Blockade of TREM-1 alleviates alveolar epithelial cell senescence through Nrf2-mediated antioxidant pathways in pulmonary fibrosis

Our previous study showed that blocking triggering receptors expressed on myeloid cell-1 (TREM-1) attenuate bleomycin (BLM)-induced pulmonary fibrosis (PF) in mice. However, its underlying mechanism remains unclear. Here, we found that blockade of TREM-1 during the fibrotic phase attenuated BLM-induced PF in mice, with less expression of the senescence-relative protein, including p16, p21, p53, and γ-H2AX in the lung tissue. Moreover, TREM-1 blockade during the fibrosis stage restored the anti-oxidant levels by increasing the percentage of Nrf2- and HO-1-positive cells in PF mice. Notably, TREM-1 was highly expressed in SFTPC-positive alveolar epithelial cells (AECs) in PF mice. In vitro , blocking TREM-1 activated Nrf2 anti-oxidant signaling, thereby decreasing intracellular ROS and diminishing BLM-induced senescence of AECs. Furthermore, inhibition of the Nrf2/HO-1 partially counteracted the anti-senescence effect of blocking TREM-1 in BLM treated-AECs. In conclusion, our findings elucidate new insights into the molecular mechanisms associated with TREM-1 and AEC senescence in the pathogenesis of PF.