Mac-1 (CD11b/CD18) Promotes Neutrophil Extracellular Trap Formation and Exacerbates Ischemic AKI

Background: Neutrophils play a critical role in the pathogenesis of acute kidney injury (AKI), in part through the formation of neutrophil extracellular traps (NETs). Mac-1 (CD11b/CD18), a β2-integrin expressed on leukocytes, is a key mediator of inflammation. We hypothesized that Mac-1 promotes NET formation and contributes to renal injury in ischemic AKI. Methods: Expression of Mac-1 and NETs was assessed in peripheral blood and kidney tissues from patients with AKI after cardiac surgery and interstitial nephritis. A murine bilateral renal ischemia-reperfusion injury (IRI) model was established using wild-type (WT) and Mac-1 knockout (Mac-1-/-) mice. Kidney injury and inflammation were evaluated 24 hours post-IRI. Bone marrow–derived neutrophils were isolated for in vitro NET assays, and ERK phosphorylation was measured. The therapeutic potential of Mac-1 blockade was tested using the anti–Mac-1 antibody M1/70 in vivo. Results: Patients with AKI showed increased expression of CD11b and NETs in both blood and renal tissues. In the IRI model, NETs were markedly increased in WT kidneys, and DNase I treatment reduced renal injury. Compared with WT mice, Mac-1-/- mice displayed significantly reduced serum creatinine, tubular damage, inflammatory cell infiltration, and NET formation. In vitro, Mac-1-/-neutrophils had impaired NET release in response to PMA and showed reduced ERK phosphorylation. Administration of M1/70 antibody in WT mice significantly decreased renal inflammation and improved functional outcomes following IRI. Conclusion: Mac-1 facilitates NET formation through ERK signaling and aggravates kidney inflammation in ischemic AKI. Pharmacologic blockade of Mac-1 mitigates NET-mediated injury, supporting its potential as a therapeutic target in AKI.