MRP14 as an important regulator of macrophage function in type 2 diabetes mellitus

Abstract Background Myeloid-related protein14 (MRP14) plays an essential role in myeloid cell-mediated innate immune function and a number of inflammatory diseases. However, the role of MRP14 in obesity-induced inflammation and insulin resistance is not well defined. This study investigated the role of MRP14 in macrophage inflammation and obesity-induced insulin resistance. Methods and Results WT and MRP14−/− mice on C57BL/6 background were fed a high-fat diet or normal chow for 12 weeks. Tissue-resident macrophages in both adipose tissue and liver from obese mice expressed higher levels of MRP14. MRP14−/− mice showed a significantly improved insulin sensitivity, as measured by intraperitoneal glucose tolerance test and insulin tolerance test, compared to WT mice. There were reduced NLRP3 expression and caspase-1 activation in MRP14−/− macrophages after LPS stimulation compared to WT macrophages. In consistency, treatment of exogenous recombinant MRP8/MRP14 complex induced NFκB and caspase-1 activation. Glycolysis and mitochondrial respiration assay of macrophage were similar between WT and MRP14−/− mice. Activated MRP14−/− macrophages produced less T cell chemokines CCL5, CXCL9, and CXLL10, accompanied by reduced NFκB activation. Depletion of MRP14 from the supernatant decreased the activation of NFκB and production of chemokines (CCL5, CXCL9, and CXLL10) in WT macrophage but not MRP14−/− macrophage. Treatment of MRP8/MRP14 complex induced NFκB activation and increased the expression of CCL5, CXCL9, and CXLL10. In addition, T cells showed reduced migration towards the supernatant from MRP14−/− macrophages. Conclusion MRP8/14 regulates chemokine production from macrophage and T cell migration.