Work

The E3 Ubiquitin ligase Cul5 limits ILC2 cell responses in the lung following helminth infection 3325

Year: 2025

Type: article

Abstract: Description Over 600 million people are currently infected with hookworms. Hookworm infection is known to cause tissue damage, malnutrition, and anemia, particularly in children. While adult hookworms live in the GI tract, significant damage occurs when larvae burrow into the skin, transit thru the lung, and enter the gut. A tissue-localised anti-helminth immune response is mediated by type 2 innate lymphocytes (ILC2s). We have identified a novel lung biased regulatory circuit in ILC2s that limits their responses to epithelial derived alarmins following infection by Nippostrongylus brasiliensis (Nb). This circuit limits the collateral damage that occurs when immune cells invade the lung to kill migrating larvae. This regulatory circuit is initiated by the E3 ubiquitin ligase Cul5. Mice lacking Cul5 in ILC2 cells (Cul5fl/fl Red5 mice) clear Nb infection more rapidly than WT controls but show increased innate cell recruitment and sustained lung damage. Single cell RNA sequencing of ILC2 cells isolated from the lungs of WT and Cul5fl/fl-Red5 mice on day 3 following infection revealed that increased larvae killing correlated with an expansion of IL-18R+ILC2 cells that produce high levels of IL-13 and help to recruit innate cells known to participate in larvicidal activity. Here we provide data supporting that IL-18R+ ILC2 cells promote larval killing in the lung following Nb infection, and provide evidence that Cul5 forms a ubiquitin complex that limits IL-18R signaling in these ILC2s. Funding Sources NIH funded-RO1AI181999 Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)

Source: The Journal of Immunology

DOI: 10.1093/jimmun/vkaf283.1141