title: The alarmin IL-1α is a master cytokine in acute lung inflammation induced by silica micro- and nanoparticles.
abstract: BACKGROUND
  Inflammasome-activated IL-1β plays a major role in lung neutrophilic inflammation induced by inhaled silica. However, the exact mechanisms that contribute to the initial production of precursor IL-1β (pro-IL-1β) are still unclear. Here, we assessed the implication of alarmins (IL-1α, IL-33 and HMGB1) in the lung response to silica particles and found that IL-1α is a master cytokine that regulates IL-1β expression.
  
  
  METHODS
  Pro- and mature IL-1β as well as alarmins were assessed by ELISA, Western Blot or qRT-PCR in macrophage cultures and in mouse lung following nano- and micrometric silica exposure. Implication of these immune mediators in the establishment of lung inflammatory responses to silica was investigated in knock-out mice or after antibody blockade by evaluating pulmonary neutrophil counts, CXCR2 expression and degree of histological injury.
  
  
  RESULTS
  We found that the early release of IL-1α and IL-33, but not HMGB1 in alveolar space preceded the lung expression of pro-IL-1β and neutrophilic inflammation in silica-treated mice. In vitro, the production of pro-IL-1β by alveolar macrophages was significantly induced by recombinant IL-1α but not by IL-33. Neutralization or deletion of IL-1α reduced IL-1β production and neutrophil accumulation after silica in mice. Finally, IL-1α released by J774 macrophages after in vitro exposure to a range of micro- and nanoparticles of silica was correlated with the degree of lung inflammation induced in vivo by these particles.
  
  
  CONCLUSIONS
  We demonstrated that in response to silica exposure, IL-1α is rapidly released from pre-existing stocks in alveolar macrophages and promotes subsequent lung inflammation through the stimulation of IL-1β production. Moreover, we demonstrated that in vitro IL-1α release from macrophages can be used to predict the acute inflammogenic activity of silica micro- and nanoparticles.
authors.affiliation: Louvain centre for Toxicology and Applied Pharmacology (LTAP), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium. virginie.rabolli@uclouvain.be.
authors.forename: Virginie
authors.initials: V
authors.lastname: Rabolli
authors.affiliation: Louvain centre for Toxicology and Applied Pharmacology (LTAP), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium. anissa.alami@student.uclouvain.be.
authors.forename: Anissa Alami
authors.initials: AA
authors.lastname: Badissi
authors.affiliation: Louvain centre for Toxicology and Applied Pharmacology (LTAP), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium. raynal.devosse@uclouvain.be.
authors.forename: Raynal
authors.initials: R
authors.lastname: Devosse
authors.affiliation: Louvain centre for Toxicology and Applied Pharmacology (LTAP), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium. francine.uwambayinema@uclouvain.be.
authors.forename: Francine
authors.initials: F
authors.lastname: Uwambayinema
authors.affiliation: Louvain centre for Toxicology and Applied Pharmacology (LTAP), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium. yousof.yakoub@uclouvain.be.
authors.forename: Yousof
authors.initials: Y
authors.lastname: Yakoub
authors.affiliation: Louvain centre for Toxicology and Applied Pharmacology (LTAP), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium. mihaly.palmai@uclouvain.be.
authors.forename: Mihaly
authors.initials: M
authors.lastname: Palmai-Pallag
authors.affiliation: Louvain centre for Toxicology and Applied Pharmacology (LTAP), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium. astrid.lebrun@student.uclouvain.be.
authors.forename: Astrid
authors.initials: A
authors.lastname: Lebrun
authors.affiliation: Louvain centre for Toxicology and Applied Pharmacology (LTAP), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium. valentin.degussem@student.uclouvain.be.
authors.forename: Valentin
authors.initials: V
authors.lastname: De Gussem
authors.affiliation: University of Orléans, CNRS, UMR7355, INEM, Transgenose Institute, Orléans, France. couillin@cnrs-orleans.fr.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Couillin
authors.affiliation: University of Orléans, CNRS, UMR7355, INEM, Transgenose Institute, Orléans, France. bryffel@cnrs-orleans.fr.
authors.forename: Bernard
authors.initials: B
authors.lastname: Ryffel
authors.affiliation: de Duve Institute, Université catholique de Louvain, Brussels, Belgium. etienne.marbaix@uclouvain.be.
authors.forename: Etienne
authors.initials: E
authors.lastname: Marbaix
authors.affiliation: Louvain centre for Toxicology and Applied Pharmacology (LTAP), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium. dominique.lison@uclouvain.be.
authors.forename: Dominique
authors.initials: D
authors.lastname: Lison
authors.affiliation: Louvain centre for Toxicology and Applied Pharmacology (LTAP), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium. francois.huaux@uclouvain.be.|Louvain centre for Toxicology and Applied Pharmacology (LTAP), Université catholique de Louvain (UCL), Avenue Mounier 52, B1.52.12, 1200, Brussels, Belgium. francois.huaux@uclouvain.be.
authors.forename: François
authors.initials: F
authors.lastname: Huaux
mesh_terms: D000393:Air Pollutants / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D005260:Female; D019570:Inhalation Exposure / Q000009:adverse effects*; D053582:Interleukin-1alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016676:Macrophages, Alveolar / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008863:Microspheres; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D020556:Neutrophil Infiltration / Q000187:drug effects; D010316:Particle Size; D011014:Pneumonia / Q000139:chemically induced* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020545:Respiratory Mucosa / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012822:Silicon Dioxide / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D023382:Toxicity Tests, Acute
chemical_list: D000393:Air Pollutants; D057134:Antibodies, Neutralizing; C587672:IL1B protein, mouse; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D012822:Silicon Dioxide