(DCP002) ABCB10, A NOVEL REGULATOR OF METABOLIC INFLAMMATION

Background: Uncontrolled inflammation triggers pro-inflammatory cytokines secretion and inappropriate immune response. Macrophages are important immune cells for the development of inflammation leading to insulin resistance and metabolic diseases. The macrophages’ activity can be regulated by metabolic reprogramming, reactive oxygen species (ROS), and mitochondrial activity. We found a novel mitochondrial antioxidant system involved in these processes and regulated by the ATP Binding Cassette B10 (ABCB10). ABCB10 allows biliverdin to export from the mitochondria to the cytosol where it is converted into the antioxidant, bilirubin. ABCB10 expression is increased in obesity, inhibiting physiological H2O2 signaling by increasing bilirubin levels which reduces mitochondrial function. Although ABCB10 expression is regulated during macrophage activation, its role in modulating macrophages functions and systemic inflammation in metabolic diseases remains unknown.

Objective: To determine how ABCB10 regulates mitochondrial function in macrophages.

METHODS AND RESULTS: We used wild-type and ABCB10 myeloid-specific KO mice (ABCB10 M-KO) to remove ABCB10 in macrophages. We isolated the bone-marrow-derived macrophages (BMDM) and polarized them into pro-inflammatory macrophages (M1) or anti-inflammatory macrophages (M2). We analyzed transcriptomic levels and signaling pathways of pro- or anti-inflammatory markers. Additionally, we assessed glucose metabolism in obese ABCB10 M-KO mice fed high-fat diet.

Results: Our results show that ABCB10 expression increases upon pro-inflammatory cytokines in BMDM. ABCB10 KO BMDM displayed lower p38 phosphorylation (Thr180 and Tyr182) in M1 macrophages suggesting less pro-inflammatory activity. Likewise, we demonstrated that ABCB10 KO BMDM decreased the transcriptomic expression of pro-inflammatory genes like TNFα and IL-1β, in response to LPS and IFN-γ treatment. Alternative macrophage activation (M2) by IL-4, measured with Arg1 mRNA expression, was unchanged by ABCB10 deletion. In macrophages from mice fed high-fat diet, ABCB10 expression increased while ABCB10 deletion in macrophages improved glucose tolerance without changing body weight or adiposity.

Conclusion: Our data suggest that ABCB10 deletion reduces pro-inflammatory macrophage activation and targeting ABCB10 could be harnessed to reduce inflammation and improve glycemic control in obesity.