IKKɑ prevents acute kidney injury after cardiac surgery via promoting efferocytosis and inhibiting pyrocytosis

Macrophage-dependent microenvironmental changes orchestrate many features of the immune response during inflammation from cardiac surgery-associated acute kidney injury (CSA-AKI). IκB kinase α (also known as IKKα) is a key transcriptional regulator of the macrophages., but its role in the pathogenesis of CSA-AKI remains unknown. In our clinical correlation research, cardiac surgery triggered an increased IKKɑ concentrations in serum and peripheral blood macrophages, and patients with high IKKɑ after cardiac surgery had a significantly reduced risk of developing AKI. CSA-AKI was induced by bilaterally clamping renal pedicles for 35 min in wild-type (WT) and myeloid-specific IKKɑ conditional knockout (MθIKKα-/-) mice. Compared to WT mice, MθIKKα-/- mice demonstrated decreased renal function, upregulated early AKI biomarkers such as NAGL, increased the expression of the pro-inflammatory cytokines TNF-ɑ, IL-18 and IL-6, as well as more macrophage infiltration were noted. In addition, these MθIKKα-/- mice exhibited an increase in the regulated cell death (necroptosis and pyrocytosis) and a decrease in efferocytosis. We further demonstrated that myeloid IKKɑ could negatively regulate ASC to inhibit NLRP3 inflammasome activation and enhance macrophage efferocytosis.Adoptive transfer of containing IKKɑ macrophages could reverse CSA-AKI. Collectively, our findings demonstrated for the first time that IKKɑ could improve the outcome of CSA-AKI by promoting efferocytosis and. inhibiting pyrocytosis.