Diverse mechanisms and consequences of immunoadoption of neuromediator systems

Modern investigations of the mechanisms of both neuroregulation of immunity and neural effects of immune reactions have focused on identification of the mediators, their receptors, and signal transduction pathways in both systems. Less attention has been directed to delineation of the tissue context of neuroregulation of immunity that determines the principal sources of neuromediators, the physiological consequences of integration of neural and immune activities, and possible approaches to pharmacological manipulation. To illustrate these points, we describe here the corticotropin-releasing hormone (CRH) and vasoactive intestinal peptide (VIP) axes. When generated by the hypothalamus in response to inflammation or other stresses, CRH is immunosuppressive through its ability to increase levels of glucocorticoids and catecholamines. In contrast, CRH from peripheral nerves and immune accessory cells is immunostimulatory in tissue immune responses through direct effects on macrophages and lymphocytes. VIP released from several sets of nerves is immunosuppressive as a result of actions on macrophages and T cells in lymphoid organs, whereas VIP from immune cells in local tissue responses to antigen enhances development of some types of memory T cells and effector Th17 cells. Better understanding of how tissue context establishes the nature of neuroregulation of immunity will improve neuropharmacological and other neurotherapeutic approaches to immune diseases.