title: Increased carbon dioxide levels stimulate neutrophils to produce microparticles and activate the nucleotide-binding domain-like receptor 3 inflammasome.
abstract: We hypothesized that elevations of carbon dioxide (CO2) commonly found in modern buildings will stimulate leukocytes to produce microparticles (MPs) and activate the nucleotide-binding domain-like receptor 3 (NLRP3) inflammasome due to mitochondrial oxidative stress. Human and murine neutrophils generate MPs with high interleukin-1β (IL-1β) content when incubated ex vivo in buffer equilibrated with 0.1-0.4% additional CO2. Enhanced MPs production requires mitochondrial reactive oxygen species production, which is mediated by activities of pyruvate carboxylase and phosphoenolpyruvate carboxykinase. Subsequent events leading to MPs generation include perturbation of inositol 1,3,5-triphosphate receptors, a transient elevation of intracellular calcium, activation of protein kinase C and NADPH oxidase (Nox). Concomitant activation of type-2 nitric oxide synthase yields secondary oxidants resulting in actin S-nitrosylation and enhanced filamentous actin turnover. Numerous proteins are linked to short filamentous actin including vasodilator-stimulated phosphoprotein, focal adhesion kinase, the membrane phospholipid translocation enzymes flippase and floppase, and the critical inflammasome protein ASC (Apoptosis-associated Speck protein with CARD domain). Elevations of CO2cause oligomerization of the inflammasome components ASC, NLRP3, caspase 1, thioredoxin interacting protein, and calreticulin - a protein from endoplasmic reticulum, leading to IL-1β synthesis. An increased production rate of MPs containing elevated amounts of IL-1β persists for hours after short-term exposures to elevated CO2.
authors.affiliation: Department of Emergency Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, United States.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Thom
authors.affiliation: Department of Emergency Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, United States.
authors.forename: Veena M
authors.initials: VM
authors.lastname: Bhopale
authors.affiliation: Department of Emergency Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, United States.
authors.forename: JingPing
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Emergency Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, United States.
authors.forename: Ming
authors.initials: M
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics* / Q000378:metabolism; D037282:Calreticulin / Q000235:genetics; D002245:Carbon Dioxide / Q000633:toxicity; D020170:Caspase 1 / Q000235:genetics; D055252:Cell-Derived Microparticles / Q000187:drug effects / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes / Q000187:drug effects / Q000378:metabolism; D053583:Interleukin-1beta / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D053468:CARD Signaling Adaptor Proteins; D037282:Calreticulin; C587672:IL1B protein, mouse; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D017382:Reactive Oxygen Species; D002245:Carbon Dioxide; D020170:Caspase 1
keywords: Indoor air pollution; Interleukin-1β; Mitochondrial carboxylation enzymes; NADPH oxidase; NLRP3 inflammasome; Nitric oxide synthase; S-nitrosylation