The transcription factor HIF-1α mediates plasticity of NKp46+ innate lymphoid cells in the gut

Ewelina Krzywinska, Michal Sobecki, Shunmugam Nagarajan, Julian Zacharjasz, Murtaza M. Tambuwala, Abigaelle Pelletier, Eoin Cummins, Dagmar Gotthardt, Joachim Fandrey, Yann M. Kerdiles, Carole Peyssonnaux, Cormac T. Taylor, Veronika Sexl, Christian Stockmann

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2 Citations (Scopus)
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Abstract

Gut innate lymphoid cells (ILCs) show remarkable phenotypic diversity, yet microenvironmental factors that drive this plasticity are incompletely understood. The balance between NKp46+, IL-22-producing, group 3 ILCs (ILC3s) and interferon (IFN)-γ-producing group 1 ILCs (ILC1s) contributes to gut homeostasis. The gut mucosa is characterized by physiological hypoxia, and adaptation to low oxygen is mediated by hypoxia-inducible transcription factors (HIFs). However, the impact of HIFs on ILC phenotype and gut homeostasis is not well understood. Mice lacking the HIF-1α isoform in NKp46+ ILCs show a decrease in IFN-γ-expressing, T-bet+, NKp46+ ILC1s and a concomitant increase in IL-22-expressing, RORγt+, NKp46+ ILC3s in the gut mucosa. Single-cell RNA sequencing revealed HIF-1α as a driver of ILC phenotypes, where HIF-1α promotes the ILC1 phenotype by direct up-regulation of T-bet. Loss of HIF-1α in NKp46+ cells prevents ILC3-to-ILC1 conversion, increases the expression of IL-22-inducible genes, and confers protection against intestinal damage. Taken together, our results suggest that HIF-1α shapes the ILC phenotype in the gut. [Abstract copyright: © 2022 Krzywinska et al.]
Original languageEnglish
Article numbere20210909
JournalJournal of Experimental Medicine
Volume219
Issue number2
Early online date13 Jan 2022
DOIs
Publication statusPublished - 7 Feb 2022

Bibliographical note

Funding Information:
We acknowledge the support of the Swiss National Fund (310030_179235), the Swiss National Centre for Competence in Research “Kidney.CH” (project grant N-403-06-26 HCP), the Swiss Cancer League (KFS-4398-02-2018 and KFS-5402-08-2021), and support from the SKINTEGRITY.CH collaborative research program. M. Sobecki was supported by the internal postdoc funding program of the University of Zurich (For-schungskredit UZH Postdoc 2019).

Funding Information:
We thank the Laboratory Animal Services Center (LASC) for animal care; the UZH Irchel Flow Cytometry core facility and cell sorting core facility for cell sorting, especially Mario Wickert; the Functional Genomics Center Zurich facility for scRNA-seq service, especially Doris Popovic and Daym? Gonzalez Ro-driguez; and the Zurich Integrative Rodent Physiology facility, especially Petra Seebeck and Nadine N?gele. We acknowledge the support of the Swiss National Fund (310030_179235), the Swiss National Centre for Competence in Research ?Kidney.CH? (project grant N-403-06-26 HCP), the Swiss Cancer League (KFS-4398-02-2018 and KFS-5402-08-2021), and support from the SKINTEGRITY.CH collaborative research program. M. Sobecki was supported by the internal postdoc funding program of the University of Zurich (For-schungskredit UZH Postdoc 2019).

Publisher Copyright:
© 2022 Krzywinska et al.

Keywords

  • Immunology
  • Immunology and Allergy

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