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bioRxiv · 10.1101/2022.03.09.483650

HOIL1 regulates group 2 innate lymphoid cell numbers and type 2 inflammation in the small intestine

Wood, M. J.·Marshall, J. N.·Hartley, V. L.·Liu, T.-C.·Iwai, K.·Stappenbeck, T. S.·MacDuff, D. A.
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Abstract

Patients with mutations in HOIL1 experience a complex immune disorder including intestinal inflammation. To investigate the role of HOIL1 in regulating intestinal inflammation, we employed a mouse model of HOIL1 deficiency. The ileum of Hoil1-/- mice displayed features of type 2 inflammation including tuft cell and goblet cell hyperplasia, and elevated expression of Il13, Il5 and Il25 mRNA. Inflammation persisted in the absence of T and B cells, and bone marrow chimeric mice revealed a requirement for HOIL1 expression in radiation-resistant cells to regulate inflammation. Although disruption of IL-4 receptor alpha (IL4R) signaling on intestinal epithelial cells ameliorated tuft and goblet cell hyperplasia, expression of Il5 and Il13 mRNA remained elevated. KLRG1hi CD90lo group 2 innate lymphoid cell (ILC2) were increased independent of IL4R signaling, tuft cell hyperplasia and IL-25 induction. Antibiotic treatment dampened intestinal inflammation indicating commensal microbes as a contributing factor. We have identified a key role for HOIL1, a component of the Linear Ubiquitin Chain Assembly Complex, in regulating type 2 inflammation in the small intestine. Understanding the mechanism by which HOIL1 regulates type 2 inflammation will advance our understanding of intestinal homeostasis and inflammatory disorders and may lead to the identification of new targets for treatment.

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Wood, M. J., Marshall, J. N., Hartley, V. L., Liu, T.-C., Iwai, K., Stappenbeck, T. S., MacDuff, D. A.. 2022-03-11. HOIL1 regulates group 2 innate lymphoid cell numbers and type 2 inflammation in the small intestine. https://doi.org/10.1101/2022.03.09.483650

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