NLRP3 in Renal Injury and Inflammation
Date
2014-07-11
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Renal cell injury, death and inflammation are hallmarks of chronic kidney disease (CKD).
Unresolved inflammation can chronically damage renal tissue resulting in fibrosis and kidney
failure. The Nlrp3 inflammasome has been implicated in the innate immune response to cellular
injury and represents a potentially important pathway in the pathogenesis of CKD. The central
hypothesis of this thesis is that NLRP3 plays a significant role in renal inflammation and chronic
renal injury. In a mouse model of progressive renal injury and fibrosis (unilateral ureteral
obstruction, UUO), Nlrp3 expression and inflammasome activation were increased in injured
kidneys. Compared to wild-type counterparts, Nlrp3-/-mice undergoing UUO displayed reduced
renal injury, fibrosis and inflammatory cytokine levels confirming an important role for Nlrp3 in
experimental kidney disease. Bone marrow chimeras in the UUO model indicated that in
addition to its inflammasome-forming capabilities in leukocytes, Nlrp3 may play a novel role in
the renal epithelial compartment. Indeed, Nlrp3 expression was found in both human and mouse
primary tubular epithelial cells. Unlike the inflammasome-forming capability of Nlrp3 in
macrophages, renal tubular epithelial cells lacked the components of the inflammasome
including caspase-1 and its substrate IL-1β. Rather, Nlrp3 primarily regulated caspase-8
activation and apoptosis in these cells. Experiments to elucidate the mechanism of Nlrp3-
regulated caspase-8 activation and apoptosis suggested the involvement of Asc, but not
inflammatory cytokines, caspase-1 or caspase-11. Furthermore, Nlrp3-/- tubular epithelial cells
were found to have impaired mitochondrial ROS production that was linked to decreased
caspase-8 activation during apoptosis. Taken together, results from this thesis identify a
significant and multidimensional role for Nlrp3 in the pathogenesis of kidney disease. First,
Nlrp3 inflammasome activation in macrophages releases cytokines such as IL-1β and IL-18 that
cause renal inflammation, fibrosis and tubular epithelial cell apoptosis. Second, Nlrp3 expressed
in tubular epithelial cells displays an intrinsic inflammasome-independent function to regulate
caspase-8, mitochondrial ROS and apoptosis. These data identify Nlrp3 as an important player in
renal injury and potential therapeutic target for CKD.
Description
Keywords
Immunology
Citation
Vilaysane, A. (2014). NLRP3 in Renal Injury and Inflammation (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/27108