Macrophage expression of P2X7 controls autoimmune uveitis

The release of danger-associated molecular patterns (DAMPs) such as ATP from stressed or damaged cells is a key initiator of sterile inflammation. In autoimmune diseases, extracellular ATP acts as a potent pro-inflammatory signal by activating the purinergic receptor P2X7, which is expressed on both mononuclear phagocytes (MPs) and T cells—key drivers of pathological processes. While it is well established that P2X7 mediates ATP-dependent immune activation, its cell-specific contributions to innate versus adaptive immunity in autoimmune conditions remain unclear, especially in autoimmune uveitis. Here we used the experimental autoimmune uveoretinitis (EAU) mouse model to delineate the cellular mechanisms underlying P2X7's role in autoimmune responses. Using a combination of multiple cell-specific conditional models and transcriptomic approaches, we showed a pivotal role forP2X7 expressed by MPs in orchestrating T-cell mediated autoimmune responses. P2X7 deficiency in MPs decreased disease severity. Additionally, cell-specific transcriptomic analyses, including single-cell analyses, revealed that P2X7 exerted distinct modulatory effects across monocyte-derived macrophages (MdM) versus microglia. In MdM, lack of P2X7 was associated with reduced expression of genes related to the inflammasome, phagocytosis pathways, and components of the complement system, leading to a marked decrease in pathogenic Th17 cell frequency in the retina. In microglia, P2X7 deficiency instead particularly impacted an IFN-responsive microglial subset that is normally characteristic of EAU. By specifically deleting P2X7 in microglia, we demonstrate its role in driving pathogenic processes in this cell population. These findings suggest that inhibition of P2X7 could be a promising therapeutic strategy in autoimmune neuroinflammatory disorders.