Group 2 Innate Lymphoid Cells Coordinate Damage Response in the Stomach

Meyer, Anne R.; Engevik, Amy C.; Madorsky, Toni; Belmont, Erika; Stier, Matthew T.; Norlander, Allison E.; Pilkinton, Mark A.; McDonnell, Wyatt J.; Weis, Jared A.; Jang, Bo Gun; Mallal, S.; Peebles, R. Stokes; Goldenring, James R.

doi:10.1053/j.gastro.2020.08.051

Cited by 58 publications

(79 citation statements)

References 51 publications

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“…In the CTLA4 insufficiency model, treatment with anti-IL4-antibody and knockout of IL4Rα did not prevent inflammation but severed its link with the initiation of tumorigenesis (Miska et al, 2018), suggesting that therapies targeting type 2 inflammation may be useful in promoting anti-cancer immunity or cancer prevention as well. This idea could be further supported by other models of gastric injury which have found that ILC2s are key mediators of a metaplastic response or that administration of IL27, an inhibitor of type 2 and other types of immunity (Yoshida and Hunter, 2015;Tait Wojno et al, 2019), protects against metaplasia (Bockerstett et al, 2020;Meyer et al, 2020).…”

Section: Type 2 Inflammatory Pathways Unveiled In Studies Of Autoimmune Tumorigenesis May Provide New Targets To Improve Cancer Immune Thmentioning

confidence: 79%

“…In this study, Miska et al (2018) show that blocking the two key type 2 cytokines IL4 and IL13 abrogates tumorigenesis. A third group that studies drug-induced stomach injury and metaplasia found that ILC2s, which are activated by and perpetuate type 2 inflammation, are required for the development of epithelial metaplasia ( Meyer et al, 2020 ).…”

Section: Ctla4 Insufficiency and Other Models Of Autoimmune Gastritis Provide Experimental Evidence Of Autoimmunity-driven Tumorigenesismentioning

confidence: 99%

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Autoimmunity as an Etiological Factor of Cancer: The Transformative Potential of Chronic Type 2 Inflammation

Chen

2021

Front. Cell Dev. Biol.

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Recent epidemiological studies have found an alarming trend of increased cancer incidence in adults younger than 50 years of age and projected a substantial rise in cancer incidence over the next 10 years in this age group. This trend was exemplified in the incidence of non-cardia gastric cancer and its disproportionate impact on non-Hispanic white females under the age of 50. The trend is concurrent with the increasing incidence of autoimmune diseases in industrialized countries, suggesting a causal link between the two. While autoimmunity has been suspected to be a risk factor for some cancers, the exact mechanisms underlying the connection between autoimmunity and cancer remain unclear and are often controversial. The link has been attributed to several mediators such as immune suppression, infection, diet, environment, or, perhaps most plausibly, chronic inflammation because of its well-recognized role in tumorigenesis. In that regard, autoimmune conditions are common causes of chronic inflammation and may trigger repetitive cycles of antigen-specific cell damage, tissue regeneration, and wound healing. Illustrating the connection between autoimmune diseases and cancer are patients who have an increased risk of cancer development associated with genetically predisposed insufficiency of cytotoxic T lymphocyte-associated protein 4 (CTLA4), a prototypical immune checkpoint against autoimmunity and one of the main targets of cancer immune therapy. The tumorigenic process triggered by CTLA4 insufficiency has been shown in a mouse model to be dependent on the type 2 cytokines interleukin-4 (IL4) and interleukin-13 (IL13). In this type 2 inflammatory milieu, crosstalk with type 2 immune cells may initiate epigenetic reprogramming of epithelial cells, leading to a metaplastic differentiation and eventually malignant transformation even in the absence of classical oncogenic mutations. Those findings complement a large body of evidence for type 1, type 3, or other inflammatory mediators in inflammatory tumorigenesis. This review addresses the potential of autoimmunity as a causal factor for tumorigenesis, the underlying inflammatory mechanisms that may vary depending on host-environment variations, and implications to cancer prevention and immunotherapy.

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Section: Type 2 Inflammatory Pathways Unveiled In Studies Of Autoimmune Tumorigenesis May Provide New Targets To Improve Cancer Immune Thmentioning

confidence: 79%

Section: Ctla4 Insufficiency and Other Models Of Autoimmune Gastritis Provide Experimental Evidence Of Autoimmunity-driven Tumorigenesismentioning

confidence: 99%

Autoimmunity as an Etiological Factor of Cancer: The Transformative Potential of Chronic Type 2 Inflammation

Chen

2021

Front. Cell Dev. Biol.

