Protective role of the novel cytokine Metrnl/ interleukin-41 in host immunity defense during sepsis by promoting macrophage recruitment and modulating Treg/Th17 immune cell balance

作者全名："Chen, Xi; Chen, Xia; Yang, Yingxue; Luo, Na; Yang, Jian; Zhong, Lingui; Guo, Tingting; Yuan, Zhongzhen; Wei, Qiang; Wang, Chuanjiang"

作者地址："[Luo, Na; Zhong, Lingui; Wang, Chuanjiang] Chongqing Med Univ, Affiliated Hosp 1, Dept Crit Care Med, Chongqing, Peoples R China; [Chen, Xia] Army Med Ctr PLA, Dept Hlth Management, Chongqing, Peoples R China; [Yuan, Zhongzhen] Chongqing Univ, Canc Hosp, Dept Pharm, Chongqing, Peoples R China; [Yuan, Zhongzhen] Chongqing Canc Inst, Chongqing, Peoples R China; [Yuan, Zhongzhen] Chongqing Canc Hosp, Chongqing, Peoples R China; [Chen, Xi; Wei, Qiang] Chongqing Med Univ, Affiliated Hosp 1, Dept Lab Med, Chongqing, Peoples R China; [Yang, Jian] Chongqing Med Univ, Affiliated Hosp 1, Dept Gastroenterol, Chongqing, Peoples R China; [Yang, Yingxue] Second Afffliated Hosp Chongqing Med Univ, Dept Gastroenterol, Chongqing, Peoples R China; [Guo, Tingting] Community Hlth Serv Ctr, Dept Gen Med, Longmenhao St, Chongqing, Peoples R China"

通信作者："Wang, CJ (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Crit Care Med, Chongqing, Peoples R China.; Wei, Q (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Lab Med, Chongqing, Peoples R China."

来源：CLINICAL IMMUNOLOGY

ESI学科分类：IMMUNOLOGY

WOS号：WOS:001045796300001

JCR分区：Q2

影响因子：4.5

年份：2023

卷号：254

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Sepsis; Metrnl; Treg; Th17 lymphocytes; ROS; P-STAT3; P-STAT5

摘要："Background: Metrnl play an immunocytokine-like role in several diseases, which is also known as meteorin-like because it is homologous to the neurotrophic factor meteorin (Metrn). Although the expression and function of Metrnl, including neurotrophic, immunomodulatory, and insulin resistance functions in different tissues have been extensively studied, its role in sepsis has remained largely limited. Methods: The present work analyzed the levels of Metrnl and cytokines in the circulation, such as tumor necrosis factor (TNF-& alpha;), interleukin (IL-1)& beta;, IL-6, IL-8, together with IL-10 among septic adult patients. Clinical information was obtained from such patients, including sofa score, procalcitonin(PCT)count, and C-reactive count (CRP) within 24 h when entering the intensive care unit (ICU). We constructed a sepsis model in Metrnl-deficient or normal wild-type mice using cecal ligation and perforation to study its functions in bacterial burden, survival, cytokine/chemokine generation, peritoneal lavage fluid neutrophils, macrophage and lymphocyte recruitment, and Treg/Th17 immune cell balance after CLP-induced sepsis. Results: The expression of Metrnl was remarkably elevated in the early phase of sepsis clinically. Its serum content in patients dying of sepsis slightly decreased relative to that in survivors. Furthermore, the concentration of Metrnl in septic cases when entering the ICU independently predicted the 28-day mortality. For septic patients who had low serum Metrnl content (& LE; 274.40 pg/mL), the death risk increased by 2.3 folds relative to those who had a high serum content. It is reported that Metrnl is probably insufficient among patients dying of sepsis. Additionally, the content of Metrnl in the serum of septic patients when entering the ICU is markedly and negatively related to the levels of TNF-& alpha;, IL-1 & beta;, IL-6, IL-8, IL-17, PCT, and Sofa score. Collectively, Metrnl could be a potential therapeutic target for sepsis. A low-lethality non-severe sepsis (NSS) model was constructed, which suggested that Metrnl insufficiency elevated the death rate and reduced bacterial clearance during sepsis. For Metrnl-deficient mice, impaired sepsis immunity defense might be related to decreased macrophage recruitment and Treg/Th17 lymphocyte imbalance. Recombinant Metrnl administered to Metrnl-deficient mice abolished the immunity defense impairment following NSS while protecting the high-lethality severe sepsis (SS) model in wildtype (WT) mice. In addition, Metrnl-induced sepsis prevention was intricately associated with the increased recruitment of peritoneal macrophages and modulation of the Treg/TH17 immune cell balance. Furthermore, CCL3 exposure in Metrnl-deficient mice reduced peritoneal bacterial loads while improving survival during sepsis partially by promoting the recruitment of peritoneal macrophages. Furthermore, Metrnl regulated the polarization of M1 macrophages through the ROS signaling pathway and promoted macrophage phagocytosis, thereby killing Escherichia coli."

基金机构："National Natural Science Foundation grants of China [81803110]; Basic science and cutting-edge technology research projects of Chongqing Science amp; Technology Commission [cstc2020jcyj-msxmX0014]; Medical Research Project of Chongqing City Health and Family Planning Committee [2020FYYX055, 2021MSXM010, 2021MSXM044]; Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in the Three Gorges Reservoir Area Project [KFKT2022009, KFKT2022006]"

基金资助正文："This study was supported by National Natural Science Foundation grants of China (81803110, to QW), Basic science and cutting-edge technology research projects of Chongqing Science & amp; Technology Commission (cstc2020jcyj-msxmX0014, to CJ-W) and the Medical Research Project of Chongqing City Health and Family Planning Committee(2020FYYX055, to CJ-W, 2021MSXM010, to ZZ-Y, 2021MSXM044, to NL). Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in the Three Gorges Reservoir Area Project(KFKT2022009, to CJ-W, KFKT2022006, to QW)."