Altered subcellular localization of IL-33 leads to non-resolving lethal inflammation.
Non-resolving inflammation is a major contributor to chronic disease pathogenesis, including that of cancer, chronic obstructive pulmonary disease, asthma, arthritis, inflammatory bowel disease, multiple sclerosis and obesity. Some cytokines, such as IL-1α and IL-33, may act as endogenous alarmins that contribute to non-resolving inflammation. These cytokines are constitutively expressed in the nucleus and are thought to promote inflammation only upon release during tissue damage or cell necrosis. However, the importance of their nuclear localization in immune homeostasis is not fully understood. We describe herein a novel mouse model in which the nuclear localization signal of IL-33 is abolished and demonstrate for the first time that, alone, altered subcellular localization of IL-33 dramatically affects immune homeostasis. Heterozygous IL33(tm1/+) mice display elevated serum IL-33 levels, indicating that IL-33 is constitutively released when not actively targeted to the nucleus. IL33(tm1/+) mice succumb to lethal inflammation characterized by eosinophil-dominated immune cell infiltration of multiple organs. The profound inflammatory phenotype is dependent on mediators downstream of ST2 as ST2-null mice are protected in spite of high serum IL-33 levels. Importantly, IL-33 transcript levels in this knock-in mouse model remain under endogenous control. We adopt the term "nuclear alarmin" to describe a danger signal that is primarily regulated by nuclear compartmentalization in this fashion.
F. Hoffmann-La Roche Ltd, pRED, Pharma Research and Early Development, Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
Juliana
J
Bessa
F. Hoffmann-La Roche Ltd, pRED, Pharma Research and Early Development, Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
Claas Aiko
CA
Meyer
F. Hoffmann-La Roche Ltd, pRED, Pharma Research and Early Development, Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
Maria Cristina
MC
de Vera Mudry
F. Hoffmann-La Roche Ltd, pRED, Pharma Research and Early Development, Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
Sonja
S
Schlicht
Stiefel, a GSK Company, Center for Skin Biology, 20 T.W. Alexander Dr., Research Triangle Park, NC 27709, USA.
Susan H
SH
Smith
F. Hoffmann-La Roche Ltd, pRED, Pharma Research and Early Development, Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
Antonio
A
Iglesias
Hoffmann-La Roche Inc., pRED, Pharma Research and Early Development, Nutley, NJ, USA. Electronic address: Javier.x.cote-sierra@stiefel.com.
Javier
J
Cote-Sierra
D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D006706:Homeostasis / Q000235:genetics / Q000276:immunology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D019913:Nuclear Localization Signals / Q000235:genetics / Q000276:immunology*; D018123:Receptors, Interleukin / Q000235:genetics / Q000276:immunology*
C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D019913:Nuclear Localization Signals; D018123:Receptors, Interleukin
Eosinophilia; IL-33; Immune homeostasis; Knock-in mouse; Non-resolving inflammation; Nuclear alarmin