Interleukin-33 in Tissue Homeostasis, Injury, and Inflammation

Abstract

Summary Interleukin-33 (IL-33) is a nuclear-associated cytokine of the IL-1 family originally described as a potent inducer of allergic type 2 immunity. IL-33 signals via the receptor ST2, which is highly expressed on group 2 innate lymphoid cells (ILC2s) and T helper 2 (Th2) cells, thus underpinning its association with helminth infection and allergic pathology. Recent studies have revealed ST2 expression on subsets of regulatory T cells, and for a role for IL-33 in tissue homeostasis and repair that suggests previously unrecognized interactions within these cellular networks. IL-33 can participate in pathologic fibrotic reactions, or, in the setting of microbial invasion, can cooperate with inflammatory cytokines to promote responses by cytotoxic NK cells, Th1 cells and CD8+ T cells. Here, we highlight the regulation and function of IL-33 and ST2, and review their roles in homeostasis, damage and inflammation, suggesting a conceptual framework for future studies.

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

“…In addition, disruption of the integrity of the lung and skin epithelial barrier has been reported to induce production of IL-33 (38). IL-33 functions as a sensor of epithelial barrier injury due to invasion of pathogens, including helminths, and induces a Th2 immune response to eliminate pathogens and repair the injured tissue through ILC2 activation (20). In this sense, loss of cell-cell adhesion due to E-cadherin deletion in BECs could trigger up-regulation of IL-33.…”

“…Among these genes, we focused on IL-33, which exhibited the 13th highest magnitude of up-regulation. IL-33 is a member of the IL-1 family originally described as an inducer of type 2 innate immunity (20), and it was recently reported to promote BEC proliferation particularly in the EHBD (21). Real-time PCR revealed an ∼75-fold increase in IL-33 mRNA levels in Cre + KTC organoids compared with Cre − KTC organoids.…”

“…S6D). Of note, IL-33 also functions as an "alarmin," released from dying cells as an indicator of infection or tissue injury (20). Actually, although cell lines established from Cre + KTC biliary organoids (termed "KTC-BO cells") did not secrete IL-33, necrosis due to repeated freeze-thaw cycles led to release of IL-33 (Fig.…”

“…S6 K and L). ILC2s have been reported to produce the effector cytokines IL-4, IL-5, IL-9, IL-13, and amphiregulin (AREG) in response to IL-33 (20), among which IL-13 was reported to contribute to proliferation of BECs (21). Although IL-4 and IL-9 mRNAs were not detected by real-time PCR, the expression levels of IL-5, IL-13, and AREG mRNA were significantly increased in the ECC tissues of KTC-K19 CreERT mice compared with control EHBD tissues of KTC mice (Fig.…”

The influence of gut-decontamination prophylactic antibiotics on acute graft-versus-host disease and survival following allogeneic hematopoietic stem cell transplantation

“…[32][33][34][35] Despite this relevant axis, an impact of the microbiota remains a less well established and controversial risk factor for aGVHD pathogenesis. 36,37 In conclusion, this study highlights the potentially detrimental role of ATB in aGVHD severity and in OS. Future prospective studies should be conducted to fully address the issue of antibioprophylaxis for gut decontamination.…”