Fig 2.
Control of immune tolerance by anti-inflammatory neuropeptides. Vasoactive intestinal peptide (VIP), α-melanocyte-stimulating hormone (αMSH), urocortin (UCN), adrenomedullin (AM), ghrelin (GHR) and cortistatin (CST) are produced by T cells or macrophages in response to antigenic and inflammatory stimulation. These neuropeptides induce immune tolerance and inhibit the autoimmune response through different non-excluding mechanisms. (A) They decrease TH1-cell functions through direct actions on differentiating T cells, or indirectly by regulating dendritic cell (DC) functions. As a consequence, the inflammatory and autoimmune responses are impaired because the infiltration and activation of neu-trophils and macrophages by interferon-γ (IFNγ) and the production of complement-fixing IgG2a antibodies are avoided. (B) Neuropeptides inhibit the production of inflammatory cytokines, chemokines, free radicals (i.e. nitric oxide) and high-mobility group box 1 (HMGB1) by macrophages and microglia. In addition, they impair the costimulatory activity of macrophages on effector T cells, inhibiting the subsequent clonal expansion. This avoids the infiltration of leucocytes and the inflammatory response and the subsequent cytotoxicity against the target tissue. (C) Neuropeptides induce the new generation of regulatory T cells (Treg) that suppress activation of autoreactive T cells through a mechanism that involves production of interleukin-10 (IL-10) and transforming growth factor-β (TGFβ), and/or expression of the cytotoxic T lymphocyte-associated protein 4 (CTLA4). In addition, neuropeptides indirectly generate Treg through the differentiation of tolerogenic DCs. This effect contributes to the maintenance of an anti-inflammatory state and restores the immune tolerance. Black arrows indicate a stimulatory effect. Red crosses indicate an inhibitory effect.