Activation of Purinergic Signaling Pathways during the Development of Inflammatory Bowel Disease

Abstract

Inflammatory bowel disease is an important illness of unclear pathogenesis associated with major defects in mucosal immunoregulation and develops in genetically susceptible individuals. These abnormalities often occur in association with microbial dysbiosis and result in unfettered inflammation of the intestine and extraintestinal tissues. Such events result in long-term morbidity and possibly even death, in otherwise healthy adults and children. Dampening inflammation and re-establishing immune tolerance in inflammatory bowel disease remain the major therapeutic goal. However, existing inflammatory bowel disease therapies albeit providing recent advances, still largely rely on broad-based immunosuppression. For example, only around half of the patients treated with anti-TNF agents show substantive clinical responses. These improvements are often self-limited, while unfortunately increasing the risk of opportunistic infections. The purpose of the study was to investigate the control of mucosal immune responses, which are based on fundamental signaling pathways. Long-term interests in the regulation of purinergic signaling are now being leveraged to develop innovative and hopefully non-toxic therapies for inflammatory bowel disease. This review and the accompanying articles in this special issue address new therapeutic concepts in inflammatory bowel disease, as based on recent, linked work in hypoxia and purinergic signaling, mucosal barrier functions and microRNA biology. In several recent, comprehensive reviews, have already addressed the biological functions of ectoenzymes, such as CD39, CD73, and CD38, in the regulation of purinergic signaling and control of extracellular adenosine levels. Others, have noted the importance of these mechanisms in immunomodulation, as in cancer and inflammation. The ectonucleotidases of the CD39 family, in particular, have major impacts on the dynamic equilibrium of proinflammatory extracellular ATP, ADP nucleotides vs. the immunosuppressive potential of adenosine nucleosides. CD39 plays a dominant role in purinergic regulation of vascular inflammation, thrombosis, and the immune response in such settings. The relevance and importance of these purinergic signaling pathways in selected neoplastic states (lymphoma and chronic leukemia) and inflammatory diseases (sepsis and autoimmunity) have been already alluded to in recent work. A brief synopsis of the major components of purinergic signaling; chiefly for those not familiar to this field, will focus on very recent work detailing the immunomodulation of CD39 on T cells and other immune cells by both genetic and environmental factors in the setting of inflammatory bowel disease and experimental colitis, inclusive of the new roles for natural metabolites such as bilirubin, and will also briefly cover the role of CD39 expression on exosomes and microparticles, in control of inflammation in the gut and touch on the relevance of the microbiome. Lastly, it will cover the emerging importance of other NTPDases of the CD39 family and speculate on their role in controlling gut inflammation. Conclusion. Review of the literature with own data is devoted to description of the recent advances in the study purinergic signaling pathways implicated in immune dysregulation, in the pathogenesis of inflammatory bowel disease. Our focus in this review is on novel aspects of the functions of CD39 and related nucleoside triphosphate diphosphohydrolases in inflammatory bowel disease