Submitted June 13, 2008
Accepted October 13, 2008
Pro-inflammatory tachykinins that signal through the neurokinin 1 receptor promote survival of dendritic cells and potent cellular immunity
Brian M Janelsins, Alicia R Mathers, Olga A Tkacheva, Geza Erdos, William J Shufesky, Adrian E Morelli, and Adriana T Larregina*
Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
Departments of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
T.E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
* Corresponding author; email: adrianal{at}pitt.edu.
Dendritic cells (DCs) are the preferred targets for immune-therapy 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 pro-inflammatory cytokines and neuropeptides. Pro-inflammatory 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 GM-CSF and IL-4, express functional NK1R. Signaling via NK1R with SP, HK-1 or the synthetic agonist [Sar9Met(O2)11]-SP (SarSP) 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.
