title: Deficiency in Toll-interacting protein (Tollip) skews inflamed yet incompetent innate leukocytes in vivo during DSS-induced septic colitis.
abstract: Functionally 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 DSS-induced 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.
authors.affiliation: Department of Biological Sciences, Biomedical Engineering, Medicine, Virginia Tech, 24061 USA.|Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 510515 People's Republic of China.
authors.forename: Na
authors.initials: N
authors.lastname: Diao
authors.affiliation: Department of Biological Sciences, Biomedical Engineering, Medicine, Virginia Tech, 24061 USA.
authors.forename: Yao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biological Sciences, Biomedical Engineering, Medicine, Virginia Tech, 24061 USA.
authors.forename: Keqiang
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Biological Sciences, Biomedical Engineering, Medicine, Virginia Tech, 24061 USA.
authors.forename: Ruoxi
authors.initials: R
authors.lastname: Yuan
authors.affiliation: Department of Biological Sciences, Biomedical Engineering, Medicine, Virginia Tech, 24061 USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences, Biomedical Engineering, Medicine, Virginia Tech, 24061 USA.
authors.forename: Shuo
authors.initials: S
authors.lastname: Geng
authors.affiliation: Department of Biological Sciences, Biomedical Engineering, Medicine, Virginia Tech, 24061 USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Kowalski
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 510515 People's Republic of China.
authors.forename: Wen
authors.initials: W
authors.lastname: Guo
authors.affiliation: Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Huabao
authors.initials: H
authors.lastname: Xiong
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 510515 People's Republic of China.
authors.forename: Mingsong
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Biological Sciences, Biomedical Engineering, Medicine, Virginia Tech, 24061 USA.
authors.forename: Liwu
authors.initials: L
authors.lastname: Li
mesh_terms: D000328:Adult; D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism / Q000473:pathology*; D016264:Dextran Sulfate / Q000009:adverse effects*; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency*; D007962:Leukocytes / Q000276:immunology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D019713:Receptors, CCR5 / Q000378:metabolism; D018805:Sepsis / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology; D055815:Young Adult
chemical_list: C584933:CCR5 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D019713:Receptors, CCR5; C410602:TOLLIP protein, human; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D016264:Dextran Sulfate