Autophagy is critical for group 2 innate lymphoid cell metabolic homeostasis and effector function

Lauriane Galle-Treger, Benjamin P. Hurrell, Gavin Lewis, Emily Howard, Pedram Shafiei Jahani, Homayon Banie, Babak Razani, Pejman Soroosh, Omid Akbari

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2 Scopus citations

Abstract

Background: Allergic asthma is a chronic inflammatory disorder characterized by airway hyperreactivity (AHR) and driven by TH2 cytokine production. Group 2 innate lymphoid cells (ILC2s) secrete high amounts of TH2 cytokines and contribute to the development of AHR. Autophagy is a cellular degradation pathway that recycles cytoplasmic content. However, the role of autophagy in ILC2s remains to be fully elucidated. Objective: We characterized the effects of autophagy deficiency on ILC2 effector functions and metabolic balance. Methods: ILC2s from autophagy-deficient mice were isolated to evaluate proliferation, apoptosis, cytokine secretion, gene expression and cell metabolism. Also, autophagy-deficient ILC2s were adoptively transferred into Rag−/−GC−/− mice, which were then challenged with IL-33 and assessed for AHR and lung inflammation. Results: We demonstrate that autophagy is extensively used by activated ILC2s to maintain their homeostasis and effector functions. Deletion of the critical autophagy gene autophagy-related 5 (Atg5) resulted in decreased cytokine secretion and increased apoptosis. Moreover, lack of autophagy among ILC2s impaired their ability to use fatty acid oxidation and strikingly promoted glycolysis, as evidenced by our transcriptomic and metabolite analyses. This shift of fuel dependency led to impaired homeostasis and TH2 cytokine production, thus inhibiting the development of ILC2-mediated AHR. Notably, this metabolic reprogramming was also associated with an accumulation of dysfunctional mitochondria, producing excessive reactive oxygen species. Conclusion: These findings provide new insights into the metabolic profile of ILC2s and suggest that modulation of fuel dependency by autophagy is a potentially new therapeutic approach to target ILC2-dependent inflammation.

Original languageEnglish
Pages (from-to)502-517.e5
JournalJournal of Allergy and Clinical Immunology
Volume145
Issue number2
DOIs
StatePublished - Feb 2020

Keywords

  • Group 2 innate lymphoid cells
  • airway hyperreactivity
  • autophagy
  • immune metabolism

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    Galle-Treger, L., Hurrell, B. P., Lewis, G., Howard, E., Jahani, P. S., Banie, H., Razani, B., Soroosh, P., & Akbari, O. (2020). Autophagy is critical for group 2 innate lymphoid cell metabolic homeostasis and effector function. Journal of Allergy and Clinical Immunology, 145(2), 502-517.e5. https://doi.org/10.1016/j.jaci.2019.10.035