Regulation of immune tolerance by anti-inflammatory neuropeptides

The loss of immune tolerance results in the breakdown of immune homeostasis and the appearance of exacerbated inflammatory conditions and autoimmune diseases.Several mechanisms act together to ensure self-tolerance, including clonal deletion, anergy, ignorance and exhaustion, effector T-cell and regulatory T-cell balance and cytokine deviation. Identifying factors that regulate these processes is crucial for the development of new therapies for inflammatory and autoimmune diseases.Certain neuropeptides and hormones are produced in response to exacerbated inflammatory responses. Some of these neuropeptides, including the vasoactive intestinal peptide, α-melanocyte-stimulating hormone, urocortin, adrenomedullin and cortistatin, have emerged as endogenous anti-inflammatory factors that are involved in regulating immune tolerance, acting at several levels.Anti-inflammatory neuropeptides bind to specific receptors that are expressed in immune cells, activate the cyclic AMP–protein kinase A pathway, and downregulate various transcription factors that are involved in the inflammatory response and in activating T cells.These neuropeptides reduce the production of pro-inflammatory cytokines, chemokines and free radicals by macrophages, dendritic cells (DCs) and microglia, and inhibit the activation and differentiation of T helper 1 (TH1) cells.These neuropeptides induce the emergence of regulatory T cells, especially under autoimmune conditions, involving several mechanisms. Neuropeptides directly induce the generation of CD4+CD25+ regulatory T cells in the periphery from the CD4+CD25− T-cell repertoire. In addition, neuropeptides generate tolerogenic DCs that have the capacity to induce interleukin-10-producing regulatory T cells.The capacity of these neuropeptides to regulate the inflammatory response, the activation of autoreactive T cells and the generation of regulatory T cells, makes them attractive candidates for treating several inflammatory and autoimmune disorders. These neuropeptides are therapeutically beneficial in experimental models of sepsis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and type 1 diabetes.Cellular therapies that are based on the use of regulatory T cells or tolerogenic DCs generated with neuropeptides are effective in treating various autoimmune diseases and transplantation.