Carbon monoxide negatively regulates NLRP3 inflammasome activation in macrophages. Academic Article uri icon

Overview

MeSH

  • Adenosine Triphosphate
  • Animals
  • Caspase 1
  • DNA-Binding Proteins
  • Interleukin-18
  • Interleukin-1beta
  • Lipopolysaccharides
  • Male
  • Mice
  • Mitochondria

MeSH Major

  • Antimetabolites
  • Carbon Monoxide
  • Carrier Proteins
  • Inflammasomes
  • Macrophages

abstract

  • Inflammasomes are cytosolic protein complexes that promote the cleavage of caspase-1, which leads to the maturation and secretion of proinflammatory cytokines, including interleukin-1β (IL-1β) and IL-18. Among the known inflammasomes, the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3)-dependent inflammasome is critically involved in the pathogenesis of various acute or chronic inflammatory diseases. Carbon monoxide (CO), a gaseous molecule physiologically produced in cells and tissues during heme catabolism, can act as an anti-inflammatory molecule and a potent negative regulator of Toll-like receptor signaling pathways. To date, the role of CO in inflammasome-mediated immune responses has not been fully investigated. Here, we demonstrated that CO inhibited caspase-1 activation and the secretion of IL-1β and IL-18 in response to lipopolysaccharide (LPS) and ATP treatment in bone marrow-derived macrophages. CO also inhibited IL-18 secretion in response to LPS and nigericin treatment, another NLRP3 inflammasome activation model. In contrast, CO did not suppress IL-18 secretion in response to LPS and poly(dA:dT), an absent in melanoma 2 (AIM2)-mediated inflammasome model. LPS and ATP stimulation induced the formation of complexes between NLRP3 and apoptosis-associated speck-like protein, or NLRP3 and caspase-1. CO treatment inhibited these molecular interactions that were induced by LPS and ATP. Furthermore, CO inhibited mitochondrial ROS generation and the decrease of mitochondrial membrane potential induced by LPS and ATP in macrophages. We also observed that the inhibitory effect of CO on the translocation of mitochondrial DNA into the cytosol was associated with suppression of cytokine secretion. Our results suggest that CO negatively regulates NLRP3 inflammasome activation by preventing mitochondrial dysfunction. Copyright © 2015 the American Physiological Society.

publication date

  • May 15, 2015

has subject area

  • Adenosine Triphosphate
  • Animals
  • Antimetabolites
  • Carbon Monoxide
  • Carrier Proteins
  • Caspase 1
  • DNA-Binding Proteins
  • Inflammasomes
  • Interleukin-18
  • Interleukin-1beta
  • Lipopolysaccharides
  • Macrophages
  • Male
  • Mice
  • Mitochondria

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4437010

Digital Object Identifier (DOI)

  • 10.1152/ajplung.00400.2014

PubMed ID

  • 25770182

Additional Document Info

start page

  • L1058

end page

  • L1067

volume

  • 308

number

  • 10