1. IL-10 production by ILC2s requires Blimp-1 and cMaf, modulates cellular metabolism, and ameliorates airway hyperreactivity.
- Author
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Howard E, Lewis G, Galle-Treger L, Hurrell BP, Helou DG, Shafiei-Jahani P, Painter JD, Muench GA, Soroosh P, and Akbari O
- Subjects
- Animals, Bronchoalveolar Lavage Fluid immunology, Female, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Mice, Asthma immunology, Bronchial Hyperreactivity immunology, Interleukin-10 immunology, Lymphocytes immunology, Positive Regulatory Domain I-Binding Factor 1 immunology, Proto-Oncogene Proteins c-maf immunology
- Abstract
Background: Group 2 innate lymphoid cells (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 and increased airway hyperreactivity. Our laboratory has identified a unique subset of ILC2s in the lungs that actively produce IL-10 (ILC2
10 s)., Objective: Our aim was to characterize the effector functions of ILC210 s in the development and pathology of allergic asthma., Methods: IL-4-stimulated ILC210 s were isolated to evaluate cytokine secretion, transcription factor signaling, metabolic dependence, and effector functions in vitro. ILC210 s were also adoptively transferred into Rag2-/- γc-/- mice, which were then challenged with IL-33 and assessed for airway hyperreactivity and lung inflammation., Results: We have determined that the transcription factors cMaf and Blimp-1 regulate IL-10 expression in ILC210 s. Strikingly, our results demonstrate that ILC210 s can utilize both autocrine and paracrine signaling to suppress proinflammatory ILC2 effector functions in vitro. Further, this subset dampens airway hyperreactivity and significantly reduces lung inflammation in vivo. Interestingly, ILC210 s demonstrated a metabolic dependency on the glycolytic pathway for IL-10 production, shifting from the fatty acid oxidation pathway conventionally utilized for proinflammatory effector functions., Conclusion: These findings provide an important and previously unrecognized role of ILC210 s in diseases associated with ILC2s such as allergic lung inflammation and asthma. They also provide new insights into the metabolism dependency of proinflammatory and anti-inflammatory ILC2 phenotypes., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)- Published
- 2021
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