ILC2 memory in asthma

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ABSTRACT Non-allergic asthma constitutes about 30% of the adult asthma population and is frequently associated with severe asthma. Unlike that of allergic asthma the mechanism of non-allergic asthma is poorly understood. Eosinophilic inflammation is common in non-allergic asthma. Whether environmental factors contribute to the pathogenesis of eosinophilic inflammation is unclear. We have developed a mouse model of asthma through repetitive exposure to allergen-associated PAMPs (Pathogen-associated Molecular Patterns). ILCs (innate lymphoid cells) from this model developed a PAMP-specific memory, which could be elicited with a subthreshold dose of the PAMP 3-15 weeks later. Based upon extensive preliminary results, we hypothesize that repetitive exposure to PAMPS leads to the formation of ILC memory, which constitutes two programs—a gene repression program and a preparedness program. The repression of previously activated genes forms the genetic basis for memory. This repression prevents host damage in the absence of the PAMPs. The preparedness program generates a rapid response to a subthreshold PAMP exposure through activation of the Fhl2-ERK1/2-AP1 pathway, which de-represses the previously marked genes and induces asthma (Fig. 1). We propose 3 specific aims to test this hypothesis. Under Aim 1 we will study allergen- and PAMP-elicited asthma and memory ILCs in mice and examine cross-reactivity among allergens and PAMPs. We will assess the importance of ILCs and the pattern recognition receptors in this asthma model. Under aim 2 we will elucidate the mechanism of formation of ILC memory. We will study the transcriptomic and epigenetic landscapes of allergen- and PAMP-induced memory ILCs and their persistence over time. The results from scRNA-seq and ATAC-seq from memory ILCs suggested a role for the repressor Bach2 and the preparedness pathway Fhl2- ERK1/2-Fosb for memory induction and recall, respectively. We will examine the role of Fhl2, Bach2 and FosB in a loss-of-function approach. Aim 3 will be devoted to human ILCs studies. We will examine the expression of the repression and preparedness program genes in human ILCs and study the mechanism of their induction. We will study the frequency of memory ILCs and their response to allergens and PAMPs in eosinophilic non- allergic asthmatic patients and establish their clinical correlation. We will employ unbiased and robust genomic approaches such as RNA-seq and ATAC-seq, and utilize innovative mouse models to test the novel concept of PAMP-elicited ILC memory. We will examine the molecular mechanism of non-allergic eosinophilic asthma, test therapeutic strategies, and seek to establish human relevance using clinical samples from asthmatic patients. We have the necessary expertise and tools to conduct the proposed experiments. The proposal will generate paradigm-shifting new knowledge and intervention strategies that will help treat non-allergic asthma.