Journal Article

Regulation of innate immune cell function by mTOR

Hengstschläger, Markus, Weichhart, Thomas, Linke, Monika

2015

Overview

Key Points Mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase that is present in two complexes: mTORC1 and mTORC2. mTORC1 is the main energy and nutrient sensor of the cell: it senses the presence of amino acids, glucose, lipids and ATP to enable efficient activation of the network in response to growth factors, Toll-like receptor (TLR) ligands and cytokines. Activation of the mTOR pathway usually promotes an anabolic response that induces the synthesis of nucleic acids, proteins and lipids. In addition, it stimulates glycolysis and mitochondrial respiration. Emerging data suggest that this metabolic reconfiguration is required for specific effector functions in myeloid cells. Translational control of gene expression in myeloid immune cells has emerged as one way in which mTORC1 controls cellular processes such as migration, expression of type I interferon and pro-inflammatory or anti-inflammatory cytokines, and metabolic reprogramming. Counterintuitively, inhibition of mTORC1 during TLR triggering generally promotes interleukin-12 (IL-12) production and inhibits expression of IL-10 and type I interferon by dendritic cells (DCs); it also augments their T cell-stimulatory capacity. Inhibition of mTORC2 enhances a pro-inflammatory response and IL-12 production in DCs. Inhibition of mTORC1 in macrophages promotes autophagy, which is important for intracellular pathogen killing and clearance of ingested complex lipids such as low-density lipoprotein (LDL) cholesterol. mTORC2 is especially important for cell polarity and chemotaxis in neutrophils and mast cells. mTORC2 controls the leading edge as well as tail retraction during chemotactic migration. Activation of mTORC1 in NK cells by IL-15 triggers a glycolytic response, which is important for their proliferation and acquisition of cytotoxicity. The rapid response of innate immune cells requires metabolic reprogramming to support their specific effector functions. As discussed here, mTOR is a key regulator of this process: it senses the environmental and intracellular nutritional status of innate immune cells to dictate and optimize the inflammatory response. The innate immune system is central for the maintenance of tissue homeostasis and quickly responds to local or systemic perturbations by pathogenic or sterile insults. This rapid response must be metabolically supported to allow cell migration and proliferation and to enable efficient production of cytokines and lipid mediators. This Review focuses on the role of mammalian target of rapamycin (mTOR) in controlling and shaping the effector responses of innate immune cells. mTOR reconfigures cellular metabolism and regulates translation, cytokine responses, antigen presentation, macrophage polarization and cell migration. The mTOR network emerges as an integrative rheostat that couples cellular activation to the environmental and intracellular nutritional status to dictate and optimize the inflammatory response. A detailed understanding of how mTOR metabolically coordinates effector responses by myeloid cells will provide important insights into immunity in health and disease.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/250/2504 / 631/250/256 / 631/443/319 / Animals / Biomedicine / Cellular control mechanisms / Cellular signal transduction / Cytokines / Cytokines - immunology / Dendritic Cells - immunology / Health aspects / Humans / Immune response / Immune system / Immunity, Innate - immunology / Immunological research / Immunology / Macrophages - immunology / Models, Immunological / Myeloid Cells - immunology / Nutritional status / review-article / Signal Transduction - immunology / TOR Serine-Threonine Kinases - immunology