Allergic airway inflammation is a hallmark of asthma, one of the most common chronic diseases in the United States. While the contribution of the adaptive immune response, particularly the CD4+ Th2 cell, to the development of allergen-induced airway inflammation has been well described, the contribution of the innate immune response to the allergic phenotype is not clearly defined. The Group 2 innate lymphoid cell (ILC2) is a recently described lineage negative (Lin-) cell type that is present in humans and mice. ILC2s are far more potent producers of IL-5 and IL-13 on a per cell basis than CD4+ Th2 cells, and therefore may be critical to both the genesis and amplification of allergic inflammatory responses. So far, there are no known inhibitors of ILC2 cytokine secretion that are approved by the FDA for use in human diseases;however, our in vivo and in vitro preliminary data strongly suggests that prostaglandin (PG) I2 negatively regulates ILC2 function. Using a model of airway challenge with an extract of Alternaria alternata, a fungal aeroallergen that has been associated with severe asthma excaerbations, we found that mice deficient in the PGI2 receptor IP had a significant increase in lung IL-13 protein expression 6 hours after challenge, a time at which innate, and not adaptive, immunity predominates. Our in vitro preliminary data reveals that the PGI2 analog cicaprost significantly inhibited IL-5 and IL-13 protein expression from ILC2 purified from mouse bone marrow. The long term objective of this application is to define the role of PGI2 in ILC2 function in an allergen challenge model in mice and also in human ILC2 cells purified from peripheral blood.
In aim 1, we hypothesize that endogenous PGI2 signaling inhibits lung ILC2 cytokine expression and cell number in vivo. Investigating the role of endogenous PGI2 is critical to understanding the effect of cyclooxygenase-inhibiting drugs, one of the most widely used classes of over-the-counter medications in the world, on the innate allergic immune response as these agents inhibit PGI2 production.
In aim 2, we hypothesize that airway administration of an exogenous PGI2 analog inhibits lung ILC2 function and proliferation. Investigating the role of exogenous PGI2 is important to understand the potential effects of inhaled PGI2 or its analogs on the innate allergic immune response as such agents are FDA approved and currently used therapeutically for pulmonary hypertension, and therefore could be used to treat allergic respiratory diseases such as asthma.
In aim 3, we will determine the effect of PGI2 on human ILC2 cytokine expression and proliferation. The proposed studies are paradigm shifting in that they may identify the first inhibitor of ILC2 and will advance the field by determining the molecular mechanism by which PGI2 regulates ILC2 function.
Allergic diseases are a major burden to public health in the United States. This is of particular relevance to Veterans of the U.S. Military in whom the prevalence of allergic rhinitis is approximately 30% and allergic asthma is approximately 6%. Thus, allergic diseases are an important cause of morbidity among Veterans. Very recently, Group 2 innate lymphoid cells (ILC2) were discovered in both in mice and in people. ILC2 produces large quantities of specific proteins called cytokines that are important in the development of allergic inflammation. Our preliminary data suggests that a medication that is currently being used for the treatment of patients with pulmonary hypertension, prostaglandin (PG)I2, may be an important inhibitor of the inflammatory function of ILC2. Our proposal will define the mechanisms by which PGI2 blocks the initial phases of allergic airway inflammation and may be a novel and effective treatment for asthma.
|Toki, Shinji; Zhou, Weisong; Goleniewska, Kasia et al. (2018) Endogenous PGI2 signaling through IP inhibits neutrophilic lung inflammation in LPS-induced acute lung injury mice model. Prostaglandins Other Lipid Mediat 136:33-43
|Bloodworth, Melissa H; Rusznak, Mark; Bastarache, Lisa et al. (2018) Association of ST2 polymorphisms with atopy, asthma, and leukemia. J Allergy Clin Immunol 142:991-993.e3
|Brunwasser, Steven M; Gebretsadik, Tebeb; Gold, Diane R et al. (2018) A new model of wheezing severity in young children using the validated ISAAC wheezing module: A latent variable approach with validation in independent cohorts. PLoS One 13:e0194739
|Celada, Lindsay J; Kropski, Jonathan A; Herazo-Maya, Jose D et al. (2018) PD-1 up-regulation on CD4+ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-?1 production. Sci Transl Med 10:
|Turi, Kedir N; Shankar, Jyoti; Anderson, Larry J et al. (2018) Infant Viral Respiratory Infection Nasal Immune-Response Patterns and Their Association with Subsequent Childhood Recurrent Wheeze. Am J Respir Crit Care Med 198:1064-1073
|Stone Jr, Cosby A; McEvoy, Cindy T; Aschner, Judy L et al. (2018) Update on Vitamin E and Its Potential Role in Preventing or Treating Bronchopulmonary Dysplasia. Neonatology 113:366-378
|Tashkin, Donald P; Peebles Jr, R Stokes (2018) Controversies in Allergy: Is Asthma Chronic Obstructive Pulmonary Disease Overlap a Distinct Syndrome That Changes Treatment and Patient Outcomes? J Allergy Clin Immunol Pract :
|Stone Jr, Cosby A; Hemler, Jonathan A; Commins, Scott P et al. (2018) Reply. J Allergy Clin Immunol 141:1957-1958
|Rosas-Salazar, Christian; Shilts, Meghan H; Tovchigrechko, Andrey et al. (2018) Nasopharyngeal Lactobacillus is associated with a reduced risk of childhood wheezing illnesses following acute respiratory syncytial virus infection in infancy. J Allergy Clin Immunol 142:1447-1456.e9
|Bloodworth, Melissa H; Rusznak, Mark; Pfister, Connor C et al. (2018) Glucagon-like peptide 1 receptor signaling attenuates respiratory syncytial virus-induced type 2 responses and immunopathology. J Allergy Clin Immunol 142:683-687.e12
Showing the most recent 10 out of 42 publications