IL-33 promotes an innate immune pathway of intestinal tissue protection dependent on amphiregulin–EGFR interactions

Abstract

The barrier surfaces of the skin, lung, and intestine are constantly exposed to environmental stimuli that can result in inflammation and tissue damage. Interleukin (IL)-33–dependent group 2 innate lymphoid cells (ILC2s) are enriched at barrier surfaces and have been implicated in promoting inflammation; however, the mechanisms underlying the tissue-protective roles of IL-33 or ILC2s at surfaces such as the intestine remain poorly defined. Here we demonstrate that, following activation with IL-33, expression of the growth factor amphiregulin (AREG) is a dominant functional signature of gut-associated ILC2s. In the context of a murine model of intestinal damage and inflammation, the frequency and number of AREG-expressing ILC2s increases following intestinal injury and genetic disruption of the endogenous AREG–epidermal growth factor receptor (EGFR) pathway exacerbated disease. Administration of exogenous AREG limited intestinal inflammation and decreased disease severity in both lymphocyte-sufficient and lymphocyte-deficient mice, revealing a previously unrecognized innate immune mechanism of intestinal tissue protection. Furthermore, treatment with IL-33 or transfer of ILC2s ameliorated intestinal disease severity in an AREG-dependent manner. Collectively, these data reveal a critical feedback loop in which cytokine cues from damaged epithelia activate innate immune cells to express growth factors essential for ILC-dependent restoration of epithelial barrier function and maintenance of tissue homeostasis.

IL-33 regulates the IgA-microbiota axis to restrain IL-1α–dependent colitis and tumorigenesis

“…al. showed that exogenous IL-33 administration expands ILC2s in the GALT and upregulates amphiregulin production (24). However, the impact of IL-33 deficiency on ILC2 and T H 2 response in the gut under homoeostatic conditions or during DSS administration has not been directly tested.…”

“…Genetic ablation of Il33 in mice of a mixed genetic background lowered clinical symptoms in the early phase of experimental colitis, but also delayed the resolution of inflammation (23). Administration of recombinant IL-33 was also shown to ameliorate colitis in Il33-sufficient (WT) mice, suggesting a protective role for IL-33 in colitis (24,25). By utilizing Il33 -/-mice generated on a congenic C57BL/6 background and employing cohousing strategies and littermate controls, we show that IL-33 protected from colitis and CAC.…”

Biliary epithelial injury-induced regenerative response by IL-33 promotes cholangiocarcinogenesis from peribiliary glands

“…S7A). AREG is a ligand for epidermal growth factor receptor and has been reported to be involved in the repair of intestinal and lung tissues as an effector of the IL-33-ILC2 axis (23,24). In fact, i.p.…”

Розвиток Імунної Відповіді При Стафілококовій Пневмонії (Частина 3)

“…Известно, что IL-10 ингибирует экспрессию антигенов II класса глав-ного комплекса гистосовместимости и костимули-рующих молекул АРС, что приводит к снижению активации Т-клеток. В отличие от ингибирующего влияния на клеточный иммунитет на гуморальное звено IL-10 оказывает стимулирующее влияние: он активирует пролиферацию B-клеток и усиливает синтез иммуноглобулинов [73,80,83,99].…”