Dataset Information

Targeting RIP Kinases in Chronic Inflammatory Disease.

ABSTRACT: Chronic inflammatory disorders are characterised by aberrant and exaggerated inflammatory immune cell responses. Modes of extrinsic cell death, apoptosis and necroptosis, have now been shown to be potent drivers of deleterious inflammation, and mutations in core repressors of these pathways underlie many autoinflammatory disorders. The receptor-interacting protein (RIP) kinases, RIPK1 and RIPK3, are integral players in extrinsic cell death signalling by regulating the production of pro-inflammatory cytokines, such as tumour necrosis factor (TNF), and coordinating the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome, which underpin pathological inflammation in numerous chronic inflammatory disorders. In this review, we firstly give an overview of the inflammatory cell death pathways regulated by RIPK1 and RIPK3. We then discuss how dysregulated signalling along these pathways can contribute to chronic inflammatory disorders of the joints, skin, and gastrointestinal tract, and discuss the emerging evidence for targeting these RIP kinases in the clinic.

SUBMITTER: Speir M

PROVIDER: S-EPMC8146010 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Targeting RIP Kinases in Chronic Inflammatory Disease.

Speir Mary M Djajawi Tirta M TM Conos Stephanie A SA Tye Hazel H Lawlor Kate E KE

Biomolecules 20210428 5

Chronic inflammatory disorders are characterised by aberrant and exaggerated inflammatory immune cell responses. Modes of extrinsic cell death, apoptosis and necroptosis, have now been shown to be potent drivers of deleterious inflammation, and mutations in core repressors of these pathways underlie many autoinflammatory disorders. The receptor-interacting protein (RIP) kinases, RIPK1 and RIPK3, are integral players in extrinsic cell death signalling by regulating the production of pro-inflammat ...[more]

PMID: 33924766

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Project description:This study will determine if the drug infliximab is safe for treating inflammatory bowel disease (IBD) in patients with chronic granulomatous disease (CGD). IBD is an inflammation or irritation of the gut that leads to symptoms such as diarrhea, bloating and stomach cramps. CGD is an inherited disease affecting white blood cells called neutrophils in which patients are susceptible to repeated bacterial and fungal infections. They also have a higher incidence of some autoimmune diseases, such as IBD. Infliximab is approved to treat Crohn’s disease, an IBD similar to that seen in patients with CGD. Patients 10 years of age and older with CGD and IBD may be eligible for this study. Candidates are screened with a medical history, physical examination, blood and urine tests, electrocardiogram (EKG), tuberculosis skin test (PPD skin testing), and stool test for the presence of infections. Additional tests may be done, including colonoscopy (procedure using a flexible tube through the rectum to examine the lining of the gut) and imaging studies such as an x-ray, chest CT scan (test using a special x-ray machine), MRI (test using a magnetic field and radio waves), and barium studies (study using a drinkable solution of barium to help enhance the x-ray pictures of the gut). Participants are divided into patients with IBD symptoms (Group 1) and patients without IBD symptoms (Group 2) for the following procedures: Group 1 Patients are evaluated every 6 months with a medical history and physical examination for signs and symptoms of IBD. Patients who are taking moderate to high doses of steroid medications have their medication slowly lowered (tapered) and are evaluated every 3 months for a total of 2 years. Patients in this group who start to develop IBD symptoms are moved to Group 2 for treatment with infliximab (see below). Group 2 Patients in Group 2 receive infliximab infusions at 2-week intervals for three doses. The drug is given over a 2-hour period through a catheter placed in a vein. Patients are evaluated with a medical history, physical exam, and blood tests the day of each dose. One week after the last dose, they have another evaluation, including a colonoscopy. Patients who respond well to infliximab may continue to receive the drug every 2 months for a total of 1 year, with evaluations at every dosing visit. At the end of the first year of receiving infliximab, all patients have follow-up evaluations every 6 months for a total of 2 years. Group 3 Subjects who volunteer to undergo colonoscopy and research biopsies that serve as controls for evaluation of the patient gut samples.

Dataset Information

Targeting RIP Kinases in Chronic Inflammatory Disease.

Publications

Targeting RIP Kinases in Chronic Inflammatory Disease.

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