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Kidney Week

Abstract: FR-PO684

Regulatory Function of FcγRIIB Involving the NLRP3 Inflammasome in a Mouse Model of IgA Nephropathy

Session Information

Category: Glomerular Diseases

  • 1401 Glomerular Diseases: From Inflammation to Fibrosis

Authors

  • Chen, Ann, Hualien Tzu Chi Hospital Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
  • Chou, Yu-Ling, National Defense Medical Center, Taipei, Taiwan
  • Ka, Shuk-Man, National Defense Medical Center, Taipei, Taiwan
Background

IgA nephropathy (IgAN) is the most common form of glomerulonephritis and represents a leading cause of end-stage renal disease. Ample evidence confirms the deposition of IgA and IgG and filtration of mononuclear leukocytes in IgAN patients. Previously, we established an experimental IgAN model in B cell-deficient mice, which implicated interactions between Fcγ receptors (FcγRs) in the pathogenesis of IgAN. Although it is generally accepted that FcγRIIB plays a regulatory role in humoral responses, it remains unknown whether this function and the cell type-specificity of FcγRIIB are reno-protective in IgAN.

Methods

We observed a dramatic increase in albuminuria, renal function impairment, and renal injury in FcγRIIB knockout mice with induced IgAN. Utilizing a mouse model of IgAN and three different 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

We demonstrated that macrophage- and dendritic cell-specific FcγRIIB deficiency blunted the activation of the NLRP3 inflammasome and inhibited the development of IgAN. Moreover, activation of the inflammasome was induced by IgA immune complexes dependent on TLR4/MyD88 signaling, associated with crosstalk between TLR4 and Dectin-2.

Conclusion

These results suggest that activation of FcγRIIB and its downstream signaling pathways could moderate progression of IgAN involving the suppression of the NLRP3 inflammasome. A cell type-specific targeting of FcγRIIB may help the establishment of therapeutic strategy for the renal disease.