The roles of cellular Inhibitor of Apoptosis Protiens 1 and 2 in the polarization of M1 and M2 macrophages

Abstract

This thesis examined the effects of genetic ablation of the anti-apoptotic protein cIAP2 and SMAC mimetic (LCL161)-induced cIAP1 and cIAP2 suppression on the polarization of pro-inflammatory (M1) and anti-inflammatory (M2) macrophages. Quantitative RT-PCR was employed to measure M1 and M2 mRNA markers in bone marrow derived macrophages (BMDMs) cultured under mild or strong M1 or M2 polarizing conditions. These measurements indicated that cIAP2 loss impaired both M1 and M2 polarization. Macrophage isolation by immunopanning suggested that cIAP2 loss also impaired dendritic cell polarization. LCL161 increased M1 mRNA marker levels in strongly M1 polarized macrophages. By contrast, LCL161 induced the massive apoptosis of strongly M2 polarized macrophages. Hence, cIAP1/2 suppression biased macrophage polarization in vitro towards a pro-inflammatory M1 state. LCL161 increased the severity of experimental autoimmune encephalomyelitis and suppressed both Th1 and Th2 cytokine plasma concentrations suggestive of impaired M1 and M2 polarization. SMAC mimetics may therefore worsen multiple sclerosis.