My laboratory focuses on the role of modulating the skin microenvironment by stimulation or blockade of neuroinflammation. We have demonstrated that agonistic signaling of the neurokinin-1 receptor (NK1R) expressed in skin inflammatory cells promotes the optimal milieu for the generation of immune-stimulatory dendritic cells (DC) the most potent Ag presenting cell known. In search for efficient ways to improve DC-based immunostimulatory functions relevant for vaccine development and focusing on the identification of low toxicity skin secreted adjuvants, we developed a particular interest in the study of substance-P (SP) and hemokinin-1 (HK-1). Our group pioneered the use of pro-inflammatory neuropeptides as adjuvants for positive immunizations. We demonstrated that human and mouse DCs express the neurokinin-1 receptor (NK1R) which is the high affinity receptor for SP and HK-1. Our group also described the molecular and, intracellular signaling mechanisms following receptor-agonist interaction in the regulation of DC immune functions. Using natural and synthetic NK1R agonists, we demonstrated that DCs become potent stimulators of CD4/Th1- and CD8/Tc1-biased lymphocytes an approach that we used to potentiate the immune response to skin immunizations.
More recently, and to understand other inflammatory mechanisms employed by NK1R agonists to modulate innate immune responses and bias of Th2 lymphocytes, we are investigating the role of signaling via NK1R in the outcome of inflammatory responses mediated by IgE activated mast cells (MCs). We described that MCs synthesize and secrete HK-1 and NK1R-signaling by autocrine HK-1 potentiates the inflammatory functions of IgE activated MCs. Mechanistic studies demonstrated that HK-1 increases the expression of the high affinity IgE receptor, triggers MC degranulation, and augments the synthesis of TNF-α and IL-6, cytokines necessary for development of Th2 responses underlying allergic diseases. These relevant data demonstrated for the first time that NK1R-signaling in vivo provides adjuvant effect to type 1 cellular immunity as well as to Th2 humoral immunity that sustains inflammatory skin and respiratory atopic diseases.
- Larregina AT (Corresponding author), Morelli AE, Spencer LA, Logar A, Watkins SC, Thomson AW and Falo LD Jr. Dermal CD14+ cells differentiate into Langerhans cells in the presence of GM-SCF, IL-4 and TGF- b1. Nature Immunol. 2: 1151-1158, 2001.
- Larregina AT (Corresponding author), Morelli AE, Tkacheva Olga , Erdos G, Watkins SC, Thomson AW and Falo LD Jr. Highly efficient expression of transgenic proteins by naked DNA-transfected dendritic cells through terminal differentiation. Blood. 103: 811-819. 2004.
- Morelli AE, Rubin P, Tkacheva O, Zahorchack A, Thomson AW, Falo LD Jr. and Larregina AT. (Corresponding author). Induction of CD4+ T cell responses by different subpopulations human skin dendritic cells. J Immunol. 175: 7905-7915, 2005.
- Mathers AR and Larregina AT (Correponding author). Professional Antigen Presenting Cells of the Skin. Immunol Res. 36: 127-136, 2006.
- Mathers AR, Tckacheva OA, Janelsins BM, Shufesky WJ, Morelli AE, and Larregina AT. (Corresponding author). In vivo signaling through the neurokinin 1 receptor favors transgene expression by Langerhans cells and promotes the generation of Th1-Tc1 biased immune responses. J Immunol. 78:7006-7017, 2007.
- Mathers AR, Janelsins BM, Rubin JP, Tkacheva OA, Shufesky WJ, Morelli AE, and Larregina AT. (Corresponding author). Differential capabilities of human cutaneous dendritic cell subsets to initiate Th17 responses. J Immunol. 182: 921-933, 2009.
- Janelsins BM, Mathers AR, Tkacheva OA, Erdos G, Shufesky WJ, Morelli AE, and Larregina AT. (Corresponding author). Pro-inflammatory tachykinins that signal through the neurokinin 1 receptor promote survival of dendritic cells and potent cellular immunity. Blood. 113: 3017-3026, 2009.
- Divito SJ, Morelli AE, and Larregina AT (Corresponding author). Role of neurokinin-1 receptor in the initiation and maintenance of skin chronic inflammatory diseases. Immunol Res. 50: 195-201, 2011.
- Sumpter TL, Ho CH, Pleet A, Tkacheva OA, Shufesky WJ, Rojas-Canales DM, Morelli AE, and Larregina AT (Corresponding author). Autocrine hemokinin-1 functions as endogenous adjuvant for IgE-mediated mast cell inflammatory responses. J Allergy Clin Immunol. 135: 1019-1030, 2015.
- Larregina AT (Corresponding author), Divito SJ and Morelli AE. Nociceptive neurons as targets to control immunity: Potential relevance for transplantation. Am J Transplant. 15: 1472-1474, 2015.