Transcriptional and metabolomic regulation of IL-10 in pulmonary ILC2s

Abstract
ILC2s are the dominant innate lymphoid cell population in the lungs at steady state and their release of type-2
cytokines is a central driver in responding eosinophil infiltration, increased airway hyperreactivity and associated
lung tissue injury. Previously, our laboratory identified a subset of ILC2s (ILC210s) that actively produce and
secrete IL-10, an anti-inflammatory cytokine with the ability to ameliorate allergic lung inflammation signaling (J
Allergy Clin Immunol., 2020). Importantly, these results have been confirmed by other groups in a variety of
allergic disease models (J Exp Med., 2020, Immunity, 2021). The proposed research plan is motivated by
recent preliminary observations demonstrating that key molecular and transcriptional requirements may be
required for the induction of IL-10, with the potential for targeted modulation. SA1 is intended to explore the
regulation of transcription factors for the induction of IL-10. We propose a series of experiments in acute and
chronic models of allergic airway inflammation to assess the involvement of key transcription factors cMaf and
Blimp-1 first by expansive, cutting-edge chromatin sequencing methods, and next by retroviral induction and
knock-out mouse models. In SA2, we also observed that production of IL-10 relies significantly on key metabolic
pathways often utilized by ILC2s. We intend to expand our studies by investigating the role of glycolysis, fatty
acid oxidation and signaling protein AMPK, with the aim of identifying mechanistic targets for the potential
modulatory therapies for allergic disease. Additionally, mitochondrial regulation of IL-10 production with be
explored through in vitro and ex vivo mitochondrial dynamic assays. Finally, the two parts of this project come
together to address specific transcriptional and metabolic requirements for the modulation of pathogenic ILC2s
with the intention of targeted conversion to ILC210s with the ability to regulate airway hyperreactivity. The results
obtained from this study will provide novel insights into an important and understudied role of ILC210s in diseases
associated with ILC2s such as allergic lung inflammation and asthma.

Grant Number: 5R01AI169687-04
NIH Institute/Center: NIH
Principal Investigator: OMID AKBARI