CD11b Deficiency Ameliorates AKI-to-CKD Progress via Promoting Alternative Activation of Macrophages

Background: Acute kidney injury (AKI), even if followed by renal recovery, is a risk factor for the future development of chronic kidney disease (CKD). Persistent chronic inflammation has been proposed to contribute to the progress of AKI-to-CKD. Macrophages are a heterogeneous cell group implicated in injury, repair, and fibrosis during AKI-to-CKD process. However, the underlying mechanism of how macrophages participate in the progress of disease is largely unclear. CD11b/CD18, a leukocyte adhesion molecule, expressed on neutrophils, eosinophils and macrophages， has been shown to mediate several adhesion-dependent processes. CD11b/CD18 also contributes to the polarization of macrophages. Methods: To determine the underlying mechanism of how CD11b/CD18 participates in AKI-to-CKD, we use a long-term ischemia/reperfusion (I/R) model in CD11b-/- mice on C57BL/6 background. Wild-type (WT) and CD11b-/- mice with unilateral renal IRI were euthanized at day 3,7,14 after disease induction. Organ damage was histologically analyzed and flow cytometric analysis, real-time PCR were performed for the evaluation of leukocyte infiltration in kidney. In vitro, we used murine bone marrow-derived macrophage (BMDM) from WT and CD11b -/- mice to determine IL-4 induced alternatively activated (M2) macrophage associated gene expression. Results: The extent of inflammation and fibrosis was alleviated in CD11b-/- mice, accompanied by an early increase of M2 macrophages in renal and higher activity of p-STAT6. We demonstrated both in vitro and in vivo that enhanced alternative activation in CD11b-knockout macrophages is regulated by the IL-4/STAT6 axis, which is mediated by the inactivation of the Src kinase family member Lyn. Importantly, the therapeutical administration of CD11b-neutralizing mAbs can effectively prevent AKI-to-CKD progression. Conclusion: CD11b plays a critical role in limiting the alternative activation of macrophages and may be a potential therapeutic target during the AKI-to-CKD process.