title: Proinflammatory tachykinins that signal through the neurokinin 1 receptor promote survival of dendritic cells and potent cellular immunity.
abstract: Dendritic cells (DCs) are the preferred targets for immunotherapy protocols focused on stimulation of cellular immune responses. However, regardless of initial promising results, ex vivo generated DCs do not always promote immune-stimulatory responses. The outcome of DC-dependent immunity is regulated by proinflammatory cytokines and neuropeptides. Proinflammatory neuropeptides of the tachykinin family, including substance P (SP) and hemokinin-1 (HK-1), bind the neurokinin 1 receptor (NK1R) and promote stimulatory immune responses. Nevertheless, the ability of pro-inflammatory tachykinins to affect the immune functions of DCs remains elusive. In the present work, we demonstrate that mouse bone marrow-derived DCs (BMDCs) generated in the presence of granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin-4 (IL-4), express functional NK1R. Signaling via NK1R with SP, HK-1, or the synthetic agonist [Sar(9)Met(O(2))(11)]-SP rescues DCs from apoptosis induced by deprivation of GM-CSF and IL-4. Mechanistic analysis demonstrates that NK1R agonistic binding promotes DC survival via PI3K-Akt signaling cascade. In adoptive transfer experiments, NK1R-signaled BMDCs loaded with Ag exhibit increased longevity in draining lymph nodes, resulting in enhanced and prolonged effector cellular immunity. Our results contribute to the understanding of the interactions between the immune and nervous systems that control DC function and present a novel approach for ex vivo-generation of potent immune-stimulatory DCs.
authors.affiliation: Department of Dermatology, University of Pittsburgh School of Medicine, PA, USA.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Janelsins
authors.forename: Alicia R
authors.initials: AR
authors.lastname: Mathers
authors.forename: Olga A
authors.initials: OA
authors.lastname: Tkacheva
authors.forename: Geza
authors.initials: G
authors.lastname: Erdos
authors.forename: William J
authors.initials: WJ
authors.lastname: Shufesky
authors.forename: Adrian E
authors.initials: AE
authors.lastname: Morelli
authors.forename: Adriana T
authors.initials: AT
authors.lastname: Larregina
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001854:Bone Marrow Cells / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology / Q000637:transplantation; D004789:Enzyme Activation / Q000187:drug effects; D007111:Immunity, Cellular / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D018836:Inflammation Mediators / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D015320:Tachykinins / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D019013:CD40 Antigens; D018836:Inflammation Mediators; D018040:Receptors, Neurokinin-1; D015320:Tachykinins; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt