Differential Cell–Specific, Regulatory Roles of Fcγ Receptor IIB through IgG in IgA Nephropathy

Key Points Fc γ receptor IIB (Fc γ RIIB) mitigates renal inflammation, highlighting its role as a protective modulator in IgA nephropathy. Fc γ RIIB deficiency in macrophages and dendritic cells accelerated disease progression in a mouse model of IgA nephropathy. Targeting NOD-, LRR- and pyrin domain–containing protein 3, toll-like receptor 4, and Dectin-2 signaling may alleviate Fc γ RIIB-deficient IgA nephropathy. Background IgA nephropathy is the most common form of GN and a leading cause of kidney failure. Ample evidence confirms the deposition of IgA and IgG, as well as the infiltration of mononuclear leukocytes in kidney biopsy specimens from IgA nephropathy patients. Previously, we established an experimental IgA nephropathy model in B-cell–deficient mice, implicating interactions between Fc γ receptor in the pathogenesis of IgA nephropathy. It is generally accepted that Fc γ receptor IIB (Fc γ RIIB) plays a regulatory role in humoral responses; we proposed that Fc γ RIIB might exert differential kidney-protective effects depending on cell type specificity, thereby influencing the progression and severity of IgA nephropathy. Methods We used a mouse model of IgA nephropathy and three different cell types of Fc γ RIIB-deficient mice, including CCAAT/enhancer-binding protein/ α Cre (myeloid cells), CD11c Cre (dendritic cells), and CD19 Cre (B cells) in floxed Fc γ RIIB mice, as well as several specific cell models. Results In this study, we observed a large increase in albuminuria, kidney function impairment, and kidney injury in Fc γ RIIB knockout mice with induced IgA nephropathy. We demonstrated that macrophage-specific and dendritic cell–specific Fc γ RIIB deficiency enhanced the activation of NOD-, LRR- and pyrin domain–containing protein 3 inflammasome and accelerated the development and severity of IgA nephropathy, whereas this effect was not observed in mice with B-cell–specific Fc γ RIIB deficiency. Moreover, activation of the inflammasome was induced by IgA immune complexes dependent on toll-like receptor 4/myeloid differentiation primary response 88 signaling, potentially associated with crosstalk between Dectin-2. Conclusions We found that Fc γ RIIB deficiency in macrophages and dendritic cells led to increased albuminuria, kidney dysfunction, and kidney injury in a mouse model of IgA nephropathy. Fc γ RIIB deficiency enhanced the activation of NOD-, LRR- and pyrin domain–containing protein 3 inflammasome through IgA immune complexes in a toll-like receptor 4/myeloid differentiation primary response 88–dependent manner.