The Role of Nutrient Sensing in Macrophage Polarization

Abstract

Macrophages are essential immune cells that belong to the innate immune system and are key orchestrators in the initiation and resolution stages of inflammation. Macrophages are found in every organ throughout the body where they function as sentinel cells that protect against invading pathogens and maintain tissue homeostasis by engulfing apoptotic cells. Thus, macrophages are able to efficiently recognize both pro- and anti-inflammatory stimuli and respond appropriately by activating a diverse set of biological programs. Over the last two decades, studies have shown that activated macrophages are able to polarize to pro-inflammatory or anti-inflammatory states with distinct phenotypes and physiological responses during inflammation. As a result, macrophages have been categorized into subtypes that include the classical pro-inflammatory M1 state, which is activated by Interferon-γ and LPS and the “alternative” M2 state, which is activated by the Th2 cytokines IL-4 and IL-13. Metabolic diseases, such as obesity and Type-II diabetes, are associated with chronic low-grade inflammation due to dysregulation of metabolic and inflammatory signaling pathways. During obesity monocytes infiltrate adipose tissue and polarize to M1 macrophages, displacing the M2 macrophages normally found in non-obese tissue. These M1 macrophages produce high levels of pro-inflammatory cytokines, which contributes to the development of insulin resistance and type-2 diabetes. Interestingly, while macrophages reside in all metabolic organs such as adipose tissue, how the nutrient status of the host affects macrophages function is not well understood. Thus, my thesis seeks to provide a clearer understanding of this important relationship and is of significant relevance to metabolic health and dysfunction.

Mammalian Target of Rapamycin (mTOR) lies downstream of TSC1/2 complex and plays a central role in integrating signals for energy sensing and other cellular processes such as cell proliferation, cell size, gene transcription, protein synthesis, and autophagy. mTOR exists in two separate complexes, mTORC1 and mTORC2, that regulate distinct signaling pathways and phosphorylation of downstream targets. Using a mouse model in which myeloid lineage specific deletion of Tsc1 (Tsc1Δ/Δ) leads to constitutive mTOR Complex 1 (mTORC1) activation, we found that Tsc1Δ/Δ macrophages are refractory to IL-4 induced M2 polarization in vitro and in vivo, but produce increased inflammatory responses to proinflammatory stimuli such as LPS. The underlying basis for this aberrant macrophage polarization is due to feedback inhibition of Akt, a critical pathway that is activated by IL-4 and LPS. Thus, we elucidate a key role for the Akt pathway in macrophage polarization. In further studies of the Akt-mTORC1 pathway we found that IL-4 activation of the Akt-mTOR nutrient-sensing pathway leads to the phosphorylation and activation of the Akt target Acly (ATP-Citrate Lyase) that catalyzes the increase in cytosolic/nuclear pools of acetyl-CoA. This acetyl-CoA is used by histone acetyltransferases to acetylate the promoters of canonical M2 markers in murine macrophages such as Arg-1, Fizz1, and Mgl2. Furthermore, we have in vitro and in vivo evidence that macrophage M2 polarization can be tuned to metabolic input/nutrient status via the Akt-ACLY pathway and thereby control M2 gene expression levels. These findings highlight a key role for the Akt-mTORC1 pathway in regulating macrophage M2 polarization, and suggest how nutrient and metabolic status can fine-tune macrophage function via nutrient sensing pathways.