title: Endogenous IL-33 is highly expressed in mouse epithelial barrier tissues, lymphoid organs, brain, embryos, and inflamed tissues: in situ analysis using a novel Il-33-LacZ gene trap reporter strain.
abstract: IL-33 (previously known as NF from high endothelial venules) is an IL-1 family cytokine that signals through the ST2 receptor and drives cytokine production in mast cells, basophils, eosinophils, invariant NKT and NK cells, Th2 lymphocytes, and type 2 innate immune cells (natural helper cells, nuocytes, and innate helper 2 cells). Little is known about endogenous IL-33; for instance, the cellular sources of IL-33 in mouse tissues have not yet been defined. In this study, we generated an Il-33-LacZ gene trap reporter strain (Il-33(Gt/Gt)) and used this novel tool to analyze expression of endogenous IL-33 in vivo. We found that the Il-33 promoter exhibits constitutive activity in mouse lymphoid organs, epithelial barrier tissues, brain, and embryos. Immunostaining with anti-IL-33 Abs, using Il-33(Gt/Gt) (Il-33-deficient) mice as control, revealed that endogenous IL-33 protein is highly expressed in mouse epithelial barrier tissues, including stratified squamous epithelia from vagina and skin, as well as cuboidal epithelium from lung, stomach, and salivary gland. Constitutive expression of IL-33 was not detected in blood vessels, revealing the existence of species-specific differences between humans and mice. Importantly, IL-33 protein was always localized in the nucleus of producing cells with no evidence for cytoplasmic localization. Finally, strong expression of the Il-33-LacZ reporter was also observed in inflamed tissues, in the liver during LPS-induced endotoxin shock, and in the lung alveoli during papain-induced allergic airway inflammation. Together, our findings support the possibility that IL-33 may function as a nuclear alarmin to alert the innate immune system after injury or infection in epithelial barrier tissues.
authors.affiliation: Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, F-31077 Toulouse, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Pichery
authors.forename: Emilie
authors.initials: E
authors.lastname: Mirey
authors.forename: Pascale
authors.initials: P
authors.lastname: Mercier
authors.forename: Emma
authors.initials: E
authors.lastname: Lefrancais
authors.forename: Arnaud
authors.initials: A
authors.lastname: Dujardin
authors.forename: Nathalie
authors.initials: N
authors.lastname: Ortega
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Girard
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism* / Q000648:ultrastructure; D005260:Female; D005326:Fetal Proteins / Q000096:biosynthesis / Q000235:genetics; D017930:Genes, Reporter; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D000067596:Interleukin-33; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D007763:Lac Operon; D008099:Liver / Q000378:metabolism; D008221:Lymphoid Tissue / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D009928:Organ Specificity; D011401:Promoter Regions, Genetic / Q000235:genetics; D011657:Pulmonary Eosinophilia / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism; D012772:Shock, Septic / Q000276:immunology / Q000378:metabolism; D013045:Species Specificity
chemical_list: D005326:Fetal Proteins; C506535:Il33 protein, mouse; D000067596:Interleukin-33; D007378:Interleukins; D009419:Nerve Tissue Proteins