by the Committee on Animal Research of Xiangya Hospital, Central South University (Approval No: 2022020242, Changsha, China). Consent for publication: Not applicable.

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