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

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.

A synthetic cationic antimicrobial peptide inhibits inflammatory response and the NLRP3 inflammasome by neutralizing LPS and ATP

“…RAW 264.7 (2 × 10 6 in 2 ml of medium) were seeded in 6-cm dishes and then treated with or without LPS (0.1 μg/ml) in the absence or presence of AMP for 6 h. Total RNA was extracted from the treated cells by TRIzol reagent (Gibco, Grand Island, NY, USA) and the cDNA was prepared as described in detail previously [ 34 ]. The mRNA expression levels of iNOS and COX-2 were measured by quantitative real-time PCR using the StepOne real-time PCR system (Applied Biosystems, Foster City, CA, USA).…”

Role of Inflammasomes in Kidney Diseases via Both Canonical and Non-canonical Pathways

“…As already indicated, the inflammasome has a close relationship with kidney; however, whether it plays a role in the IGAN remains unknown. Recently, Tsai et al (2017) found that IgA immune complexes can activate the inflammasome through the ROS in macrophage and induce the secretion of IL-1β and caspase-1, which indicated that the NLRP3 might participate in the inflammation in IGAN. Moreover, other factors that regulate NLRP3 activation can relieve the inflammation in IgA to some degree.…”

Acrylamide moiety, a Valuable Fragment in Medicinal Chemistry: Insight into Synthetic Methodologies, Chemical Reactivity and Spectrum of Biological Activities of Acrylamide Derivatives

“…Its role involves a caspase-1 activity for activation of chemokines as IL-1β and induction of chemotaxis, as well as roles in induction of necrosis and pyroptotic cell death 60 . Aberrations of NLRP3 inflammasome activity have been linked to number of diseases as neurological disorders 61 , Alzheimer's disease 62 , auto-immune disorders 63 and inflammatory disorders 64 .…”