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Updated: Aug 28, 2025
Th17 Inflammation Model of Oropharyngeal Candidiasis in Immunodeficient Mice
Published on: February 18, 2015
IL-23 signaling prevents ferroptosis-driven renal immunopathology during candidiasis
Nicolas Millet1,2, Norma V Solis1,2, Diane Aguilar2
1Division of Infectious Diseases, Harbor-UCLA Medical Center, Torrance, CA, USA.
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.
Insights
The EphA2 receptor drives kidney damage during Candida infections by hindering anti-inflammatory IL-23. Blocking EphA2 reduces kidney injury and inflammation, offering new therapeutic targets for fungal infections.
Area of Science:
- Immunology
- Mycology
- Pathology
Background:
- Host immune cells use pattern-recognition receptors to detect fungal pathogens and initiate defense.
- During disseminated candidiasis, myeloid cells can cause significant tissue damage.
- The ephrin type-A 2 receptor (EphA2) is known to be crucial for immune responses in oral Candida infections.
Purpose of the Study:
- To investigate the role of EphA2 in renal immunopathology during disseminated candidiasis.
- To understand the mechanisms by which EphA2 influences kidney inflammation and injury.
- To explore the connection between EphA2, dendritic cell function, IL-23 signaling, and ferroptosis.
Main Methods:
- Utilized mouse models of disseminated candidiasis.
- Analyzed renal inflammation and injury in wild-type and EphA2-deficient mice.
- Performed comprehensive analyses of dendritic cell function, including IL-23 secretion and migration.
- Investigated the role of IL-23 signaling and ferroptosis in the host's response to Candida.
Main Results:
- EphA2 deficiency significantly reduced renal inflammation and injury during disseminated candidiasis.
- EphA2 was found to restrain the secretion and migration of dendritic cells, impacting IL-23 levels.
- IL-23 signaling was shown to protect against ferroptotic host cell death, thereby limiting inflammation.
- Host cell ferroptosis was identified as a mechanism that impairs antifungal immunity by releasing 4-hydroxynonenal.
Conclusions:
- EphA2 plays a critical role in promoting kidney immunopathology during disseminated candidiasis.
- Targeting EphA2 or modulating IL-23 signaling may offer therapeutic strategies to mitigate Candida-induced renal damage.
- Ferroptotic cell death is a key pathway in Candida-mediated renal immunopathology, presenting a novel target for intervention.
