Group 2 innate lymphoid cells (ILC2s) constitute a recently identified cell population that produces type 2 cytokines such as IL-5 and IL-13 in response to a growing number of environmental signals and epithelial cell-derived cytokines. Initially described as a key source of IL-13 in anti-helminth innate immunity, studies now show increased ILC2 activity in asthma and many widespread allergic diseases. In murine models of asthma, ILC2s are sufficient to provoke eosinophilic inflammation accompanied by airway hyperreactivity (AHR) independent of adaptive immunity. Based on these findings, identifying agents capable of modulating ILC2 function is an important step towards advancing treatment of asthma. This project is motivated by our recent finding that sodium butyrate, a short-chain fatty acid (SCFA) naturally present in our body?s tissues and fluids, significantly suppresses the production of type 2 cytokines by ILC2s and relieves ILC2-dependent AHR. We additionally found that pulmonary ILC2s highly express a receptor for sodium butyrate, GPR109a and do not express GPR41 or GPR43. Further transcriptome analyses revealed that GATA-3, a key transcription factor in ILC2 development and function, was significantly down-regulated after treatment with sodium butyrate. Given that intestinal bacteria are the predominant source of butyrate in mammals, we now propose to characterize the mechanisms by which microbial-derived sodium butyrate potentially modulates ILC2 effector function in distal tissues and reduces ILC2-dependent AHR. The overall goal of this research project is to discover a comprehensive set of molecular signatures and markers that can be used as therapeutic targets to treat allergic disease and asthma. In order to achieve this objective, we will first fully characterize the phenotype, function, and mechanisms of action of sodium butyrate in animal models of AHR. Next, utilizing a recently described ILC2 humanized mice (Maazi et al, Immunity 2015, Galle et al, Nature Communications 2016), we intend to assess the capacity for therapeutic intervention in the presence of absence of GPR109a receptor. Finally, we will aim to prevent development of ILC2 dependent AHR via altering microbiome of mice with high butyrate producing strains of bacteria and compare the results to the recipients of microbiome without capacity to produce butyrate. This translational research proposal will provide critical clues that enable us to develop therapeutic approaches for the treatment of patients with allergic disease and asthma.
The results of these studies will have a direct impact on our fundamental understanding of the immune responses that occur in the respiratory system. We propose to study for the first time a novel cell type that primarily influences the development of respiratory inflammation such as asthma. Asthma represents a significant public health problem, as it affects 10-15% of the general population, and its prevalence has doubled over the past two decades.
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|Maazi, Hadi; Akbari, Omid (2017) Type two innate lymphoid cells: the Janus cells in health and disease. Immunol Rev 278:192-206|
|Poposki, Julie A; Klingler, Aiko I; Tan, Bruce K et al. (2017) Group 2 innate lymphoid cells are elevated and activated in chronic rhinosinusitis with nasal polyps. Immun Inflamm Dis 5:233-243|