Extracellular nucleotides as negative modulators of immunity

Abstract

Nucleotides are well known for being the universal currency of intracellular energy transactions, but over the past decade it has become clear that they are also ubiquitous extracellular messengers. In the immune system there is increasing awareness that nucleotides serve multiple roles as stimulants of lymphocyte proliferation, ROS generation, cytokine and chemokine secretion: in one word as pro-inflammatory mediators. However, although often neglected, extracellular nucleotides exert an additional more subtle function as negative modulators of immunity, or as immunodepressants. The more we understand the peculiar biochemical composition of the microenvironment generated at inflammatory sites, the more we appreciate how chronic exposure to low extracellular nucleotide levels affect immunity and inflammation. A deeper understanding of this complex network will no doubt help design more effective therapies for cancer and chronic inflammatory diseases.

Figure 1

Diverging roles of high or low extracellular ATP concentrations in shaping the immune response. Panel A: Tissue cells release large ATP amounts in response to high pathogen titers. The increase in extracellular ATP level drives inflammatory dendritic cell (DC) and macrophage (Mϕ) differentiation, accompanied by release of pro-inflammatory mediators (TNF-α, IL-12, IL-1β, ROS), naive TH cells to TH1 lymphocyte differentiation and initiation of inflammation. Panel B: In response to low grade stimulation by pathogens, tissue cells release modest amounts of ATP which cause down-modulation of pro-inflammatory cytokines, preferential release of immunodepressive cytokines, differentiation of naive TH cells into TH2 lymphocytes, and a state of immunosuppression or allergy.

Figure 2

Extracellular ATP drives the differentiation of lamina propria TH17 lymphocytes. Bacteria hosted in the gut lumen continuously release ATP which moulds the differentiation of mucosal dendritic cells (DCs) which are stimulated to secrete IL-6, IL-23 and TGF-β. These cytokines are needed to allow the establishment of a normal population of IL-17-secreting lymphocytes (TH17) lymphocytes in the lamina propria. However, in response to massive releases of ATP, such as those occurring during uncontrolled bacterial growth or epithelial cell damage, secretion of these cytokines can so large to an unphysiological/pathogenic expansion of TH17 lymphocytes. This may trigger an inappropriate local immune response, which eventually causes inflammatory bowel disease.