Altered subcellular localization of IL-33 leads to non-resolving lethal inflammation

• DOI: 10.1016/j.jaut.2014.02.012
• Publication Date: 2014-04-29T14:00:39Z
• Authors: Juliana Bessa; Claas Aiko Meyer; Maria Cristina de...; Sonja Schlicht; Susan H. Smith; Antonio Iglesias; Javier Cote-Sierra
• Keywords: Cell Nucleus; Inflammation; Mice, Knockout; 0301 basic medicine; Mice, Inbred BALB C; 0303 health sciences; Interleukins; Nuclear Localization Signals; Receptors, Interleukin; Interleukin-33; Interleukin-1 Receptor-Like 1 Protein; 6. Clean water; 3. Good health; Mice; 03 medical and health sciences; Animals; Homeostasis

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.