Succinate Receptor 1: An Emerging Regulator of Myeloid Cell Function in Inflammation

The signaling properties of the G-protein-coupled SUCNR1 depend on cell and tissue specificity, as well as pathophysiological context. SUCNR1 activation can not only drive proinflammatory responses, but also directly participate in the resolution of inflammation. Succinate signaling via SUCNR1 has a role in the progression of tissue damage and resolution of inflammation in the CNS. Careful consideration of these aspects must be adopted when targeting SUCNR1 signaling to develop new candidate therapies aimed at mitigating the effects of persistent CNS inflammation. The rapidly evolving area of immunometabolism has shed new light on the fundamental properties of products and intermediates of cellular metabolism (metabolites), highlighting their key signaling roles in cell-to-cell communication. Recent evidence identifies the succinate–succinate receptor 1 (SUCNR1) axis as an essential regulator of tissue homeostasis. Succinate signaling via SUCNR1 guides divergent responses in immune cells, which are tissue and context dependent. Herein, we explore the main cellular pathways regulated by the succinate–SUCNR1 axis and focus on the biology of SUCNR1 and its roles influencing the function of myeloid cells. Hence, we identify new therapeutic targets and putative therapeutic approaches aimed at resolving detrimental myeloid cell responses in tissues, including those occurring in the persistently inflamed central nervous system (CNS). The rapidly evolving area of immunometabolism has shed new light on the fundamental properties of products and intermediates of cellular metabolism (metabolites), highlighting their key signaling roles in cell-to-cell communication. Recent evidence identifies the succinate–succinate receptor 1 (SUCNR1) axis as an essential regulator of tissue homeostasis. Succinate signaling via SUCNR1 guides divergent responses in immune cells, which are tissue and context dependent. Herein, we explore the main cellular pathways regulated by the succinate–SUCNR1 axis and focus on the biology of SUCNR1 and its roles influencing the function of myeloid cells. Hence, we identify new therapeutic targets and putative therapeutic approaches aimed at resolving detrimental myeloid cell responses in tissues, including those occurring in the persistently inflamed central nervous system (CNS). antigen-dependent immune response involving clonal expansion and activation of lymphoid cells, including T and B lymphocytes (days to weeks to be established). rapidly released endogenous molecule following disease, trauma, or infection; recruits and activates various types of immune cell. secreted signaling protein able to induce the growth of cartilage and bone. movement of cells (i.e., phagocytotic) towards an increasing gradient (e.g., ligand) to elicit inflammatory responses, antigen presentation, and phagocytosis. animal model reproducing certain aspects of clinical rheumatoid arthritis by immunization of a joint with methylated bovine serum albumin. murine model of MS, induced either by injected myelin protein or by myelin-activated T cells. largest family of membrane receptors with diverse intracellular signaling properties resulting from G-protein subunit activity. drug concentration needed to induce half of a maximum biological response (e.g., upon a ligand binding to a receptor). drug concentration needed to reduce a biological response by 50%. disease of iron homeostasis causing accumulation of iron in the body. here, brain injury (e.g., stroke resulting from cardiac arrest) leading to oxygen deprivation in the brain (brain hypoxia). intermediate product generated during cellular metabolism that can act on intracellular and extracellular signaling pathways to shape and modulate immune responses. immediate, nonspecific immune response mediated by innate immune cells (e.g., myeloid cells); based on myeloid cell recognition of evolutionary-conserved molecular features of pathogens (e.g., LPS) to elicit an immune response. signaling product derived from cellular metabolism that binds to and regulates dedicated cell surface G-protein-coupled and ionotropic receptors. G-protein-coupled receptors; membrane-bound receptors that act via signaling on secondary messengers, such as G-proteins. resident MPs responsible for CNS surveillance in an ‘immune-privileged’ tissue behind two anatomical ‘barriers’ (i.e., the blood–brain barrier and the blood–cerebrospinal fluid barrier); they restrict the free movement of circulating peripherally derived immune cells and soluble factors, such as metabolites, into the CNS parenchyma. innate immune myeloid cells residing within the tissue (e.g., microglia) or are blood borne (e.g., monocytes). molecular entities based on a fused double-ringed aromatic diazanaphthalene core. inflammatory liver disease marked by the accumulation of fat in the organ, often accompanied by fibrosis. subset of proinflammatory CD4+ T cells that produce proinflammatory interleukin (IL)-17. response, generally anti-inflammatory, resembling that of T helper (Th)2 cells, a subset of CD4+ T cells characterized by the production of IL-4, IL-5, IL-10, and IL-13. single-pass membrane-spanning receptor proteins that commonly recognize structurally conserved molecular patterns from infectious pathogens; they have a significant role in innate immunity.