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

Mucosal Immunol. 2022 Apr;15(4):642-655. doi: 10.1038/s41385-022-00520-z. Epub 2022 May 9.


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 partial HOIL1 deficiency. The ileum of HOIL1-deficient 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 (IL4Rα) 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 cells were increased independent of IL4Rα 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Hyperplasia
  • Immunity, Innate*
  • Inflammation
  • Interleukin-13*
  • Interleukin-5
  • Intestine, Small
  • Lymphocytes
  • Mice
  • RNA, Messenger
  • Ubiquitin-Protein Ligases / metabolism*


  • Interleukin-13
  • Interleukin-5
  • RNA, Messenger
  • Rbck1 protein, mouse
  • Ubiquitin-Protein Ligases