Obesity is an important risk factor for asthma, but obese asthmatics have limited therapeutic options. The goal of this project is to understand the mechanistic basis for obesity-related asthma so as uncover novel therapeutic targets. Our data indicate that obese mice exhibit increased responses to acute ozone (O3) exposure, a human asthma trigger. We will examine the hypothesis that obesity-related increases in responses to O3, including airway closure, airway hyperresponsiveness (AHR), and neutrophil recruitment, are the result of interactions between IL-17A and IL-33. Rationale: IL-17A and IL-33 are known to synergize to induce AHR. We show that O3 causes greater increases in BAL IL-17A and IL-33 in obese than lean mice, and that anti-IL-17A and anti-ST2 both reduce obesity-related increases in pulmonary responses to O3. ST2 is the receptor for IL-33. Our data suggest a novel role for GRPR in the effects of IL-17A, likely released from type 3 innate lymphoid cells (ILCs). GRPR is the receptor for gastrin releasing peptide (GRP), a peptide released from pulmonary neuroendocrine cells. Our data also suggest that type 2 ILCs (ILC2), are one target of IL-33, but that effects of IL-33 on epithelial cells may also be involved.
Three aims are proposed.
In Aim 1, using GRPR or IL-17A deficient mice, we will test the hypothesis that IL-17A promotes obesity-related increases in the response to O3 by inducing GRPR expression. We will determine whether obesity alters lung GRP and GRPR amount and localization. Our hypothesis is that GRPR on epithelial cells is involved and we will evaluate synergy between IL-17A and IL-33 both in vivo and in vitro. For the latter experiments, we have established that IL-33 and IL-17A synergize to induce GRPR expression in human airway epithelial cells in ALI culture, and we will determine whether GRP acting on these epithelial cells produces moieties that promote bronchoconstriction, AHR, or neutrophil recruitment.
In Aim 2, we will test the hypothesis that IL-33 promotes obesity-related increases in the response to O3 by evoking release of type 2 cytokines, using obese and lean ST2 deficient mice. Flow cytometry will be used to assess IL-13+, IL-5+, and IL-9+ ILC2s and IL-13+, IL-5+, and IL-9+ ?? T cells (which may also be involved) in lungs of these mice.
In Aim 3, we will use Rag2-/- and Rag2-/-/?c-/- mice to determine whether ILC3 are the source of IL-17A and whether ILC2 and/or ?? T cells are the source of type 2 cytokines that contribute to augmented effects of O3 in obese mice. Adoptive transfer of ILC3 from WT or IL-17A-/- mice into obese IL-17A-/- mice and adoptive transfer of ILC2 or ?? T cells from WT or ST2-/- mice into obese ST2-/- mice will be used to determine the importance of these cells. Impact: If borne out, these studies would provide proof of concept for therapeutic strategies (anti IL-17A, anti-GRP, anti-IL-33, ligands targeting ILC2s) for the treatment of obese asthmatics.
Obesity is a risk factor for asthma, but standard asthma drugs have reduced efficacy in obese asthmatics, leaving these patients with limited therapeutic options. The purpose of these studies is to determine how two key cytokines, IL-17A and IL-33, contribute to asthma-like changes in the lungs. Such studies could lead to the development of new treatments for obesity-related asthma.
| Mathews, Joel A; Krishnamoorthy, Nandini; Kasahara, David I et al. (2018) Augmented Responses to Ozone in Obese Mice Require IL-17A and Gastrin-Releasing Peptide. Am J Respir Cell Mol Biol 58:341-351 |
| Cho, Youngji; Abu-Ali, Galeb; Tashiro, Hiroki et al. (2018) The Microbiome Regulates Pulmonary Responses to Ozone in Mice. Am J Respir Cell Mol Biol 59:346-354 |
| Kasahara, D I; Mathews, J A; Ninin, F M C et al. (2017) Role of ROCK2 in CD4+ cells in allergic airways responses in mice. Clin Exp Allergy 47:224-235 |
| Mathews, Joel Andrew; Kasahara, David Itiro; Cho, Youngji et al. (2017) Effect of acute ozone exposure on the lung metabolomes of obese and lean mice. PLoS One 12:e0181017 |
| Mathews, Joel A; Krishnamoorthy, Nandini; Kasahara, David Itiro et al. (2017) IL-33 Drives Augmented Responses to Ozone in Obese Mice. Environ Health Perspect 125:246-253 |
| Shore, Stephanie A (2017) Mechanistic Basis for Obesity-related Increases in Ozone-induced Airway Hyperresponsiveness in Mice. Ann Am Thorac Soc 14:S357-S362 |
| Brand, Jeffrey D; Mathews, Joel A; Kasahara, David I et al. (2016) Regulation of IL-17A expression in mice following subacute ozone exposure. J Immunotoxicol 13:428-38 |
| Rosenblum Lichtenstein, Jamie H; Molina, Ramon M; Donaghey, Thomas C et al. (2016) Repeated Mouse Lung Exposures to Stachybotrys chartarum Shift Immune Response from Type 1 to Type 2. Am J Respir Cell Mol Biol 55:521-531 |
| Shore, Stephanie A; Cho, Youngji (2016) Obesity and Asthma: Microbiome-Metabolome Interactions. Am J Respir Cell Mol Biol 54:609-17 |
| Cho, Youngji; Shore, Stephanie A (2016) Obesity, Asthma, and the Microbiome. Physiology (Bethesda) 31:108-16 |
Showing the most recent 10 out of 49 publications
