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CGAS restricts colon cancer development by protecting intestinal barrier integrity.

ABSTRACT: The DNA-sensing enzyme cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) regulates inflammation and immune defense against pathogens and malignant cells. Although cGAS has been shown to exert antitumor effects in several mouse models harboring transplanted tumor cell lines, its role in tumors arising from endogenous tissues remains unknown. Here, we show that deletion of cGAS in mice exacerbated chemical-induced colitis and colitis-associated colon cancer (CAC). Interestingly, mice lacking cGAS were more susceptible to CAC than those lacking stimulator of interferon genes (STING) or type I interferon receptor under the same conditions. cGAS but not STING is highly expressed in intestinal stem cells. cGAS deficiency led to intestinal stem cell loss and compromised intestinal barrier integrity upon dextran sodium sulfate-induced acute injury. Loss of cGAS exacerbated inflammation, led to activation of STAT3, and accelerated proliferation of intestinal epithelial cells during CAC development. Mice lacking cGAS also accumulated myeloid-derived suppressive cells within the tumor, displayed enhanced Th17 differentiation, but reduced interleukin (IL)-10 production. These results indicate that cGAS plays an important role in controlling CAC development by defending the integrity of the intestinal mucosa.

SUBMITTER: Hu S

PROVIDER: S-EPMC8201956 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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cGAS restricts colon cancer development by protecting intestinal barrier integrity.

Hu Shuiqing S Fang Yan Y Chen Xiang X Cheng Tianlei T Zhao Miaoqing M Du Mingjian M Li Tuo T Li Minghao M Zeng Zhiqun Z Wei Yonglong Y Gu Zhimin Z Zhang Conggang C Sun Lijun L Chen Zhijian J ZJ

Proceedings of the National Academy of Sciences of the United States of America 20210601 23

The DNA-sensing enzyme cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) regulates inflammation and immune defense against pathogens and malignant cells. Although cGAS has been shown to exert antitumor effects in several mouse models harboring transplanted tumor cell lines, its role in tumors arising from endogenous tissues remains unknown. Here, we show that deletion of cGAS in mice exacerbated chemical-induced colitis and colitis-associated colon cancer (CAC). Interestingl ...[more]

PMID: 34074794

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Project description:Social isolation (SI) is a prevalent issue in modern society, particularly exacerbated during the COVID-19 pandemic, and it is a significant contributor to depressive disorders. Inflammation-related markers are upregulated in patients with major depressive disorder (MDD) unresponsive to first-line selective serotonin reuptake inhibitor (SSRI) antidepressants. This study investigates the role of formyl peptide receptor 2 (FPR2), a G-protein coupled receptor expressed in central and peripheral immune cells, in SI-induced depression. We developed a mouse model of SI by housing mice individually for three weeks. SI mice exhibited increased capillary-associated microglia (CAMs) with upregulated FPR2 expression in the prefrontal cortex (PFC) and hippocampus compared to group-housed controls. Notably, subcutaneous administration of the FPR2 antagonist WRW4 alleviated depressive and anxiety-like behaviors in SI mice, reducing microglial activation and neuronal damage. WRW4 treatment decreased CAM numbers and their FPR2 expression. RNA sequencing revealed that SI primarily induced changes in genes associated with blood-brain barrier (BBB) function, followed by alterations in genes related to hormone activity, immune activation, and neuronal function. Transcriptomic changes in brain endothelial cells from SI mice resembled those observed in animal models of several neurological disorders and in MDD patients. WRW4 treatment partially reversed these transcriptomic alterations and restored compromised BBB integrity. Additionally, intracerebroventricular (ICV) injection of WRW4 also alleviated depressive and anxiety-like behaviors in SI mice. Finally, our analysis of public transcriptome databases indicates FPR2 upregulation in the orbital ventral PFC of MDD patients and peripheral blood mononuclear cells of those in severe depressive episodes. These findings suggest that the pharmacological targeting of FPR2 may rescue SI-induced pathology in mice by protecting BBB integrity.

Dataset Information

CGAS restricts colon cancer development by protecting intestinal barrier integrity.

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cGAS restricts colon cancer development by protecting intestinal barrier integrity.

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