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Emerging insights on the role of gasdermins in infection and inflammatory diseases.

ABSTRACT: The gasdermins, family of pore-forming proteins, are emerging key regulators of infection, autoinflammation and antitumor immunity. Multiple studies have recently characterised their crucial roles in driving pyroptosis, a lytic pro-inflammatory type of cell death. Additionally, gasdermins also act as key effectors of NETosis, secondary necrosis and apoptosis. In this review, we will address current understanding of the mechanisms of gasdermin activation and further describe the protective and detrimental roles of gasdermins in host defence and autoinflammatory diseases. These data suggest that gasdermins play a prominent role in innate immunity and autoinflammatory disorders, thereby providing potential new therapeutic avenues for the treatment of infection and autoimmune disease.

SUBMITTER: Tang L

PROVIDER: S-EPMC7533414 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Emerging insights on the role of gasdermins in infection and inflammatory diseases.

Tang Lipeng L Lu Chuanjian C Zheng Guangjuan G Burgering Boudewijn Mt BM

Clinical & translational immunology 20201004 10

The gasdermins, family of pore-forming proteins, are emerging key regulators of infection, autoinflammation and antitumor immunity. Multiple studies have recently characterised their crucial roles in driving pyroptosis, a lytic pro-inflammatory type of cell death. Additionally, gasdermins also act as key effectors of NETosis, secondary necrosis and apoptosis. In this review, we will address current understanding of the mechanisms of gasdermin activation and further describe the protective and de ...[more]

PMID: 33033617

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Project description:To improve quality of life and prevent long-term risks in patients with inflammatory bowel diseases (IBDs: Crohn's disease, ulcerative colitis), it is essential to suppress inflammatory activity adequately. However, corticosteroids are only suitable for therapy of acute flares and the evidence for positive effects of immunosuppressive substances like azathioprine or 6-mercapropurine is mainly limited to maintenance of remission. In addition, only subgroups of patients benefit from biologicals targeting tumour necrosis factor ? or ?4?7 integrins. In summary, until now the disease activity is not sufficiently controlled in a relevant fraction of the patients with IBD. Thus, there is an urge for the development of new substances in the therapy of ulcerative colitis and Crohn's disease. Fortunately, new oral and parenteral substances are in the pipeline. This review will focus on oral substances, which have already passed phase II studies successfully at this stage. In this article, we summarize data regarding AJM300, phosphatidylcholine (LT-02), mongersen, ozanimod, filgotinib and tofacitinib. AJM300 and ozanimod were tested in patients with ulcerative colitis and target lymphocyte trafficking through inhibition of the ? subunit of integrin, respectively binding to the sphingosine-1-phosphate receptor (subtypes 1 and 5) on lymphocytes. Mongersen was utilized in patients with Crohn's disease and accelerates the degradation of SMAD7 mRNA, which consequently strengthens the mainly anti-inflammatory signalling pathway of transforming growth factor ?1. Various Janus kinase (JAK) inhibitors were developed, which inhibit the intracellular signalling pathway of cytokines. For example, the JAK1 blocker filgotinib was tested in Crohn's disease, whereas the JAK1/3 inhibitor tofacitinib was tested in clinical trials for both Crohn's disease and ulcerative colitis. A different therapeutic approach is the substitution of phosphatidylcholine (LT-02), which might recover the colonic mucus. Taken together, clinical trials with these new agents have opened avenues for further clinical studies and it can be expected that at least some of these agents will be finally approved for clinical therapy.

Dataset Information

Emerging insights on the role of gasdermins in infection and inflammatory diseases.

Publications

Emerging insights on the role of gasdermins in infection and inflammatory diseases.

Similar Datasets

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