Mac-1 Promotes Neutrophil Extracellular Traps Formation via ERK Phosphorylation in Renal Ischemia-Reperfusion Injury.

Neutrophils are key effector cells in the pathogenesis of acute kidney injury (AKI), where neutrophil extracellular traps (NETs) play a critical role. Mac-1 (CD11b/CD18), a leukocyte surface integrin, is known to mediate inflammation. We hypothesized that Mac-1 regulates NETs formation and exacerbates ischemic AKI. The expression of Mac-1 and NETs was analyzed in peripheral blood and renal tissues from patients with kidney diseases. Mac-1 knockout (Mac-1(⁻/⁻)) mice were used to establish a bilateral renal ischemia-reperfusion injury (IRI) model and compared with wild-type (WT) controls. Primary neutrophils were isolated from bone marrow in vitro to investigate the mechanisms underlying NETs formation. CD11b and NETs were both implicated in patients with either AKI following cardiac surgery or interstitial nephritis. In a murine bilateral renal IRI model, NETs formation was detected in WT kidneys at 24 h, and DNase I treatment significantly alleviated renal injury. Compared to WT mice, Mac-1(⁻/⁻) mice exhibited reduced dysfunction, inflammation, and NETs infiltration. In vitro, Mac-1(⁻/⁻) neutrophils showed decreased PMA-induced NETs formation and reduced ERK phosphorylation. Furthermore, treatment with anti-Mac-1 antibody (M1/70) in the murine IRI model significantly attenuated kidney inflammation and injury. Mac-1 exacerbates kidney inflammation and dysfunction in ischemic AKI by mediating NETs formation through an ERK phosphorylation-dependent mechanism. Blockade of Mac-1 using the antibody M1/70 effectively ameliorates this injury, highlighting its potential as a therapeutic target. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10753-025-02327-z.