Is the inflammasome a potential therapeutic target in renal disease?

Mervyn Singer,Nishkantha Arulkumaran,Robert J Unwin,Frederick WK Tam,Clare M Turner

doi:10.1186/1471-2369-15-21

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.

Highlights

Inflammation is central to the pathogenesis of many renal diseases
The innate immune system, a first line defense against pathogens, is usually involved in the initiation and propagation of inflammation. It is activated by a series of germ-line encoded pattern recognition receptors (PRRs) that allow discrimination of ‘self’ from ‘non-self’ antigens
The innate immune system is ‘primed’ by activation of PRRs by Pathogenassociated molecular pattern (PAMP) or Damage-associated molecular pattern (DAMP), which leads to activation of numerous proinflammatory transcription factors, the best characterized being nuclear factor kappa-B (NF-κB) and activator protein-1 (AP-1), with subsequent transcription of multiple mediators and receptors

Summary

Introduction

Inflammation is central to the pathogenesis of many renal diseases. The innate immune system, a first line defense against pathogens, is usually involved in the initiation and propagation of inflammation. Many systemic diseases affecting the kidneys are associated with NLRP3 inflammasome/IL-1β/IL-18 axis activation (Table 2) These include UUO [68,76,80,83], I-R injury [43,44,45,61,66,81], GN [46,47,48,67,70,90,97,119], sepsis [91,92,94], CKD [80,120], hypoxia [96], glycerol-induced renal failure [93], and crystal nephropathy [121]. Complications associated with CKD are clearly multifactorial and a greater understanding of the role of the NLRP3 inflammasome/IL-1/IL-18 axis in mediating these complications is required before any therapeutic strategy can be developed and applied

Conclusions

58. Dinarello CA