Regulation of ferroptosis in type-2 immune responses

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Type-2 immune responses can drive inflammation (e.g. in asthma) or promote host defense and repair (e.g. during infection with worm parasites (helminths)). Type-2 immunity is typically associated with tissue damage, caused e.g. by helminth larvae or protease allergens. Ferroptosis, a form of programmed oxidative cell death, is involved in tissue injury (e.g. in the kidney or brain), but its involvement and regulation in type-2 immune contexts are poorly understood. Type-2 immune responses are instrumental for tissue repair, suggesting that ferroptosis has to be tightly regulated in order to prevent excessive damage in type-2 immune settings. The current project aims at characterizing ferroptosis markers in mouse models of type-2 immunity (allergic airway inflammation and helminth infection) and to define mechanisms of ferroptosis regulation in these settings. We will focus on ferroptosis in macrophages and epithelial cells as key cells involved in the initiation of type-2 immune responses and in inflammation, immune regulation and tissue repair. In our previous work, we have identified helminth proteins (Hpb glutamate dehydrogenase (GDH) and Hpb Ferritin), which can regulate the expression and/ or activity of lipoxygenases implicated in lipid peroxidation. The main activities of these helminth enzymes are glutamate metabolism (GDH) and iron binding (Ferritin). As lipoxygenase products, glutamate and iron promote ferroptosis, we aim to study whether and how Hpb GDH and Hpb Ferritin can suppress ferroptosis in human and murine macrophages as well as in human airway epithelial cells. In addition to studying ferroptosis regulation by helminth proteins, we have identified host factors that may regulate ferroptosis in type-2 immune responses: While the enzyme transglutaminase-2 (TG2) may act as a positive regulator of ferroptosis, apolipoprotein E (ApoE) may prevent macrophage and epithelial cell ferroptosis. To study the role of TG2, we will make use of macrophages from mice lacking TG2 in immune cells or of pharmacological inhibitors, CRISPR/Cas9 or siRNA to target TG2 in human cells. Ferroptosis markers will be assessed in mice with a conditional TG2 deficiency, to study the involvement of immune cell-derived TG2 in ferroptosis during intestinal helminth infection or allergic airway inflammation. Our previous work has shown that ApoE is downregulated in the nasal epithelium and in macrophages of patients suffering from nasal polyps and asthma. Thus, we aim to study whether low ApoE levels in patient cells result in increased susceptibility to ferroptotic cell death and to define the mechanisms by which ApoE may protect cells against lipid peroxidation and ferroptosis. The project will provide insights into ferroptosis regulation in type-2 immunity with potential relevance for type-2 driven pathologies and interrogate helminth proteins as regimens against ferroptosis with potential therapeutic application in inflammatory and degenerative diseases.