Virginia Research Day 2025

Medical Student Research Biomedical

21 The Role of Adenosine Receptor Modulation on Systemic Lupus Erythematosus Disease Progression

Hilary Montano; Tyler McCormick; Emma Poehler; Rana Estaleen; David N Oakland; Christopher M. Reilly Corresponding author: epoehler@vt.vcom.edu Department of Biomedical Sciences, Edward Via College of Osteopathic Medicine Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine

Systemic Lupus Erythematosus (SLE) is an autoimmune disease associated with chronic inflammation and loss of self-tolerance causing the body to attack itself. The etiology and pathogenesis of SLE are poorly understood, with clinical manifestations varying significantly between patients. While there is currently no cure for SLE, current therapies center around anti-malarial drugs and immunosuppressants like dexamethasone, an anti-inflammatory steroid. Adenosine receptor dysregulation has been specifically linked with lupus disease exacerbation. These receptors play crucial roles in immune modulation and inflammation through alterations in cytokine production. The Adenosine A2A Receptor (A2AR) has been found to have anti-inflammatory effects, while the Adenosine A2B Receptor (A2BR) is associated with

pro-inflammatory effects. We hypothesized that either activation of A2AR or inhibition of the A2BR would decrease disease severity. Lupus prone NZB/W F1 mice were intraperitoneally injected daily for 12 weeks with ADO-5024 (A2BR antagonist) or ADO-6001 (A2AR agonist) with Dexamethasone as the standard treatment control and PBS as the negative control beginning at 20 weeks-of-age (n=8). Urine was measured weekly for proteinuria as an indication of lupus nephritis. At 32 weeks-of-age the mice were euthanized, and spleen and kidney were harvested and analyzed by flow cytometry. Glomerular morphology was also analyzed by PAS staining and immunohistochemical staining for IgG and C3 deposition. Our findings showed that mice treated with the A2BR antagonist had overall

attenuated lupus disease similar to dexamethasone treatment, while those treated with the A2AR agonist developed lupus symptoms similar to the PBS control group. The animals treated with ADO-5024 showed reduced inflammatory profiles as observed through flow cytometry, compared the PBS or the ADO-6001 treated mice. The ADO-5024 treated mice showed reduced IgG and C3 deposition and statistically decreased glomerulonephritis compared to the PBS treated or ADO-6001 treated animals. Overall, our data suggests that inhibition of the adenosine A2BR may have therapeutic potential in treati.ng lupus disease and more specifically lupus nephritis. Study approved by the Virginia Tech IACUC, protocol #23-271

86