Dual immuno-renal targeting of 7-benzylidenenaltrexone alleviates lupus nephritis via FcγRIIB and HO-1

Known as a selective δ1 opioid receptor (dor1) antagonist, the 7-benzylidenenaltrexone (bntx) is also a dor1-independent immunosuppressant with unknown mechanisms. here we investigated if bntx could be beneficial for diseased mrl/lpr lupus mice. we treated mice with 0.5, 2, 5 or 10 mg/kg/day of bntx for 2 weeks. at as low as 2 mg/kg/day, bntx significantly improved splenomegaly and lymphadenopathy. notably, b cell numbers, particularly autoreactive plasma cells, were preferentially reduced; moreover, bntx enhanced surface expression of fcγriib, an immune complex (ic)-dependent apoptotic trigger of b cells. consequently, serum autoantibody concentrations were significantly decreased, leading to diminished glomerular ic deposition and renal fibrosis, thereby improving proteinuria. microarray and pathway analyses revealed heme oxygenase-1 (ho-1) and p38 mapk as key mediators of bntx-induced upregulation of fcγriib. moreover, ho-1 expression was also induced by bntx via p38 mapk at renal proximal tubules to further cytoprotection. taken together, we demonstrate that bntx can alleviate lupus nephritis by reducing autoreactive b cells via fcγriib and by augmenting renal protection via ho-1. accordingly, we propose a new strategy to treat lupus nephritis via such a dual immuno-renal targeting using either a single agent or combined agents to simultaneously deplete b cells and enhance renal protection.