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“…Interleukin-33 is an important ILC2 activator, but the modulation of ILC2s under intestinal I/R injury and the role of ILC2s in the protective effect of IL-33 on intestinal I/R injury remain unclear. We depleted ILC2s using a previously described antibody depletion method to confirm the role of ILC2s in IL-33-mediated protection against intestinal I/R injury ( Supplementary Figure S4A ) ( 29 – 32 ). Recombinant murine IL-33 (rmIL-33) increased the ratio (%) of ILC2/ILCs and IL-13 + ILC2/ILC2 but not in ILC2-deleted mice ( Figures 5A–C ).…”

Section: Resultsmentioning

confidence: 99%

Gut Microbial Metabolite Pravastatin Attenuates Intestinal Ischemia/Reperfusion Injury Through Promoting IL-13 Release From Type II Innate Lymphoid Cells via IL−33/ST2 Signaling

Deng

Yang

et al. 2021

Front. Immunol.

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Intestinal ischemia/reperfusion (I/R) injury is a grave condition with high morbidity and mortality. We previously confirmed that intestinal I/R induces intestinal flora disorders and changes in metabolites, but the role of different metabolites in intestinal I/R injury is currently unclear. Based on targeted metabolic sequencing, pravastatin (PA) was determined to be a metabolite of the gut microbiota. Further, intestinal I/R model mice were established through superior mesenteric artery obstruction. In addition, a co-culture model of small intestinal organoids and type II innate lymphoid cells (ILC2s) was subjected to hypoxia/reoxygenation (H/R) to simulate an intestinal I/R model. Moreover, correlation analysis between the PA level in preoperative feces of patients undergoing cardiopulmonary bypass and the indices of postoperative intestinal I/R injury was carried out. IL-33-deficient mice, ILC2-deleted mice, and anti-IL-13 neutralizing antibodies were also used to explore the potential mechanism through which PA attenuates intestinal I/R injury. We demonstrated that PA levels in the preoperative stool of patients undergoing cardiopulmonary bypass were negatively correlated with the indices of postoperative intestinal I/R injury. Furthermore, PA alleviated intestinal I/R injury and improved the survival of mice. We further showed that PA promotes IL-13 release from ILC2s by activating IL-33/ST2 signaling to attenuate intestinal I/R injury. In addition, IL-13 promoted the self-renewal of intestinal stem cells by activating Notch1 and Wnt signals. Overall, results indicated that the gut microbial metabolite PA can attenuate intestinal I/R injury by promoting the release of IL-13 from ILC2s via IL-33/ST2 signaling, revealing a novel mechanism of and therapeutic strategy for intestinal I/R injury.

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“…Therefore, multi-label flow cytometry was applied to determine the source of IL-13 in the heart. According to the description of previous studies ( Meyer et al, 2020 ), we applied CD90.2 antibody in vivo to eliminate ILC2 and found that IL-13 decreased drastically after eliminating ILC2. Based on these results, the main source of IL-13 in the heart is determined to be ILC2.…”

Section: Discussionmentioning

confidence: 99%

IL-13 Derived Type 2 Innate Lymphocytes Ameliorates Cardiomyocyte Apoptosis Through STAT3 Signaling Pathway

Hong

Guo

et al. 2021

Front. Cell Dev. Biol.

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The involvement of cardiomyopathy during sepsis means higher mortality and prolonged length of hospital stay. Many efforts have been made to alleviate the apoptosis of cardiomyocytes in sepsis. The huge potential of IL-13 in tissue repair has attracted increasing attention. In the present study, we used LPS-treated mice or primary cardiomyocytes as a sepsis model to explore the anti-apoptotic ability of IL-13. It was found that an increased level of exogenous IL-13 was beneficial to the recovery of heart function in sepsis, and this anti-apoptotic effect of IL-13 was probably through enhancing the phosphorylation of STAT3 Ser727. In addition, we identified that the heart protective effect of IL-13 was associated with type 2 innate lymphocytes (ILC2). All these findings may provide a potential promising treatment for sepsis-induced cardiomyopathy.

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Group 2 Innate Lymphoid Cells Coordinate Damage Response in the Stomach

Cited by 58 publications

References 51 publications

Autoimmunity as an Etiological Factor of Cancer: The Transformative Potential of Chronic Type 2 Inflammation

Autoimmunity as an Etiological Factor of Cancer: The Transformative Potential of Chronic Type 2 Inflammation

Gut Microbial Metabolite Pravastatin Attenuates Intestinal Ischemia/Reperfusion Injury Through Promoting IL-13 Release From Type II Innate Lymphoid Cells via IL−33/ST2 Signaling

IL-13 Derived Type 2 Innate Lymphocytes Ameliorates Cardiomyocyte Apoptosis Through STAT3 Signaling Pathway

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