title: Oxidation of the alarmin IL-33 regulates ST2-dependent inflammation.
abstract: In response to infections and irritants, the respiratory epithelium releases the alarmin interleukin (IL)-33 to elicit a rapid immune response. However, little is known about the regulation of IL-33 following its release. Here we report that the biological activity of IL-33 at its receptor ST2 is rapidly terminated in the extracellular environment by the formation of two disulphide bridges, resulting in an extensive conformational change that disrupts the ST2 binding site. Both reduced (active) and disulphide bonded (inactive) forms of IL-33 can be detected in lung lavage samples from mice challenged with Alternaria extract and in sputum from patients with moderate-severe asthma. We propose that this mechanism for the rapid inactivation of secreted IL-33 constitutes a 'molecular clock' that limits the range and duration of ST2-dependent immunological responses to airway stimuli. Other IL-1 family members are also susceptible to cysteine oxidation changes that could regulate their activity and systemic exposure through a similar mechanism.
authors.affiliation: Department of Respiratory, Inflammation and Autoimmunity, MedImmune Ltd, Granta Park, Great Abington, CB21 6GH, UK.
authors.forename: E Suzanne
authors.identifier: http://orcid.org/0000-0002-4470-1680
authors.initials: ES
authors.lastname: Cohen
authors.affiliation: Department of Respiratory, Inflammation and Autoimmunity, MedImmune Ltd, Granta Park, Great Abington, CB21 6GH, UK.
authors.forename: Ian C
authors.initials: IC
authors.lastname: Scott
authors.affiliation: Department of Respiratory, Inflammation and Autoimmunity, MedImmune Ltd, Granta Park, Great Abington, CB21 6GH, UK.
authors.forename: Jayesh B
authors.initials: JB
authors.lastname: Majithiya
authors.affiliation: Department of Respiratory, Inflammation and Autoimmunity, MedImmune Ltd, Granta Park, Great Abington, CB21 6GH, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Rapley
authors.affiliation: Department of Antibody Discovery and Protein Engineering, MedImmune Ltd, Granta Park, Great Abington, CB21 6GH, UK.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Kemp
authors.affiliation: Department of Antibody Discovery and Protein Engineering, MedImmune Ltd, Granta Park, Great Abington, CB21 6GH, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: England
authors.affiliation: Department of Antibody Discovery and Protein Engineering, MedImmune Ltd, Granta Park, Great Abington, CB21 6GH, UK.
authors.forename: D Gareth
authors.initials: DG
authors.lastname: Rees
authors.affiliation: Department of Respiratory, Inflammation and Autoimmunity, MedImmune Ltd, Granta Park, Great Abington, CB21 6GH, UK.
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Overed-Sayer
authors.affiliation: Department of Respiratory, Inflammation and Autoimmunity, MedImmune Ltd, Granta Park, Great Abington, CB21 6GH, UK.
authors.forename: Joanne
authors.initials: J
authors.lastname: Woods
authors.affiliation: Department of Biopharmaceutical Development, Analytical Biotechnology, MedImmune Ltd, Granta Park, Great Abington, CB21 6GH, UK.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Bond
authors.affiliation: Department of Biopharmaceutical Development, Analytical Biotechnology, MedImmune Ltd, Granta Park, Great Abington, CB21 6GH, UK.
authors.forename: Christel Séguy
authors.initials: CS
authors.lastname: Veyssier
authors.affiliation: Department of Discovery Sciences, Innovative Medicines, AstraZeneca, Mereside, Alderley Park, SK10 4TG, UK.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Embrey
authors.affiliation: Department of Respiratory, Inflammation and Autoimmunity, MedImmune LLC, Gaithersburg, Maryland 20878, USA.
