A Non-Canonical Function for NLRP3 and AIM2 in Kidney Diseases
Abstract
NLRP3 and AIM2 are inflammasome-forming proteins that have been mostly studied in leukocytes. Canonical NLRP3 or AIM2 inflammasomes regulate cytokine maturation and pyroptosis via ASC and caspase-1 activation. Emerging studies demonstrate that NLRP3 or AIM2 is expressed in non-haematopoietic cells such as tubular epithelial cells (TEC) in the kidney. The central hypothesis of this thesis is that NLRP3 and AIM2 regulate host response to renal injury in the kidney. Primary mouse TEC lacking Nlrp3 displayed reduced caspase-8 activation downstream of the tumor necrosis factor (TNF) receptor and CD95. TNFα/cycloheximide treatment induced NLRP3/ASC/caspase-8 speck-like complex formation at the mitochondria during apoptosis. The assembly of NLRP3/ASC/caspase-8 specks was downstream of TNFR signaling and independent of caspase-1 or -11 activation. This data shows that NLRP3 and ASC form a conserved non-canonical platform for caspase-8 activation, independent of the inflammasome that regulates apoptosis within epithelial cells. Interestingly, AIM2 was detected primarily in podocytes in the glomerulus and distal tubules at a low level. In a mouse model of nephrotoxic serum (NTS)-mediated anti-GBM, Aim2-/- mice displayed increased glomerular cellular crescent (multilayered accumulation of activated parietal cells) formation, tubular injury and inflammation, and worse renal function compared to wild-type controls. In vitro outgrowth of podocyte lacking Aim2 was greater than wild-type and Aim2-/- podocytes did not express Nhps2 (podocin) mRNA, a podocyte maturation marker. Furthermore, AIM2 was found to augment transcriptional activity of Wilm’s tumour-1 that regulates Nphs1 expression. This data suggests that non-canonical AIM2 regulates podocyte maturation, proliferation and potentially podocyte-to-parietal cell trans-differentiation during cellular crescent formation in vivo. In a mouse model of kidney ischemia/reperfusion in vivo, a significant difference in tubular injury was not detected between wild type and Aim2-/- mice. In vitro, tubular Aim2 did not regulate caspase-8 activation during apoptosis, confirming a limited role for Aim2 in tubular cell death. However, Aim2 deficiency attenuated TGFβ-mediated Smad phosphorylation and αSMA induction. Overall, these data increase the understanding of NLRP3 and AIM2 biology in the kidney diseases and highlight overarching non-canonical roles for NLRP3 and AIM2 to regulate critical biological processes in the kidney independent of inflammasome activation
Description
Keywords
Biology--Cell, Immunology
Citation
Chung, H. J. (2017). A Non-Canonical Function for NLRP3 and AIM2 in Kidney Diseases (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/24925