Map Kinase Phosphatase-5 Deficiency in Macrophages Protects Against Atherogenesis

Objective: To determine the role of macrophage MAP Kinase Phosphatase-5 (MKP-5) in the pathogenesis of atherosclerosis. Approach and Results: Lethally irradiated LDLR -/- mice were transplanted with wild-type (WT) or MKP-5 deficient (MKP-5 -/- ) bone marrow and subjected to high-fat feeding. Mice transplanted with MKP-5 -/- bone marrow developed smaller atherosclerotic lesions accompanied by decreased lipid deposition and macrophage content compared to WT. Lack of MKP-5 in macrophages led to decreased plasma levels of interleukin-1α (IL-1α) and IL-7, elevated anti-inflammatory cytokines IL-1 receptor antagonist (IL-1rn) and IL-4. Mechanistically, lack of MKP-5 in macrophages inhibited ox-LDL-induced foam cell formation through enhanced cholesterol efflux mediated by increased expression of ATP-binding cassette transporters ABCA1 and ABCG1. Conclusions: These data suggest that the macrophage MKP-5 deficiency reduces atherosclerosis progression and foam cell formation through amelioration of cholesterol efflux and inhibition of inflammation.