- Skin Immunology
- Role of neuroinflammation in the outcome of the skin immune function
- Manipulation of neuroinflammation to treat chronic inflammatory skin disorders
Skin whole mount showing normal lymphatic and blood vessels in WT mice (left) and pathologic ones in neurokinin 1 receptor KO mice (right)
Relevant Finds from our lab:
- For more than two decades, the focus of my research has been to understand how the skin immune system works. We are interested in modifying the skin microenvironment for the development of immune-stimulatory or -suppressive vaccines. We focus in how skin secreted neuropeptides modify the function ofdendritic cells (DCs), mast cells (MCs) and T cells as initiators and effectors of cutaneous innate and adaptive immune responses.
- In search for efficient ways to improve or suppress DC and MC functions we developed a particular interest in the study of substance-P (SP) and hemokinin-1 (HK-1) two of the most potent pro-inflammatory neuropeptides secreted in the skin.
- We demonstrated that DCs express the neurokinin-1 receptor (NK1R) which is the high affinity receptor for SP and HK-1. Agonistic signaling of the receptor in the context of skin genetic immunizations promotes DC survival during Ag presentation resulting in potent cellular immune responses.
- We further described the cellular and molecular mechanisms following NK1R signaling in the activation and bias of naïve T cells in skin draining lymph nodes (sDLNs). Using NK1R agonists, we demonstrated that skin migratory DCs downregulate IL-10 to potentiate the T cell-stimulatory and type 1 functions of other DC residents or recruited to the sDLN.
- 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 the receptor 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.
Together 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 skin chronic inflammatory and atopic diseases.
Our new Projects:
Currently we are investigating the molecular mechanisms involved in the direct stimulation T cells by SP and HK-1 and in the role of blocking the NK1R for immune-suppressive immunizations to treat contact and atopic dermatitis. To this purpose, we use Ag and NK1R antagonists incorporated in self-dissolving microneedles arrays a technology that allows simultaneous, efficient and consistent delivery of biologics to specific skin strata.
- Sumpter TL, Ho CH, Pleet A, Tkacheva OA, Shufesky WJ, Rojas-Canales DM, Morelli AE, and Larregina AT. Autocrine hemokinin-1 functions as endogenous adjuvant for IgE-mediated mast cell inflammatory responses. J Allergy Clin Immunol. 135: 1019-1030, 2015.
- Larregina AT, Divito SJ and Morelli AE. Nociceptive neurons as targets to control immunity: Potential relevance for transplantation. Am J Transplant. 15: 1472-1474, 2015.
- Liu Q, Rojas-Canales DM, Divito SJ, Shufesky WJ, Stolz DB, Erdos G, Sullivan ML, Gibson GA, Watkins SC, Larregina AT, Morelli AE. Donor dendritic cell-derived exosomes promote allograft-targeting immune response. J Clin Invest. 126:2805-2820. 2016
- Li G, Larregina AT, Domsic RT, Stolz DB, Medsger TA Jr, Lafyatis R, Fuschiotti P. Skin-Resident Effector Memory CD8+CD28- T Cells Exhibit a Profibrotic Phenotype in Patients with Systemic Sclerosis. J Invest Dermatol. 137: 1042-1050. 2017
- Janelsins BM, Sumpter TL, Tkacheva OA, Erdos G, Mathers AR, Shufesky WJ, Storkus WJ, Falo LD Jr., Morelli AE, and Larregina AT. Neurokinin-1 receptor agonists bias therapeutic dendritic cells to induce type-1 immunity by licensing host dendritic cells to produce IL-12. Blood. 121: 2923-2933, 2013.
- Divito SJ, Morelli AE, and Larregina AT. Role of neurokinin-1 receptor in the initiation and maintenance of skin chronic inflammatory diseases. Immunol Res. 50: 195-201, 2011.
- Janelsins BM, Mathers AR, Tkacheva OA, Erdos G, Shufesky WJ, Morelli AE, and Larregina AT. Pro-inflammatory tachykinins that signal through the neurokinin 1 receptor promote survival of dendritic cells and potent cellular immunity. Blood. 113: 3017-3026, 2009
- Mathers AR, Janelsins BM, Rubin JP, Tkacheva OA, Shufesky WJ, Morelli AE, and Larregina AT. Differential capabilities of human cutaneous dendritic cell subsets to initiate Th17 responses. J Immunol. 182: 921-933, 2009.
- Mathers AR, Tckacheva OA, Janelsins BM, Shufesky WJ, Morelli AE, and Larregina AT. 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 and Larregina AT. Professional Antigen Presenting Cells of the Skin. Immunol Res. 36: 127-136, 2006
- Morelli AE, Rubin P, Tkacheva O, Zahorchack A, Thomson AW, Falo LD Jr. Larregina AT. Induction of CD4+ T cell responses by different subpopulations human skin dendritic cells. J Immunol. 175: 7905-7915, 2005.
- 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- β1. Nature Immunol. 2: 1151-1158, 2001.
NIH/NIAMS: R01 AR068249.
Title: Manipulating Cutaneous Neuroimmunity to Treat Contact Dermatitis
NIH/NIAMS: 1R01 AR071277
Title: MNA Delivery of Neurokinin 1 Receptor Antagonists to Treat Atopic Dermatitis
NIH/ NIHLBI: R01HL130191.
Title: Exosomes as paracrine signal mediators in cardiac allograft rejection.
Role: CoI. PI Adriana Morelli
Years: 02/1/2016 – 1/31/2020
NIH/NIAMS: K01 AR067250 Manipulating Neuropeptide Receptors in Mast Cells for Atopic Dermatitis Treatment
Role: Scientific Mentor. PI Tina Sumpter
Title Skin microenvironment targeted delivery for promoting immune and other responses. Falo LD Jr. Larregina AT. Co-Inventors.Ref. No. 8123-95880-03 Application No. 16/067,812, filed July 2, 2018. Country: USA