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

Nicolas Millet, Norma V. Solis, Diane Aguilar, Michail S. Lionakis, Robert T. Wheeler, Nicholas Jendzjowsky and Marc Swidergall ()
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Nicolas Millet: Harbor-UCLA Medical Center
Norma V. Solis: 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
Marc Swidergall: Harbor-UCLA Medical Center

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-33327-4

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