NLRP3 in Renal Injury and Inflammation

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.

Name thesis:degree_name

Doctor of Philosophy (PhD)

Discipline thesis:degree_discipline

Immunology

Grantor dc:publisher.institution

Graduate Studies

Year dc:date.issued

2014

Author dc:creator

• Vilaysane, Akosua

Advisor dc:contributor.advisor

• Muruve, Daniel

• Immunology

Statement dc:rights

• University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.

Language dc:language.iso

eng

DOI

http://dx.doi.org/10.11575/PRISM/27108

OAI identifier oai:identifier

oai:ucalgary.scholaris.ca:11023/1626