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Deficiency in Toll-interacting protein (Tollip) skews inflamed yet incompetent innate leukocytes in vivo during DSS-induced septic Colitis

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dc.contributor.authorDiao, Naen
dc.contributor.authorZhang, Yaoen
dc.contributor.authorChen, Keqiangen
dc.contributor.authorYuan, Ruoxien
dc.contributor.authorLee, Christina K.en
dc.contributor.authorGeng, Shuoen
dc.contributor.authorKowalski, Elizabeth A.en
dc.contributor.authorLi, Liwuen
dc.contributor.departmentBiological Sciencesen
dc.date.accessioned2017-11-13T19:43:19Zen
dc.date.available2017-11-13T19:43:19Zen
dc.date.issued2016-10-05en
dc.description.abstractFunctionally compromised neutrophils contribute to adverse clinical outcomes in patients with severe inflammation and injury such as colitis and sepsis. However, the ontogeny of dysfunctional neutrophil during septic colitis remain poorly understood. We report that the dysfunctional neutrophil may be derived by the suppression of Toll-interacting-protein (Tollip). We observed that Tollip deficient neutrophils had compromised migratory capacity toward bacterial product fMLF due to reduced activity of AKT and reduction of FPR2, reduced potential to generate bacterial-killing neutrophil extra-cellular trap (NET), and compromised bacterial killing activity. On the other hand, Tollip deficient neutrophils had elevated levels of CCR5, responsible for their homing to sterile inflamed tissues. The inflamed and incompetent neutrophil phenotype was also observed in vivo in Tollip deficient mice subjected to DSSinduced colitis. We observed that TUDCA, a compound capable of restoring Tollip cellular function, can potently alleviate the severity of DSS-induced colitis. In humans, we observed significantly reduced Tollip levels in peripheral blood collected from human colitis patients as compared to blood samples from healthy donors. Collectively, our data reveal a novel mechanism in Tollip alteration that underlies the inflamed and incompetent polarization of neutrophils leading to severe outcomes of colitis.en
dc.description.sponsorshipWe would like to acknowledge the funding support from NIH R01HL135835, R56 AI108264 to LL.en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1038/srep34672en
dc.identifier.urihttp://hdl.handle.net/10919/80361en
dc.identifier.volume6en
dc.language.isoenen
dc.publisherNatureen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.titleDeficiency in Toll-interacting protein (Tollip) skews inflamed yet incompetent innate leukocytes in vivo during DSS-induced septic Colitisen
dc.title.serialScientific Reportsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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