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Open Access Highly Accessed Review

Is the inflammasome a potential therapeutic target in renal disease?

Clare M Turner1, Nishkantha Arulkumaran12*, Mervyn Singer2, Robert J Unwin3 and Frederick WK Tam1

Author Affiliations

1 Imperial College Kidney and Transplant Institute, Hammersmith Hospital, Imperial College London, London, UK

2 Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, WC1E 6BT London, UK

3 UCL Centre for Nephrology, Division of Medicine, Royal Free Campus and Hospital, University College London, WC1E 6BT London, UK

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BMC Nephrology 2014, 15:21  doi:10.1186/1471-2369-15-21

Published: 23 January 2014

Abstract

The inflammasome is a large, multiprotein complex that drives proinflammatory cytokine production in response to infection and tissue injury. Pattern recognition receptors that are either membrane bound or cytoplasmic trigger inflammasome assembly. These receptors sense danger signals including damage-associated molecular patterns and pathogen-associated molecular patterns (DAMPS and PAMPS respectively). The best-characterized inflammasome is the NLRP3 inflammasome. On assembly of the NLRP3 inflammasome, post-translational processing and secretion of pro-inflammatory cytokines IL-1β and IL-18 occurs; in addition, cell death may be mediated via caspase-1. Intrinsic renal cells express components of the inflammasome pathway. This is most prominent in tubular epithelial cells and, to a lesser degree, in glomeruli. Several primary renal diseases and systemic diseases affecting the kidney are associated with NLRP3 inflammasome/IL-1β/IL-18 axis activation. Most of the disorders studied have been acute inflammatory diseases. The disease spectrum includes ureteric obstruction, ischaemia reperfusion injury, glomerulonephritis, sepsis, hypoxia, glycerol-induced renal failure, and crystal nephropathy. In addition to mediating renal disease, the IL-1/ IL-18 axis may also be responsible for development of CKD itself and its related complications, including vascular calcification and sepsis. Experimental models using genetic deletions and/or receptor antagonists/antiserum against the NLRP3 inflammasome pathway have shown decreased severity of disease. As such, the inflammasome is an attractive potential therapeutic target in a variety of renal diseases.

Keywords:
Inflammasome; NLRP3; Renal disease; IL-1β; IL-18; PAMPs; DAMPs; P2X7R