GPR65 (TDAG8) inhibits intestinal inflammation and colitis-associated colorectal cancer development in experimental mouse models

Marie, Mona A.; Sanderlin, Edward J.; Satturwar, Swati; Hong, Hao; Lertpiriyapong, Kvin; Donthi, Deepak; Yang, Li V.

doi:10.1016/j.bbadis.2021.166288

Cited by 24 publications

(30 citation statements)

References 61 publications

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“…In order to clarify the reason why GPR65 was increased in intestinal mucosal tissues of IBD patients, we collected intestinal mucosal tissues from 10 HC, 14 A‐CD and 12 A‐UC patients, and detected the expression of CD3, CD4, CD8, CD14, IL‐4, IFN‐γ, IL17A and GPR65 mRNA by qRT‐PCR, followed by a correlation analysis (Figure S2A‐H). Notably, we detected that GPR65 expression was only positively relevance with the expression of IFN‐γ and IL17A (Figure S2G,H), implying that an increase of GPR65 mRNA is mainly ascribed to high level of IFN‐γ + and IL17A + cells in inflamed mucosa of IBD patients, which is consistent with the recent report 32 . These results indicate that GPR65 plays a vital role in orchestrating Th1 and Th17 cell differentiation.…”

Section: Resultssupporting

confidence: 91%

“…Notably, we detected that GPR65 expression was only positively relevance with the expression of IFN‐γ and IL17A (Figure S2G,H ), implying that an increase of GPR65 mRNA is mainly ascribed to high level of IFN‐γ + and IL17A + cells in inflamed mucosa of IBD patients, which is consistent with the recent report. 32 These results indicate that GPR65 plays a vital role in orchestrating Th1 and Th17 cell differentiation.…”

Section: Resultsmentioning

confidence: 87%

“…Moreover, the recent studies found that GPR65 deficiency aggravates LPS‐induced lung injury and atopic dermatitis in mouse models 15,19 . Another study found that GPR65 can inhibit intestinal inflammation and colitis‐associated colorectal cancer development 32 . These differences may be ascribed to different biological backgrounds, disease models, mouse strains, microbiomes and potential effects of GPR65 on different immune cells.…”

Section: Discussionmentioning

confidence: 99%

“…*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 GPR65 can inhibit intestinal inflammation and colitisassociated colorectal cancer development. 32 These differences may be ascribed to different biological backgrounds, disease models, mouse strains, microbiomes and potential effects of GPR65 on different immune cells.…”

Section: Discussionmentioning

confidence: 99%

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GPR65 promotes intestinal mucosal Th1 and Th17 cell differentiation and gut inflammation through downregulating NUAK2

Lin

Chen

et al. 2022

Clinical & Translational Med

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G protein‐coupled receptor 65 (GPR65), a susceptibility gene for inflammatory bowel diseases (IBD), has been identified to promote Th17 cell pathogenicity and induce T cell apoptosis. However, the potential role of GPR65 in modulating CD4+ T cell immune responses in the pathogenesis of IBD stills not entirely understood. Here, we displayed that GPR65 expression was increased in inflamed intestinal mucosa of IBD patients and positively associated with disease activity. It was expressed in CD4+ T cells and robustly upregulated through the TNF‐α‐caspase 3/8 signalling pathway. Ectopic expression of GPR65 significantly promoted the differentiation of peripheral blood (PB) CD4+ T cells from IBD patients and HC to Th1 and Th17 cells in vitro. Importantly, conditional knockout of Gpr65 in CD4+ T cells ameliorated trinitrobenzene sulfonic acid (TNBS)‐induced acute murine colitis and a chronic colitis in Rag1–/– mice reconstituted with CD45RBhighCD4+ T cells in vivo, characterised by attenuated Th1 and Th17 cell immune response in colon mucosa and decreased infiltration of CD4+ T cells, neutrophils and macrophages. RNA‐seq analysis of Gpr65ΔCD4 and Gpr65flx/flxCD4+ T cells revealed that NUAK family kinase 2 (Nuak2) acts as a functional target of Gpr65 to restrict Th1 and Th17 cell immune response. Mechanistically, GPR65 deficiency promoted NUAK2 expression via the cAMP‐PKA‐C‐Raf‐ERK1/2‐LKB1‐mediated signalling pathway. Consistently, silencing of Nuak2 facilitated the differentiation of Gpr65ΔCD4 and Gpr65flx/flxCD4+ T cells into Th1 and Th17 cells. Therefore, our data point out that GPR65 promotes Th1 and Th17 cell immune response and intestinal mucosal inflammation by suppressing NUAK2 expression, and that targeting GPR65 and NUAK2 in CD4+ T cells may represent a novel therapeutic approach for IBD.

