Nuclear Localization of Suppressor of Cytokine Signaling-1 Regulates Local Immunity in the Lung.

Jana Zimmer, Michael Weitnauer, Sébastien Boutin, Günter Küblbeck, Sabrina Thiele, Patrick Walker, Felix Lasitschka, Lars Lunding, Zane Orinska, Christina Vock, Bernd Arnold, Michael Wegmann, Alexander Dalpke


Suppressor of cytokine signaling 1 (SOCS1) is a negative feedback inhibitor of cytoplasmic Janus kinase and signal transducer and activator of transcription (STAT) signaling. SOCS1 also contains a nuclear localization sequence (NLS), yet, the in vivo importance of nuclear translocation is unknown. We generated transgenic mice containing mutated Socs1ΔNLS that fails to translocate in the cell nucleus (MGL(tg) mice). Whereas mice fully deficient for SOCS1 die within the first 3 weeks due to excessive interferon signaling and multiorgan inflammation, mice expressing only non-nuclear Socs1ΔNLS (Socs1(-/-)MGL(tg) mice) were rescued from early lethality. Canonical interferon gamma signaling was still functional in Socs1(-/-)MGL(tg) mice as shown by unaltered tyrosine phosphorylation of STAT1 and whole genome expression analysis. However, a subset of NFκB inducible genes was dysregulated. Socs1(-/-)MGL(tg) mice spontaneously developed low-grade inflammation in the lung and had elevated Th2-type cytokines. Upon ovalbumin sensitization and challenge, airway eosinophilia was increased in Socs1(-/-)MGL(tg) mice. Decreased transepithelial electrical resistance in trachea epithelial cells from Socs1(-/-)MGL(tg) mice suggests disrupted epithelial cell barrier. The results indicate that nuclear SOCS1 is a regulator of local immunity in the lung and unravel a so far unrecognized function for SOCS1 in the cell nucleus.
ZeitschriftFrontiers in Immunology
Seiten (von - bis)514
PublikationsstatusVeröffentlicht - 2016
Extern publiziertJa