Metabolic Reprogramming in Macrophage Fate and Immunity.
It has long been recognized that macrophages are important effector cells playing pleiotropic roles in nearly all tissues. In addition to their crucial roles in host immune defense, inflammation and wound healing, macrophages also play a central function in tissue metabolic homeostasis.
In tissues, resting macrophages are capable of responding to environmental cues and assuming exhibiting phenotypically distinct functions. Th1 cytokine interferon-γ (IFN-γ) in combination with Toll-like receptor (TLR) agonists, promote classical activation which is pro-inflammatory, and associated with bacterial infections, obesity, diabetes and cardiovascular diseases; whereas, the Th2 cytokines interleukin-4 (IL-4) and IL-13 prime alternative activation which is largely anti-inflammatory, and is instrumental in combating helminth infections and mitigating inflammatory disease. Our research has been focusing on the metabolic regulation of alternatively activated macrophages, which are critically dependent on cell-intrinsic lysosomal lipolysis and mitochondrial fatty acid oxidation (FAO). We, also, found that the mTORC2-IRF4 signal axis is critical for the core gene expression, and for metabolic reprogramming to establish the alternative activation state and immunosuppression during melanoma tumorigenesis.
A number of studies have demonstrated that nutrition interventions affect macrophage fate and immunity, but the underlying mechanisms remain unclear. Thus, we are attempting to understand the metabolic and bioenergetic requirements for dictating the cellular function of macrophages, and further to develop tangible clinical immunotherapies targeting macrophages through metabolism for cancer and infections.