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IL-23 signaling prevents ferroptosis-driven renal immunopathology during candidiasis

Author

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  • Nicolas Millet

    (Harbor-UCLA Medical Center
    The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center)

  • Norma V. Solis

    (Harbor-UCLA Medical Center
    The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center)

  • Diane Aguilar

    (The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center)

  • Michail S. Lionakis

    (National Institute of Allergy and Infectious Diseases (NIAID))

  • Robert T. Wheeler

    (University of Maine)

  • Nicholas Jendzjowsky

    (The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
    David Geffen School of Medicine at UCLA)

  • Marc Swidergall

    (Harbor-UCLA Medical Center
    The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
    David Geffen School of Medicine at UCLA)

Abstract

During infection the host relies on pattern-recognition receptors to sense invading fungal pathogens to launch immune defense mechanisms. While fungal recognition and immune effector responses are organ and cell type specific, during disseminated candidiasis myeloid cells exacerbate collateral tissue damage. The β-glucan receptor ephrin type-A 2 receptor (EphA2) is required to initiate mucosal inflammatory responses during oral Candida infection. Here we report that EphA2 promotes renal immunopathology during disseminated candidiasis. EphA2 deficiency leads to reduced renal inflammation and injury. Comprehensive analyses reveal that EphA2 restrains IL-23 secretion from and migration of dendritic cells. IL-23 signaling prevents ferroptotic host cell death during infection to limit inflammation and immunopathology. Further, host cell ferroptosis limits antifungal effector functions via releasing the lipid peroxidation product 4-hydroxynonenal to induce various forms of cell death. Thus, we identify ferroptotic cell death as a critical pathway of Candida-mediated renal immunopathology that opens a new avenue to tackle Candida infection and inflammation.

Suggested Citation

  • Nicolas Millet & Norma V. Solis & Diane Aguilar & Michail S. Lionakis & Robert T. Wheeler & Nicholas Jendzjowsky & Marc Swidergall, 2022. "IL-23 signaling prevents ferroptosis-driven renal immunopathology during candidiasis," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33327-4
    DOI: 10.1038/s41467-022-33327-4
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    1. Yilei Zhang & Robert V. Swanda & Litong Nie & Xiaoguang Liu & Chao Wang & Hyemin Lee & Guang Lei & Chao Mao & Pranavi Koppula & Weijie Cheng & Jie Zhang & Zhenna Xiao & Li Zhuang & Bingliang Fang & Ju, 2021. "mTORC1 couples cyst(e)ine availability with GPX4 protein synthesis and ferroptosis regulation," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
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    3. Bartosz Wiernicki & Sophia Maschalidi & Jonathan Pinney & Sandy Adjemian & Tom Vanden Berghe & Kodi S. Ravichandran & Peter Vandenabeele, 2022. "Cancer cells dying from ferroptosis impede dendritic cell-mediated anti-tumor immunity," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
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