Dataset Information

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.

SUBMITTER: Vuerich M

PROVIDER: S-EPMC7544737 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Control of Gut Inflammation by Modulation of Purinergic Signaling.

Vuerich Marta M Mukherjee Samiran S Robson Simon C SC Longhi Maria Serena MS

Frontiers in immunology 20200925

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 ...[more]

PMID: 33072065

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Project description:Adenosine triphosphate (ATP) is essential for the myriad of metabolic processes upon which life is based and is known widely as the universal energy currency unit of intracellular biologic reactions. ATP, adenosine diphosphate, adenosine, as well as other purines and pyrimidines also serve as ubiquitous extracellular mediators which function through the activation of specific receptors (viz. P2 receptors for nucleotides and purinergic P1 receptors for adenosine). Extracellular nucleotides are rapidly converted to nucleosides, such as adenosine, by highly regulated plasma membrane ectonucleotidases that modulate many of the normal biological and metabolic processes in the liver - such as gluconeogenesis and insulin signaling. Under inflammatory conditions, as with ischemia reperfusion, sepsis or metabolic stress, ATP and other nucleotides can also act as 'damage-associated molecular patterns' causing inflammasome activation in innate immune cells and endothelium resulting in tissue damage. The phosphohydrolysis of ATP by ectonucleotidases, such as those of the CD39/ENTPD family, results in the generation of immune suppressive adenosine, which in turn markedly limits inflammatory processes. Experimental studies by others and our group have implicated purinergic signaling in experimental models of hepatic ischemia reperfusion and inflammation, transplant rejection, hepatic regeneration, steatohepatitis, fibrosis and cancer, amongst others. Expression of ectonucleotidases on sinusoidal endothelial, stellate or immune cells allows for homeostatic integration and linking of the control of vascular inflammatory and immune cell reactions in the liver. CD39 expression also identifies hepatic myeloid dendritic cells and efficiently distinguishes T-regulatory-type cells from other resting or activated T cells. Our evolving data strongly indicate that CD39 serves as a key 'molecular switch' and is an integral component of the suppressive machinery of myeloid, dendritic and T cells. Increased understanding of mechanisms of extracellular ATP scavenging and specifically conversion to nucleosides by ectonucleotidases of the CD39 family have also led to novel insights into the exquisite balance of nucleotide P2-receptor and adenosinergic P1-receptor signaling in inflammatory and hepatic diseases. Further, CD39 and other ectonucleotidases exhibit genetic polymorphisms in humans which alter levels of expression/function and are associated with predisposition to inflammatory and immune diseases, diabetes and vascular calcification, amongst other problems. Development of therapeutic strategies targeting purinergic signaling and ectonucleotidases offers promise for the management of disordered inflammation and aberrant immune reactivity.

Dataset Information

Control of Gut Inflammation by Modulation of Purinergic Signaling.

Publications

Control of Gut Inflammation by Modulation of Purinergic Signaling.

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