Ambiguities in NLRP3 inflammasome regulation: is there a role for mitochondria?

Abstract

BACKGROUND:

The NLRP3 inflammasome is a sensor of specific pathogen, host and environmental danger molecules. Upon activation NLRP3 recruits caspase-1, which cleaves and thereby activates precursor interleukin-1β (IL-1β) and IL-18 to initiate immune responses. Several recent studies have posited that the mitochondria are a central regulator of NLRP3 function.

SCOPE OF REVIEW:

Mitochondrial reactive oxygen species (mtROS) production, mitochondrial apoptosis, mitochondrial DNA (mtDNA) release, mitophagy, calcium induced mitochondrial damage and mitochondrial co-ordination of NLRP3 localization have all been implicated in regulating NLRP3 activity. In this article we review the literature both for and against these models of NLRP3 inflammasome activation, and highlight other recent contentious issues concerning NLRP3 functioning.

MAJOR CONCLUSIONS:

Although many mechanisms have been proposed for activating NLRP3, no unified model has yet to gain acceptance. Further research is required to clarify how the mitochondria might influence NLRP3 activity.

GENERAL SIGNIFICANCE:

While the NLRP3 inflammasome is important for host protection against microbial infection, rare genetic mutations in NLRP3 also cause severe auto-inflammatory diseases. More recent research has implicated NLRP3 activity in pathologies such as atherosclerosis, cancer, type 2 diabetes and Alzheimer's disease. Understanding the mechanisms of NLRP3 inflammasome formation and regulation therefore has the potential to uncover new inflammasome and disease specific therapeutic targets. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research.

• Authors: Kate E Lawlor, James E Vince
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1840 Issue 4 Pg. 1433-40 (Apr 2014) ISSN: 0006-3002 [Print] Netherlands
• PMID: 23994495 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: © 2013.

Chemical References

• Carrier Proteins
• Inflammasomes
• NLR Family, Pyrin Domain-Containing 3 Protein
• NLRP3 protein, human
• Proto-Oncogene Proteins c-bcl-2
• Reactive Oxygen Species

Topics

• Animals
• Apoptosis (physiology)
• Carrier Proteins (physiology)
• Humans
• Inflammasomes (genetics, metabolism)
• Lysosomes (physiology)
• Mitochondria (physiology)
• Mitophagy (physiology)
• NLR Family, Pyrin Domain-Containing 3 Protein
• Proto-Oncogene Proteins c-bcl-2 (physiology)
• Reactive Oxygen Species (metabolism)