Immunometabolic Control of Macrophage Function by Bmal1

Abstract

Activated immune cells have increased energetic demands, often favoring a shift in core energy metabolism toward acquiring metabolic intermediates from glycolysis and the mitochondrial tricarboxylic acid (TCA) cycle for anabolic processes at the expense of reduced fuel economy. Little is known concerning cell-autonomous mechanisms that restore energetic homeostasis in effector immune cells following activation and how this may influence their functional plasticity. Anabolic reprogramming in macrophages, sentinel cells that play roles in the initiation and propagation of inflammation, coincides with an active repression of mitochondrial oxidative phosphorylation (Oxphos) and increased production of mitochondrial reactive oxygen species (mROS) that regulate inflammatory signaling processes. However, given that macrophages must operate under nutrient-restricted conditions in various disease settings, it is counter-intuitive that these cells would decrease energetic efficiency indefinitely following activation. I propose that brain and muscle ARNT-like 1 (Bmal1), a transcriptional regulator canonically recognized as a core component of the circadian oscillator, regulates mitochondrial energetics in inflammatory macrophages and consequently modulates inflammatory signaling. Firstly, pro-inflammatory (or M1) activation of mouse bone marrow-derived macrophages (BMDMs) with interferon-g priming and bacterial lipopolysaccharide stimulation induces Bmal1 expression and protein stability. Bmal1 promotes mitochondrial oxidative metabolism in macrophages, and myeloid-specific Bmal1 deletion (“M-BKO”) exacerbates mitochondrial dysfunction and energetic stress in M1-activated BMDMs. M-BKO promotes anaplerotic succinate accumulation and Oxphos complex II-dependent mROS production, which enhances hypoxia-inducible factor (Hif)-1a-dependent metabolic reprogramming toward glycolytic and amino acid metabolism during M1 activation. M-BKO and mROS are also associated with impaired activation of interferon regulatory factor 3 (Irf3) and type I interferon signaling, which regulate genes involved in lymphocyte recruitment and activation. I also propose that Bmal1 regulates tumor-associated macrophage function at least in part through an analogous mechanism. Tumor-conditioned medium elicits a similar metabolic stress and defective Irf3 activation in M-BKO macrophages. Consistently, M-BKO increases melanoma tumor burden in mice associated with local suppression of tumoricidal lymphocytes in a macrophage cell- autonomous manner. These findings suggest that M1 and tumor-associated macrophages share similar energetically challenged conditions and that Bmal1 regulates a metabolic checkpoint integrating macrophage mitochondrial metabolism, redox homeostasis, and effector functions. This regulatory mechanism may provide therapeutic opportunities for inflammatory diseases and immunotherapy.