M1 macrophage inhibits ferroptosis in Pseudomonas aeruginosa induced kidney epithelial cell injury through INOS/ NO pathway without thiol

Peixiang Lu¹Xiaojie Bai¹Linfa Guo¹Kuerban Tuoheti²Shanzhi Zhan¹Tongzu Liu^1*

• ¹Zhongnan Hospital, Wuhan University, Wuhan, China
• ²Fourth Affiliated Hospital, Xinjiang Medical University, Urumqi, China

Pseudomonas aeruginosa (PA) is one of the common pathogens of urinary tract infection. In severe cases, it can lead to urosepsis and renal damage. However, the mechanism by which P. aeruginosa affects epithelial cells is not clear. Our study found that PA can induce lipid peroxidation using its specially secreted 15-lipoxygenase (pLoxA), thereby triggering ferroptosis in epithelial cells. At the same time, PA can also damage the GPx4/GSH defense system of epithelial cells. This effect is not through the proteasome pathway but through activating lysosomal chaperone-mediated autophagy (CMA) to reduce the host's GPx4 expression. In retaliation, the host initiates an antiferroptosis response mediated by iNOS/NO• produced by macrophages to inhibit lipid peroxidation and protect cells lacking GPx4/GSH. Through the co-culture model of epithelial cells and macrophages, we demonstrated that NO• produced by macrophages can remotely prevent PA-induced ferroptosis of renal epithelial cells. When iNOS, which is responsible for NO• production, is pharmacologically inhibited, the antiferroptotic effect of NO• is reduced. In conclusion, our study reveals an intercellular mechanism for inhibiting ferroptosis, which may provide a new strategy for the host to combat P. aeruginosa -induced ferroptosis.