Differential Cell-Specific, Regulatory Roles of FcγRIIB through IgG in IgA Nephropathy

Abstract

Background: IgA nephropathy is the most common form of glomerulonephritis 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 Fcγ receptors (FcγRs) in the pathogenesis of IgA nephropathy. It is generally accepted that FcγRIIB plays a regulatory role in humoral responses; we proposed that FcγRIIB might exert differential kidney-protective effects depending on cell-type specificity, thereby influencing the progression and severity of IgA nephropathy.

Methods: Utilizing a mouse model of IgA nephropathy and three different cell types of FcγRIIB-deficient mice, including CEBP/α Cre (myeloid cells), CD11c Cre (dendritic cells) and CD19 Cre (B cells) in floxed FcγRIIB mice, as well as several specific cell models.

Results: In the present study, we observed a large increase in albuminuria, kidney function impairment, and kidney injury in FcγRIIB knockout mice with induced IgA nephropathy. We demonstrated that macrophage- and dendritic cell-specific FcγRIIB deficiency enhanced the activation of NLRP3 inflammasome and accelerated the development and severity of IgA nephropathy, whereas this effect was not observed in mice with B cell-specific FcγRIIB deficiency. Moreover, activation of the inflammasome was induced by IgA immune complexes dependent on TLR4/MyD88 signaling, potentially associated with crosstalk between Dectin-2.

Conclusions: We found that FcγRIIB deficiency in macrophages and dendritic cells led to increased albuminuria, kidney dysfunction, and kidney injury in a mouse model of IgA nephropathy. FcγRIIB deficiency enhanced activation of NLRP3 inflammasome through IgA immune complexes in a TLR4/MyD88-dependent manner.