Abstract: FR-PO824
Cell Type Specificity of FcγRIIB Involving NLRP3 Inflammasome and Dectin-2 in a Mouse Model of IgA Nephropathy
Session Information
- Glomerular Diseases: Inflammation and Immunology
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Ka, Shuk-Man, Department of Medicine, National Defense Medical Center, Taipei, Taiwan
- Chen, Ann, Department of Pathology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, 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 the filtration of mononuclear leukocytes in renal biopsy specimens from 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 suggested 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 FcγRIIB may help in establishing a therapeutic strategy for this renal disease.
Funding
- Government Support – Non-U.S.