authors.forename: Dorothy A
authors.initials: DA
authors.lastname: Sims
authors.affiliation: Department of Antibody Discovery and Protein Engineering, MedImmune Ltd, Granta Park, Great Abington, CB21 6GH, UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Snaith
authors.affiliation: Department of Antibody Discovery and Protein Engineering, MedImmune Ltd, Granta Park, Great Abington, CB21 6GH, UK.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Vousden
authors.affiliation: Department of Antibody Discovery and Protein Engineering, MedImmune Ltd, Granta Park, Great Abington, CB21 6GH, UK.
authors.forename: Martin D
authors.initials: MD
authors.lastname: Strain
authors.affiliation: Department of Antibody Discovery and Protein Engineering, MedImmune Ltd, Granta Park, Great Abington, CB21 6GH, UK.
authors.forename: Denice T Y
authors.initials: DT
authors.lastname: Chan
authors.affiliation: Department of Antibody Discovery and Protein Engineering, MedImmune Ltd, Granta Park, Great Abington, CB21 6GH, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Carmen
authors.affiliation: Department of Antibody Discovery and Protein Engineering, MedImmune Ltd, Granta Park, Great Abington, CB21 6GH, UK.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Huntington
authors.affiliation: Department of Discovery Sciences, Innovative Medicines, AstraZeneca, Mereside, Alderley Park, SK10 4TG, UK.
authors.forename: Liz
authors.initials: L
authors.lastname: Flavell
authors.affiliation: Department of Antibody Discovery and Protein Engineering, MedImmune Ltd, Granta Park, Great Abington, CB21 6GH, UK.
authors.forename: Jianqing
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Antibody Discovery and Protein Engineering, MedImmune Ltd, Granta Park, Great Abington, CB21 6GH, UK.
authors.forename: Bojana
authors.initials: B
authors.lastname: Popovic
authors.affiliation: Department of Infection, Immunity and Inflammation, Institute for Lung Health, Leicester LE3 9QP, UK; NIHR Respiratory Biomedical Research Unit, University Hospitals of Leicester, Leicester LE3 9QP, UK.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Brightling
authors.affiliation: Department of Antibody Discovery and Protein Engineering, MedImmune Ltd, Granta Park, Great Abington, CB21 6GH, UK.
authors.forename: Tristan J
authors.initials: TJ
authors.lastname: Vaughan
authors.affiliation: Department of Antibody Discovery and Protein Engineering, MedImmune Ltd, Granta Park, Great Abington, CB21 6GH, UK.
authors.forename: Robin
authors.initials: R
authors.lastname: Butler
authors.affiliation: Department of Antibody Discovery and Protein Engineering, MedImmune Ltd, Granta Park, Great Abington, CB21 6GH, UK.
authors.forename: David C
authors.initials: DC
authors.lastname: Lowe
authors.affiliation: Department of Biopharmaceutical Development, Analytical Biotechnology, MedImmune Ltd, Granta Park, Great Abington, CB21 6GH, UK.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Higazi
authors.affiliation: Department of Respiratory, Inflammation and Autoimmunity, MedImmune Ltd, Granta Park, Great Abington, CB21 6GH, UK.
authors.forename: Dominic J
authors.initials: DJ
authors.lastname: Corkill
authors.affiliation: Department of Respiratory, Inflammation and Autoimmunity, MedImmune Ltd, Granta Park, Great Abington, CB21 6GH, UK.
authors.forename: Richard D
authors.initials: RD
authors.lastname: May
authors.affiliation: Department of Respiratory, Inflammation and Autoimmunity, MedImmune Ltd, Granta Park, Great Abington, CB21 6GH, UK.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Sleeman
authors.affiliation: Department of Respiratory, Inflammation and Autoimmunity, MedImmune LLC, Gaithersburg, Maryland 20878, USA.
authors.forename: Tomas
authors.initials: T
authors.lastname: Mustelin
mesh_terms: D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010084:Oxidation-Reduction; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology*; D018123:Receptors, Interleukin / Q000235:genetics / Q000276:immunology*
chemical_list: C079241:IL1RL1 protein, human; C506536:IL33 protein, human; C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D011956:Receptors, Cell Surface; D018123:Receptors, Interleukin