Epithelial-derived IL-33 promotes intestinal tumorigenesis in Apc
                     
                        Min/+ mice

He, Zhengxiang; Chen, Lili; Souto, Fabrício Oliveira; Canasto-Chibuque, Claudia; Bongers, Gerold; Deshpande, Madhura; Harpaz, Noam; Ko, Huaibin M.; Kelley, Kevin; Furtado, Gláucia C.; Lira, Sérgio A.

doi:10.1038/s41598-017-05716-z

Cited by 66 publications

(83 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For CD4 + T-cell isolation, mLNs and large intestine were digested in collagenase as described previously 27 . CD4 + T cells were enriched by positive immunoselection using CD4-(L3T4) microbeads (Miltenyi Biotec).…”

Section: T Cell Purificationmentioning

confidence: 99%

Diet Modifies Colonic Microbiota and CD4⁺ T Cell Repertoire to Trigger Flares in a Novel Model of Colitis Induced by IL-23

Chen

Iuga

Filho

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

A wealth of experimental data points to immunological and environmental factors in the pathogenesis of inflammatory bowel disease (IBD). Here we study the role of IL-23, the microbiome, and the diet in the development of colitis. To promote IL-23 expression in vivo,we generated a mouse model in which IL-23 was conditionally expressed by CX 3 CR1 + myeloid cells, upon cyclic administration of tamoxifen in a specific diet (diet 2019). IL-23 expression induced an intestinal inflammatory disease that resembled ulcerative colitis in humans with cycles of acute disease and remission. The relapses were caused by the diet switch from the conventional diet used in our facility (diet 5053) to the diet 2019, and were not dependent on tamoxifen after the first cycle. The switch in the diet modified the microbiota, but did not alter the levels of IL-23. Colitis induction depended on the microbiota and required CD4 T lymphocytes. Colitis-inducing CD4 + T cells were found in the mesenteric lymph node and large intestine during remission and were able to trigger disease when transferred to lymphopenic mice, but only upon diet modification. The CD4 TCR repertoire in the diseased recipient Rag -/-mice had reduced diversity associated with the expansion of dominant T cell clones. These findings reveal a critical role for IL-23 in generation of a CD4 + T cell population in mice that is sensitive to a modification of intestinal bacterial flora subsequent to a dietary manipulation. Dietary changes occurring in the context of altered IL-23 expression may contribute to the onset and progression of IBD.

show abstract

Section: T Cell Purificationmentioning

confidence: 99%

Diet Modifies Colonic Microbiota and CD4⁺ T Cell Repertoire to Trigger Flares in a Novel Model of Colitis Induced by IL-23

Chen

Iuga

Filho

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…This led to the novel finding that Sprouty2 deletion induces IL-33 production in colonic epithelial cells. IL-33 is expressed by epithelial, stromal, and immune cells, though at homeostasis, epithelial expression is normally low 49,50 . IL-33 regulation has predominantly been studied in immune cells 51 and control of its expression in the intestinal epithelial compartment is not well understood.…”

Section: Discussionmentioning

confidence: 99%

Sprouty2 limits intestinal tuft and goblet cell numbers through GSK3β-mediated restriction of epithelial IL-33

Schumacher

Hsieh

Liu

et al. 2020

Preprint

View full text Add to dashboard Cite

Dynamic regulation of intestinal cell differentiation is crucial for both homeostasis and the response to injury or inflammation. Sprouty2, an intracellular signaling regulator, controls pathways including PI3K and MAPKs that are implicated in differentiation and are dysregulated in inflammatory bowel disease. Here, we asked whether Sprouty2 controls secretory cell differentiation and the response to colitis. We report that colonic epithelial Sprouty2 deletion led to expanded goblet and tuft cell populations. Sprouty2 loss induced PI3K/Akt signaling, leading to GSK3β inhibition and epithelial interleukin (IL)-33 expression. In vivo, this resulted in increased stromal IL-13+ cells. IL-13 in turn induced tuft and goblet cell expansion in vitro and in vivo. Sprouty2 was downregulated by inflammation; this appeared to be a protective response, as VillinCre;Sprouty2 F/F mice were resistant to DSS colitis. In contrast, Sprouty2 was elevated in colons of inflammatory bowel disease patients, suggesting that this protective epithelial-stromal signaling mechanism is lost in disease.

