NLRP3 inflammasome: Pathogenic role and potential therapeutic target for IgA nephropathy

Yu-Ling Tsai,Kuo-Feng Hua,Yung-Luen Yu,Ching-Liang Chu,Shuk-Man Ka,Chyou-Wei Wei,Chia-Wen Lo,Cheng-Yeu Wu,Wen-Shiang Chen,Ann Chen

doi:10.1038/srep41123

Abstract

We have previously showed that IL-1β is involved in the pathogenesis of both spontaneously occurring and passively induced IgA nephropathy (IgAN) models. However, the exact causal-relationship between NLRP3 inflammasome and the pathogenesis of IgAN remains unknown. In the present study, we showed that [1] IgA immune complexes (ICs) activated NLRP3 inflammasome in macrophages involving disruption of mitochondrial integrity and induction of mitochondrial ROS, bone marrow-derived dendritic cells (BMDCs) and renal intrinsic cells; [2] knockout of NLRP3 inhibited IgA ICs-mediated activation of BMDCs and T cells; and [3] knockout of NLRP3 or a kidney-targeting delivery of shRNA of NLRP3 improved renal function and renal injury in a mouse IgAN model. These results strongly suggest that NLRP3 inflammasome serves as a key player in the pathogenesis of IgAN partly through activation of T cells and mitochondrial ROS production and that a local, kidney-targeting suppression of NLRP3 be a therapeutic strategy for IgAN.

Highlights

That addresses the NLRP3 inflammasome activation involved in the development and progression of IgA nephropathy (IgAN), based on our mechanistic investigations using [1] cultured macrophages, dendritic cells (DCs), glomerular mesangial cells (MCs), and renal tubular epithelial cells (TECs), [2] NLRP3 knockout (NLRP3 KO) mice, and [3] gene delivery of shRNA using a kidney-targeting, ultrasound-mediated microbubble technique
The role of NLRP3 in IgA immune complexes (ICs)-induced IL-1βsecretion was confirmed in peritoneal macrophages, as caspase-1 activation and IL-1βsecretion were significantly reduced in the cells derived from NLRP3 KO mice compared to those of peritoneal macrophages from WT mice (Fig. 1d)
We chose an IgAN model passively induced by repeated injections of IgA and pneumococcal C-polysaccharide (PnC) antigen to make it feasible inducing the experimental IgAN in NLRP3 KO mice (NLRP3 KO +IgAN mice), with which we examined the impact of lack of NLRP3 inflammasome activation on the development of the IgAN model

Summary

Introduction

That addresses the NLRP3 inflammasome activation involved in the development and progression of IgAN, based on our mechanistic investigations using [1] cultured macrophages, DCs, glomerular MCs, and renal tubular epithelial cells (TECs), [2] NLRP3 knockout (NLRP3 KO) mice, and [3] gene delivery of shRNA using a kidney-targeting, ultrasound-mediated microbubble technique

Methods

Results

Conclusion