A little ER stress isn’t bad: the IRE1α/XBP1 pathway shapes ILC3 functions during intestinal inflammation
Cinzia Fionda, Giuseppe Sciumè
Cinzia Fionda, Giuseppe Sciumè
Published July 1, 2024
Citation Information: J Clin Invest. 2024;134(13):e182204. https://doi.org/10.1172/JCI182204.
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Commentary

A little ER stress isn’t bad: the IRE1α/XBP1 pathway shapes ILC3 functions during intestinal inflammation

Abstract

Type 3 innate lymphoid cells (ILC3s) are key regulators of intestinal homeostasis and epithelial barrier integrity. In this issue of the JCI, Cao and colleagues found that a sensor of endoplasmic reticulum (ER) stress, the inositol-requiring kinase 1α/X-box–binding protein 1 (IRE1α/XBP1) pathway, fine-tuned the functions of ILC3s. Activation of IRE1α and XBP1 in ILC3s limited intestinal inflammation in mice and correlated with the efficacy of ustekinumab, an IL-12/IL-23 blocker, in patients with Crohn’s disease. These results advance our understanding in the use of ILCs as biomarkers not only to predict disease outcomes but also to indicate the response to biologicals in patients with inflammatory bowel disease.

Authors

Cinzia Fionda, Giuseppe Sciumè

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Figure 1

XBP1s has a role in controlling IL-22 production from intestinal ILC3s.

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XBP1s has a role in controlling IL-22 production from intestinal ILC3s. ...
(A) XBP1s expression in ILC3s follows a circadian rhythm and can be induced by VIP, a neuropeptide produced by enteric neurons during feeding. XBP1s triggers IL-22 release, which helps maintain epithelial barrier integrity. (B) Inflammatory cytokines, namely IL-23 and IL-1β, induce mitochondrial ROS–mediated IRE1α/XBP1 pathway activation. XBP1s is required for optimal IL-22 and IL-17 production by ILC3s and protects these cells from unresolved ER stress. Moreover, XBP1s in ILC3s is required for protection against C. rodentium and C. difficile and to avoid aberrant acute intestinal inflammation in mice. (C) The expression levels of XBP1s in ILC3s in intestinal mucosa correlate with the response to the therapeutic antagonist anti–IL-12/IL-23 antibody (also known as ustekinumab) in patients with IBD.