title: A fundamental bimodal role for neuropeptide Y1 receptor in the immune system.
abstract: Psychological conditions, including stress, compromise immune defenses. Although this concept is not novel, the molecular mechanism behind it remains unclear. Neuropeptide Y (NPY) in the central nervous system is a major regulator of numerous physiological functions, including stress. Postganglionic sympathetic nerves innervating lymphoid organs release NPY, which together with other peptides activate five Y receptors (Y1, Y2, Y4, Y5, and y(6)). Using Y1-deficient (Y1(-/-)) mice, we showed that Y1(-/-) T cells are hyperresponsive to activation and trigger severe colitis after transfer into lymphopenic mice. Thus, signaling through Y1 receptor on T cells inhibits T cell activation and controls the magnitude of T cell responses. Paradoxically, Y1(-/-) mice were resistant to T helper type 1 (Th1) cell-mediated inflammatory responses and showed reduced levels of the Th1 cell-promoting cytokine interleukin 12 and reduced interferon gamma production. This defect was due to functionally impaired antigen-presenting cells (APCs), and consequently, Y1(-/-) mice had reduced numbers of effector T cells. These results demonstrate a fundamental bimodal role for the Y1 receptor in the immune system, serving as a strong negative regulator on T cells as well as a key activator of APC function. Our findings uncover a sophisticated molecular mechanism regulating immune cell functions that can lead to stress-induced immunosuppression.
authors.affiliation: The Arthritis and Inflammation Research Program, The Garvan Institute of Medical Research, Darlinghurst NSW 2010, Australia.
authors.forename: Julie
authors.initials: J
authors.lastname: Wheway
authors.forename: Charles R
authors.initials: CR
authors.lastname: Mackay
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Newton
authors.forename: Amanda
authors.initials: A
authors.lastname: Sainsbury
authors.forename: Dana
authors.initials: D
authors.lastname: Boey
authors.forename: Herbert
authors.initials: H
authors.lastname: Herzog
authors.forename: Fabienne
authors.initials: F
authors.lastname: Mackay
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D001327:Autoimmune Diseases / Q000097:blood / Q000235:genetics / Q000276:immunology; D003092:Colitis / Q000097:blood / Q000235:genetics / Q000276:immunology; D005260:Female; D007249:Inflammation / Q000097:blood / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D018655:Lymphocyte Count; D008221:Lymphoid Tissue / Q000276:immunology / Q000294:innervation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009478:Neuropeptide Y / Q000276:immunology*; D017476:Receptors, Neuropeptide Y / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013315:Stress, Psychological / Q000097:blood / Q000235:genetics / Q000276:immunology*; D017779:Sympathetic Fibers, Postganglionic / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology* / Q000637:transplantation
chemical_list: D009478:Neuropeptide Y; D017476:Receptors, Neuropeptide Y; C097212:neuropeptide Y-Y1 receptor; D018664:Interleukin-12; D007371:Interferon-gamma