eATP differentially modulates inflammation in mice and humans. In mice (left), eATP activates the ionotropic receptor P2X7, which can also be activated by NAD⁺ through ART2.2-mediated ADP ribosylation. P2X7 activation leads to K⁺ efflux that triggers NLRP3 inflammasome activation, thereby promoting inflammation (red lines). P2X7 can also induce apoptosis of Tregs, thus amplifying inflammation. On the other hand, Tregs contribute to a reduction in eATP concentration by expressing the CD39 ectoenzyme, which hydrolyzes ATP into ADP and AMP (blue lines). In humans (right), the high-affinity ATP receptor P2Y11 mediates immunosuppressive effects by increasing the intracellular cAMP concentration. Moreover, because of the absence of a human ortholog of the murine ART2.2 gene, NAD⁺ does not activate P2X7.