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Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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GPR65 promotes intestinal mucosal Th1 and Th17 cell differentiation and gut inflammation through downregulating NUAK2

Lin

Chen

et al. 2022

Clinical & Translational Med

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“…Upon the initiation of CAC, a large number of inflammatory cells, such as macrophage, natural killer cells, and dendritic cells, infiltrate around the colonic tissues [ 16 , 17 ], leading to the increased production of proinflammatory cytokines, which makes colonic tissues in an inflammatory microenvironment. Without effective treatment, persistent inflammatory stimulation will further aggravate CAC [ 18 ]. Therefore, control of inflammation is pivotal for the prevention of CAC.…”

Section: Introductionmentioning

confidence: 99%

Wumei Pill Ameliorates AOM/DSS-Induced Colitis-Associated Colon Cancer through Inhibition of Inflammation and Oxidative Stress by Regulating S-Adenosylhomocysteine Hydrolase- (AHCY-) Mediated Hedgehog Signaling in Mice

Wang

Ding

Wang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Wumei Pill (WMP) is a traditional Chinese herbal formulation and widely used to treat digestive system diseases in clinical. S-Adenosylhomocysteine hydrolase (AHCY) can catalyze the hydrolysis of S-adenosylhomocysteine to adenosine and homocysteine in living organisms, and its abnormal expression is linked to the pathogenesis of many diseases including colorectal cancer (CRC). A previous study reported that WMP could prevent CRC in mice; however, the underlying mechanisms especially the roles of AHCY in WMP-induced anti-CRC remain largely unknown. Here, we investigated the regulatory roles and potential mechanisms of AHCY in WMP-induced anti-CRC. WMP notably alleviated the azoxymethane/dextran sulfate sodium- (AOM/DSS-) induced colitis-associated colon cancer (CAC) in mice. Besides, WMP inhibited the inflammation and oxidative stress in AOM/DSS-induced CAC mice. AHCY was high expression in clinical samples of colon cancer compared to the adjacent tissues. WMP inhibited the AHCY expression in AOM/DSS-induced CAC mice. An in vitro study found that AHCY overexpression induced cell proliferation, colony formation, invasion, and tumor angiogenesis, whereas its knockdown impaired its oncogenic function. AHCY overexpression enhanced, while its knockdown weakened the inflammation and oxidative stress in colon cancer cells. Interestingly, WMP potently suppressed the hedgehog (Hh) signaling in AOM/DSS-induced CAC mice. A further study showed that AHCY overexpression activated the Hh signaling while AHCY knockdown inactivated the Hh signaling. Moreover, activation of the Hh signaling reversed the effect of AHCY silencing on inflammation and oxidative stress in vitro. In conclusion, WMP alleviated the AOM/DSS-induced CAC through inhibition of inflammation and oxidative stress by regulating AHCY-mediated hedgehog signaling in mice. These findings uncovered a potential molecular mechanism underlying the anti-CAC effect of WMP and suggested WMP as a promising therapeutic candidate for CRC.

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Transwell In Vitro Cell Migration and Invasion Assays

Justus

Marie

Sanderlin

et al. 2023

Methods in Molecular Biology

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GPR65 (TDAG8) inhibits intestinal inflammation and colitis-associated colorectal cancer development in experimental mouse models

Cited by 24 publications

References 61 publications

GPR65 promotes intestinal mucosal Th1 and Th17 cell differentiation and gut inflammation through downregulating NUAK2

GPR65 promotes intestinal mucosal Th1 and Th17 cell differentiation and gut inflammation through downregulating NUAK2

Wumei Pill Ameliorates AOM/DSS-Induced Colitis-Associated Colon Cancer through Inhibition of Inflammation and Oxidative Stress by Regulating S-Adenosylhomocysteine Hydrolase- (AHCY-) Mediated Hedgehog Signaling in Mice

Transwell In Vitro Cell Migration and Invasion Assays

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