Mac-1 Regulates IL-13 Activity in Macrophages by Directly Interacting with IL-13Rα1

Background: Mac-1 strongly suppresses IL-13-induced JAK/STAT activation in macrophages, but the mechanism is unknown. Results: Our data demonstrate that Mac-1 interacts with the IL-13R1 subunit of IL-13R and thereby suppresses IL-13 signaling. Conclusion: Mac-1 regulates macrophage to foam cell transformation by binding to IL-13R1. Significance: This study identifies a novel interaction and provides a potential mechanism by which Mac-1 safeguards macrophages from foam cell differentiation. Mac-1 exhibits a unique inhibitory activity toward IL-13-induced JAK/STAT activation and thereby regulates macrophage to foam cell transformation. However, the underlying molecular mechanism is unknown. In this study, we report the identification of IL-13R1, a component of the IL-13 receptor (IL-13R), as a novel ligand of integrin Mac-1, using a co-evolution-based algorithm. Biochemical analyses demonstrated that recombinant IL-13R1 binds Mac-1 in a purified system and supports Mac-1-mediated cell adhesion. Co-immunoprecipitation experiments revealed that endogenous Mac-1 forms a complex with IL-13R1 in solution, and confocal fluorescence microscopy demonstrated that these two receptors co-localize with each other on the surface of macrophages. Moreover, we found that genetic inactivation of Mac-1 promotes IL-13-induced JAK/STAT activation in macrophages, resulting in enhanced polarization along the alternative activation pathway. Importantly, we observed that Mac-1(-/-) macrophages exhibit increased expression of foam cell differentiation markers including 15-lipoxygenase and lectin-type oxidized LDL receptor-1 both in vitro and in vivo. Indeed, we found that Mac-1(-/-)LDLR(-/-) mice develop significantly more foam cells than control LDLR-/- mice, using an in vivo model of foam cell formation. Together, our data establish for the first time a molecular mechanism by which Mac-1 regulates the signaling activity of IL-13 in macrophages. This newly identified IL-13R1/Mac-1-dependent pathway may offer novel targets for therapeutic intervention in the future.