Background: Purinergic receptors are critical modulators of inflammation, tissue damage, and pain in rheumatologic diseases. 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. Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease that affects both peripheral organs and brain. Neuropsychiatric manifestations in SLE are common, affecting roughly 30%-60% of patients, with cognitive dysfunction, headaches, mood disorders (depression, anxiety), psychosis, and seizures being the most frequent symptoms. The mechanisms leading to psychiatric manifestations in NPSLE is still not clear.

Objectives: We hypothesized that causes of neuroinflammation and consequential neuropsychiatric behavior 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. We set out to ask the question if attenuating P2X7R signaling in the periphery ameliorates neuroinflammation and neuropsychiatric behavior in a mouse model of lupus disease.

Methods: We used the MRL/lpr lupus-prone mouse model, a classic model to study NPSLE, and tested the peripheral blockade of P2X7R signaling using the Brilliant-Blue G (BBG) compound (45mg/kg injected i.p. every other day for 2 weeks). We performed tail-suspension test to assess depressive-like behavior, 48 hr before the endpoint of the experiment. We measured circulating ATP and soluble P2X7R in plasma by ELISA. We analyzed gene expression of P2X7R by RT-qPCR using Taqman probes.

Results: We observed 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.

Conclusions: Our results indicate that P2X7R signaling may play a role in neuroinflammation with increased expression of the receptor in the brain in older MRL/lpr mice than young mice. Attenuation of P2X7R signaling in the periphery reduces not only peripheral inflammation via P2X7R but also possibly neuroinflammation in the pre-clinical lupus mouse model. Therapeutic targets attenuating systemic inflammation in SLE could also ameliorate NPSLE. We are continuing to investigate the mechanisms of regulation of NPSLE via the P2X7R pathway.

REFERENCES: NIL.

Acknowledgments: NIL.

Disclosure of Interests: None declared.