Key Points

Fcγ receptor IIB (FcγRIIB) mitigates renal inflammation, highlighting its role as a protective modulator in IgA nephropathy.FcγRIIB 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 FcγRIIB-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 Fcγ receptor in the pathogenesis of IgA nephropathy. It is generally accepted that Fcγ receptor IIB (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

We used a mouse model of IgA nephropathy and three different cell types of FcγRIIB-deficient mice, including CCAAT/enhancer-binding protein/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 this 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-specific and dendritic cell–specific FcγRIIB 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 FcγRIIB 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 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 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.