Neuropeptides as Pleiotropic Modulators of the Immune Response

Abstract

Although necessary to eliminate pathogens, inflammation can lead to serious deleterious effects in the host if left unchecked. During the inflammatory response, further damage may arise from potential autoimmune responses occurring when the immune cells and molecules that respond to pathogen-derived antigens also react to self-antigens. In this sense, the identification of endogenous factors that control exacerbated immune responses is a key goal for the development of new therapeutic approaches for inflammatory and autoimmune diseases. Some neuropeptides that are produced during the ongoing inflammatory response have emerged as endogenous anti-inflammatory agents that could collaborate in tuning the balanced steady state of the immune system. These neuropeptides participate in maintaining immune tolerance through two distinct mechanisms: by regulating the balance between pro-inflammatory and anti-inflammatory factors, and by inducing the emergence of regulatory T cells with suppressive activity against autoreactive T cell effectors. Indeed, a functioning neuropeptide system contributes to general health, and alterations in the levels of these neuropeptides and/or their receptors lead to changes in susceptibility to inflammatory and autoimmune diseases. Recently, we found that some neuropeptides also have antimicrobial and antiparasitic actions, suggesting that they could act as primary mediators of innate defense, even in the most primitive organisms. In this review, we use the vasoactive intestinal peptide as example of an immunomodulatory neuropeptide to summarize the most relevant data found for other neuropeptides with similar characteristics, including adrenomedullin, urocortin, cortistatin and ghrelin.

The Effects of Neurotrophins and the Neuropeptides VIP and PACAP on HIV-1 Infection: Histories with Opposite Ends

“…PACAP shares 68% amino acid sequence homology with VIP and exists in two isoforms, which are designated PACAP-27 and PACAP-38 according to their amino acid numbers [130,131,132,133,134,135,136]. PACAP (predominantly PACAP-38) is widely expressed in the CNS and peripheral tissues, and can play a large number of modulatory roles in the nervous tissue and the immune system [10,137]. …”

“…thymus and spleen), in which thymocytes and CD4+ T helper (Th) 2 and CD8+ T lymphocytes are their main sources [132,149,156,157]. VIP and PACAP regulate metabolic and endocrine activities and gastrointestinal tract functioning, and act as immunomodulatory and anti-inflammatory agents [127,128,137]. These peptides participate in neural development and exert neuroprotective effects due to their ability to protect nervous tissue from injuries caused by a number of neurotoxic agents, such as ethanol, hydrogen peroxide and the HIV-1 gp120 [158,159,160,161].…”

“…The anti-inflammatory effects of VIP and PACAP derive from the ability of both neuropeptides to inhibit the activity or production of several proinflammatory molecules (such as chemokines, reactive oxygen and nitrogen species, IL-12, IL-6, IL-1β, TNF-α and macrophage migration inhibitory factor), in addition to their capacity to stimulate the production of anti-inflammatory factors (e.g. IL-4 and IL-10) [127,128,137]. VIP and PACAP also participate in Th2 cell differentiation by inhibiting IL-12 production and inducing IL-4 and IL-5 synthesis in macrophages and dendritic cells [127,128,137].…”

“…IL-4 and IL-10) [127,128,137]. VIP and PACAP also participate in Th2 cell differentiation by inhibiting IL-12 production and inducing IL-4 and IL-5 synthesis in macrophages and dendritic cells [127,128,137]. Moreover, VIP- or PACAP-treated macrophages stimulate CD4+ T cells to produce the Th2 cytokines IL-4 and IL-5 and inhibit the ability of the same cells to synthesize the Th1 cytokines IFN-γ and IL-2 [127,128,137].…”

Neuro-endocrine-immune Crosstalk and Implications for Cancer Therapy

“…Since the early evidence that inflammatory signals in the periphery can alter signaling in the hypothalamus [5], the focus has been on identifying a common molecular basis for this bidirectional communication shared through receptors and signaling ligands which cross sequestered anatomical locations [6]. Recent research suggests that neurotransmitters and neurohormones act by binding not only to their classical receptors on target cells in the nervous and endocrine systems, but also to receptors on various immune cells [7], thereby affecting many immunological processes in a powerful and rapid manner [8]. Primary and secondary lymphoid organs are innervated by nervous terminals secreting a variety of neurotransmitters [8].…”