Purinergic receptor P2X7R regulates neuropsychiatric lupus 2259440

Abstract

Abstract Introduction Neuropsychiatric lupus (NPSLE) is one of the common manifestations of human systemic lupus erythematosus (SLE), a complex autoimmune disease that affects both peripheral organs and brain. The mechanisms leading to psychiatric manifestations in NPSLE is still not clear. The P2X7R, one of the well-studied purinergic receptors, is activated by high levels of ATP and has broad expression in innate and adaptive immune cells. We hypothesize that causes of neuroinflammation in NPSLE could be due to cell communication from the periphery via ATP and/or P2X7R, as we have shown in other settings of organ injury. Methods We used the MRL/lpr lupus-prone mouse model and tested the effects P2X7R blockade using Brilliant-Blue G (BBG) compound, 45mg/kg injected i.p. every other day for 2 weeks. Tail-suspension test was performed to assess depressive-like behavior, 48 hr before the endpoint of the experiment. Circulating ATP and soluble P2X7R were measured in plasma by ELISA. Gene expression of P2X7R was measured by RT-qPCR using Taqman probes. Results We show increased expression of P2X7R in spleen and brain and increased plasma ATP levels in old mice (diseased) as compared to young mice (pre-disease). Blockade of P2X7R showed decreased circulating ATP, and P2X7R and reduced depressive-like behavior in the MRL/lpr mice. Conclusion Our results, in pre-clinical model using lupus-prone mice, show that reduced peripheral inflammation via P2X7R reduces neuroinflammation. Therapeutic targets attenuating systemic inflammation in SLE could also ameliorate NPSLE. We are continuing to investigate the mechanisms of regulation of NPSLE via P2X7R pathway. Funding Source n/a Topic Categories Therapeutic Approaches to Autoimmunity (THER)