Control of Gut Inflammation by Modulation of Purinergic Signaling

Abstract

Inflammatory bowel disease (IBD) is a serious inflammatory condition of the gastrointestinal tract. Crohn's disease (CD) and ulcerative colitis (UC) are two of the most common IBD manifestations and are both associated with unfettered inflammation, often refractory to conventional immunosuppressive treatment. In both conditions, imbalance between effector and regulatory cell immune responses has been documented and is thought to contribute to disease pathogenesis. Purinergic signaling is a known modulator of systemic and local inflammation and growing evidences point to extracellular ATP/adenosine imbalance as a key determinant factor in IBD-associated immune dysregulation. In vitro and pre-clinical studies suggest a role for both ATP (P2) and adenosine (P1) receptors in dictating onset and severity of the disease. Moreover, our experimental data indicate ENTPD1/CD39 and CD73 ectoenzymes as pivotal modulators of intestinal inflammation, with clear translational importance. Here we will provide an updated overview of the current knowledge on the role of the purinergic signaling in modulating immune responses in IBD. We will also review and discuss the most promising findings supporting the use of purinergic-based therapies to correct immune dysregulation in CD and UC.

Characterization of a Murine Model System to Study MicroRNA-147 During Inflammatory Organ Injury

“…Inflammation is commonly observed in many pathogenic conditions including infection, acute organ injury, and chronic organ dysfunctions [46][47][48][49][50][51][52][53][54]. Initially intended as a response to help resolve tissue injury, inflammation could become excessive and uncontrolled, which leads to further tissue injury and, occasionally, systemic inflammation [55][56][57][58][59]. For example, uncontrolled alveolar epithelial inflammation results in ARDS [1,16,60,61], which is the common and main cause of death in COVID-19 [62,63].…”

MicroRNA: Crucial modulator in purinergic signalling involved diseases

“…It was demonstrated that the pharmacological manipulation of purinergic signalling represents a viable way to counteract several gastrointestinal diseases [50]. For example, purinergic-mediated strategies as adjunctive treatments were used to correct immune dysregulation in inflammatory bowel disease (IBD) patients [51]. Whether the P2 receptor was modulated by miRNAs in gastrointestinal diseases remain to be studied.…”

Dysfunctional Immune Regulation in Autoimmune Hepatitis: From Pathogenesis to Novel Therapies

“…However, since CD39 also plays an important role in tumor development and progression (99,(118)(119)(120)(121) and inhibition of effector immune responses against pathogens (99,122,123), the safety of long-term treatments aimed at restoring the levels of this ectoenzyme in the context of autoimmune diseases should be considered and carefully evaluated. A2A receptor agonists that enhance the adenosinergic signal might also have a role in restoring immunotolerance by reconstituting the purinergic milieu (41).…”

“…Extracellular nucleotides and nucleosides are strong modulators of T-cell immunity ( 40 ). Mounting evidence links alterations of purinergic signaling with the immunological dysfunction present in autoimmune conditions ( 41 ). Both Treg and Th17-cells obtained from AIH patients express low levels and impaired activity of the immunoregulatory ectoenzyme CD39 ( 42 , 43 ).…”