Characterization of Small Molecule Gβγ Inhibitors in the Context of Inflammation

Abstract

Systemic Lupus Erythematosus (SLE) is an autoimmune disease with widespread inflammation. A significant contributor to SLE is the excessive recruitment and activation of immune cells to inflamed sites via chemokines. Chemokine receptors are G‐protein coupled receptors, which liberates free Gβγ from the heterotrimeric G‐protein. Gβγ is vital in migration of immune cells. We propose that Gβγ inhibitors could be potential therapeutic candidates for SLE treatment. The NZB/W mice develop lupus similar to human SLE such as elevated autoantibodies and immune complex‐induced nephritis. To characterize the effects of Gβγ inhibition on SLE, three groups NZB/W mice were injected with vehicle, low dose (20 mg/kg), or high dose (35 mg/kg) of the Gβγ inhibitor gallein for 19 weeks. Our results show that mice treated with gallein had lower proteinuria compared to control. Furthermore, Gβγ inhibition markedly reduced infiltration in the kidneys of gallein treated mice. Specifically, the number of T‐cell, B‐cell, and, antibody secreting plasma cells were reduced by Gβγ inhibition. Ellagic acid and F067, like gallein, are small molecule inhibitors of Gβγ that attenuate neutrophil and T‐cell migration. Upon agonist stimulation, neutrophils isolated from gallein treated mice migrate less efficiently compared to control. Furthermore, this effect persists over time after the initial treatment with gallein. Similarly, an in vitro treatment model showed inhibited neutrophil migration upon agonist stimulation, after initial treatment with gallein and F067. In conclusion, our results suggest that inhibition of Gβγ attenuates immune cell migration and have a beneficial effect against lupus nephritis.