title: TLR4-dependent internalization of CX3CR1 aggravates sepsis-induced immunoparalysis.
abstract: Sepsis, the most severe manifestation of infection, poses a major challenge to health-care systems around the world. Limited ability to clean and remove the pathogen renders difficulty in septic patients to recover from the phase of immunoparalysis. The present study found the vital role of CX3CR1 internalization on sepsis-induced immunoparalysis. A mouse model with cecal ligation and puncture (CLP) and cell model with lipopolysaccharides (LPS) were employed to explore the relationship between CX3CR1 internalization and septic immunoparalysis. Immunoparalysis model in mice was established 4 days after CLP with significantly decreased proinflammatory cytokines. Flow cytometry analysis found a decreased surface expression of CX3CR1 during immunoparalysis, which was associated with reduced mRNA level and increased internalization of CX3CR1. G-protein coupled receptor kinase 2 (GRK2) and β-arrestin2 were significantly increased during septic immunoparalysis and involved in the internalization of CX3CR1. TLR4-/-or TLR4 inhibitor-treated macrophages exhibited an inhibited expression of GRK2 and β-arrestin2, along with reduced internalization of CX3CR1. Moreover, the knockdown of GRK2 and β-arrestin2 inhibited the internalization of CX3CR1 and led to a higher response on the second hit, which was associated with an increased activation of NF-κB. The critical association between internalization of CX3CR1 and immunosuppression in sepsis may provide a novel reference for clinical therapeutics.
authors.affiliation: Department of Anesthesiology, Changzheng Hospital, The Second Military Medical UniversityShanghai, P. R. China; Hebei North University School of MedicineZhangjiakou, Hebei, P. R. China.
authors.forename: Xin-Yu
authors.initials: XY
authors.lastname: Ge
authors.affiliation: Department of Anesthesiology, Changzheng Hospital, The Second Military Medical University Shanghai, P. R. China.
authors.forename: Shang-Ping
authors.initials: SP
authors.lastname: Fang
authors.affiliation: Department of Anesthesiology and SICU, Xinhua Hospital, Shanghai Jiaotong University, School of Medicine Shanghai, P. R. China.
authors.forename: Miao
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical UniversityXuzhou, Jiangsu Province, P. R. China; Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University School of MedicineShanghai, P. R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Luo
authors.affiliation: Soochow UniversitySuzhou, P. R. China; Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University School of MedicineShanghai, P. R. China.
authors.forename: Juan
authors.initials: J
authors.lastname: Wei
authors.affiliation: Department of Orthopedics, Ningxiang People's Hospital of Hunan Province Ningxiang, Hunan, P. R. China.
authors.forename: Xue-Ping
authors.initials: XP
authors.lastname: Wen
authors.affiliation: Department of Anesthesiology, Changzheng Hospital, The Second Military Medical University Shanghai, P. R. China.
authors.forename: Xiao-Di
authors.initials: XD
authors.lastname: Yan
authors.affiliation: Department of Anesthesiology, Changzheng Hospital, The Second Military Medical UniversityShanghai, P. R. China; Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical UniversityXuzhou, Jiangsu Province, P. R. China.
authors.forename: Zui
authors.initials: Z
authors.lastname: Zou
keywords: CX3CR1; Sepsis; TLR4; immunoparalysis; internalization