IL-23 signaling prevents ferroptosis-driven renal immunopathology during candidiasis.
During infection, a dysregulated immune response can lead to tissue damage, organ dysfunction and finally death. This pathologic immune response, called immunopathology, can be triggered by several host factors such as the age of the host, previous exposure to the same or other pathogens, dose and route of infection, genetics and many others. However, in many infectious diseases, cell death is a critical factor that can elicit immune responses resulting in uncontrolled immunopathology. In our recent Nature Communications paper, we demonstrated that during invasive fungal infection caused by Candida albicans, immunopathology results from a specific form of oxidative-induced cell death. This cell death, namely ferroptosis, leads to membrane damage and cell lysis. Ferroptosis occurs in infected tissues and exacerbates immune responses while at the same time reducing fungal killing capacity of immune cell such as macrophages. Interestingly, pharmacological blockade or treatment with a specific inflammatory mediator can prevent ferroptotic host cell death during infection; thus, limiting inflammation, and immunopathology. Therefore, we identify ferroptotic cell death as a critical pathway of Candida-mediated immunopathology that may provide a new perspective for therapy for fungal diseases.
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 beta-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.