show abstract

“…Recent study using engineered mice model has shown that epithelial-derived IL-33 increases ST2 1 regulatory T cells population, Th2 cytokines production and M2 macrophages infiltration to promote gut tumorigenesis. 38 Soluble ST2 has been shown to act as a decoy receptor to disrupt the signaling transduced by IL-33 to its membrane-bound receptor, ST2. 11,15,35 Consistently, we found that knockdown of sST2 in tumor cells displayed an in vivo growth advantage compared to control group (Fig.…”

Section: Discussionmentioning

confidence: 99%

Rab37 in lung cancer mediates exocytosis of soluble ST2 and thus skews macrophages toward tumor‐suppressing phenotype

Tzeng

Chang

et al. 2018

Intl Journal of Cancer

View full text Add to dashboard Cite

Interplay between cancer epithelial cells and the surrounding immune cells shape the tumor microenvironment to promote cancer progression. Tumor-associated macrophages are well recognized for their roles in cancer progression. Accumulating evidence also indicates implication of Rab small GTPase-mediated exocytosis in tumorigenesis. However, the mechanism for Rab-mediated exocytosis in regulation of macrophage polarization is not clear. We have previously identified Rab37 as a metastasis suppressor in lung cancer. In our study, we identified a novel Rab37 trafficking cargo soluble ST2 (sST2), which skewed macrophage polarization toward anti-tumoral M1-like phenotype in vitro. We further demonstrated that Rab37-mediated sST2 secretion significantly increased the ratio of M1 vs. M2 in xenografts and thus reduced tumor growth. Moreover, lung cancer patients with low Rab37, low sST2 and low ratio of M1 vs. M2 macrophages expression profile correlated with worse overall survival examined by Kaplan-Meier survival analysis. Multivariate Cox regression analysis showed that this Rab37-sST2-M1/M2 expression profile predicted poor prognosis. Our findings reveal a novel regulation of cancerous Rab37 in microenvironmental macrophages polarization, which preferentially shifts to anti-tumoral phenotype and thereby suppresses lung tumor growth.

show abstract

Epithelial-derived IL-33 promotes intestinal tumorigenesis in Apc Min/+ mice

Cited by 66 publications

References 71 publications

Diet Modifies Colonic Microbiota and CD4⁺ T Cell Repertoire to Trigger Flares in a Novel Model of Colitis Induced by IL-23

Diet Modifies Colonic Microbiota and CD4⁺ T Cell Repertoire to Trigger Flares in a Novel Model of Colitis Induced by IL-23

Sprouty2 limits intestinal tuft and goblet cell numbers through GSK3β-mediated restriction of epithelial IL-33

Rab37 in lung cancer mediates exocytosis of soluble ST2 and thus skews macrophages toward tumor‐suppressing phenotype

Contact Info

Product

Resources

About

Epithelial-derived IL-33 promotes intestinal tumorigenesis in Apc Min/+ mice

Cited by 66 publications

References 71 publications

Diet Modifies Colonic Microbiota and CD4+ T Cell Repertoire to Trigger Flares in a Novel Model of Colitis Induced by IL-23

Diet Modifies Colonic Microbiota and CD4+ T Cell Repertoire to Trigger Flares in a Novel Model of Colitis Induced by IL-23

Sprouty2 limits intestinal tuft and goblet cell numbers through GSK3β-mediated restriction of epithelial IL-33

Rab37 in lung cancer mediates exocytosis of soluble ST2 and thus skews macrophages toward tumor‐suppressing phenotype

Contact Info

Product

Resources

About

Diet Modifies Colonic Microbiota and CD4⁺ T Cell Repertoire to Trigger Flares in a Novel Model of Colitis Induced by IL-23

Diet Modifies Colonic Microbiota and CD4⁺ T Cell Repertoire to Trigger Flares in a Novel Model of Colitis Induced by IL-23