title: IL-37 requires IL-18Rα and SIGIRR/IL-1R8 to diminish allergic airway inflammation in mice.
abstract: BACKGROUND
  Interleukin (IL) 37 has been described as a negative regulator of innate immunity, as it reduces the activation and cytokine production of different innate immune cells. Recently, results from the CLARA childhood asthma cohort suggested an implication of IL-37 for human asthma pathogenesis. This study aimed to investigate the effects of IL-37 on allergic airway inflammation in a mouse model of experimental asthma.
  
  
  METHODS
  Peripheral blood mononuclear cells (PBMCs) of children were cultured for 48 h (anti-CD3/anti-CD28 stimulation or unstimulated), and IL-37 concentrations in supernatants were determined. Wild-type, IL-18Rα-deficient ((-/-) ), and SIGIRR(-/-) C57BL/6 mice were sensitized to ovalbumin (OVA) and challenged with OVA aerosol to induce acute experimental asthma, and IL-37 was applied intranasally prior to each OVA challenge. Airway hyper-responsiveness (AHR), airway inflammation, cytokine levels in broncho-alveolar lavage fluid, and mucus production were determined.
  
  
  RESULTS
  IL-37 production of human PBMCs was significantly lower in allergic asthmatics vs healthy children. In wild-type mice, intranasal administration of IL-37 ablated allergic airway inflammation as well as cytokine production and subsequently diminished the hallmarks of experimental asthma including mucus hyperproduction and AHR. In contrast, local application of IL-37 produced none of these effects in mice lacking either IL18Rα or SIGIRR/IL-1R8.
  
  
  CONCLUSIONS
  This study demonstrates that IL-37 is able to ablate a TH2 cell-directed allergic inflammatory response and the hallmarks of experimental asthma in mice, suggesting that IL-37 may be critical for asthma pathogenesis. Furthermore, these data suggest a mode of action of IL-37 that involves IL18Rα as well as the orphan receptor SIGIRR/IL-1R8.
authors.affiliation: Division of Asthma Mouse Models, Priority Area Asthma & Allergy, Research Center Borstel, Airway Research Center North, Member of the German Center for Lung Research, Borstel, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Lunding
authors.forename: S
authors.initials: S
authors.lastname: Webering
authors.forename: C
authors.initials: C
authors.lastname: Vock
authors.forename: A
authors.initials: A
authors.lastname: Schröder
authors.forename: D
authors.initials: D
authors.lastname: Raedler
authors.forename: B
authors.initials: B
authors.lastname: Schaub
authors.forename: H
authors.initials: H
authors.lastname: Fehrenbach
authors.forename: M
authors.initials: M
authors.lastname: Wegmann
mesh_terms: D000293:Adolescent; D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007375:Interleukin-1 / Q000097:blood / Q000378:metabolism*; D053727:Interleukin-18 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D012130:Respiratory Hypersensitivity / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D016207:Cytokines; D007375:Interleukin-1; D053727:Interleukin-18 Receptor alpha Subunit; D017472:Receptors, Interleukin-1; C484529:SIGIRR protein, mouse
keywords: IL-18 receptor; IL-37; SIGIRR/IL-1R8; animal models, asthma