Xue Lin1, Hongchun Luo2, Xingxing Yan1, Zhixin Song3, Xun Gao3, Yun Xia1, Liping Zhang1, Yibing Yin3, Ju Cao1. 1. Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. 2. Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. 3. Key Laboratory of Diagnostic Medicine designated by the Ministry of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing, China.
Abstract
OBJECTIVES: Sepsis is a devastating condition with a high mortality rate and limited treatments. Sepsis is characterized by a failed host immune response to contain the infection, resulting in organ dysfunction. Interleukin-34 is new cytokine involved in infection and immunity. Whether interleukin-34 is beneficial or deleterious to sepsis and the underlying mechanisms remains unknown. DESIGN: Prospective randomized animal investigation and in vitro studies. SETTING: Research laboratory at a university hospital. SUBJECTS: Wild-type C57BL/6 mice were used for in vivo studies, and septic human patients and healthy human subjects were used to obtain blood for in vitro studies. INTERVENTIONS: Interleukin-34 concentrations were measured in human sepsis patients and healthy individuals. The effects of interleukin-34 administration on survival, bacterial burden, organ injury, and inflammatory response were assessed in a murine model of cecal ligation and puncture-induced polymicrobial sepsis. MEASUREMENTS AND MAIN RESULTS: Interleukin-34 levels were significantly elevated in human sepsis and cecal ligation and puncture-induced experimental sepsis. Interleukin-34 administration improved survival and bacterial clearance, although suppressed vascular leakage and organ injury after cecal ligation and puncture-induced polymicrobial sepsis. Neutralization of interleukin-34 increased mortality rate and decreased bacterial clearance in septic mice. An increased neutrophil and macrophage influx were developed in interleukin-34-treated mice at the site of infection, accompanied by elevated production of neutrophil chemokine chemokine (C-X-C motif) ligand 1 and macrophage chemokine C-C motif chemokine ligand 2 in the peritoneal cavity. Depletion of neutrophils or macrophages reversed interleukin-34-mediated protection against polymicrobial sepsis. CONCLUSIONS: We reported for the first time a potential therapeutic role for interleukin-34 in sepsis and suggested that interleukin-34 is a novel target for the development of therapeutic agents against sepsis.
OBJECTIVES:Sepsis is a devastating condition with a high mortality rate and limited treatments. Sepsis is characterized by a failed host immune response to contain the infection, resulting in organ dysfunction. Interleukin-34 is new cytokine involved in infection and immunity. Whether interleukin-34 is beneficial or deleterious to sepsis and the underlying mechanisms remains unknown. DESIGN: Prospective randomized animal investigation and in vitro studies. SETTING: Research laboratory at a university hospital. SUBJECTS: Wild-type C57BL/6 mice were used for in vivo studies, and septic humanpatients and healthy human subjects were used to obtain blood for in vitro studies. INTERVENTIONS:Interleukin-34 concentrations were measured in humansepsispatients and healthy individuals. The effects of interleukin-34 administration on survival, bacterial burden, organ injury, and inflammatory response were assessed in a murine model of cecal ligation and puncture-induced polymicrobial sepsis. MEASUREMENTS AND MAIN RESULTS:Interleukin-34 levels were significantly elevated in humansepsis and cecal ligation and puncture-induced experimental sepsis. Interleukin-34 administration improved survival and bacterial clearance, although suppressed vascular leakage and organ injury after cecal ligation and puncture-induced polymicrobial sepsis. Neutralization of interleukin-34 increased mortality rate and decreased bacterial clearance in septic mice. An increased neutrophil and macrophage influx were developed in interleukin-34-treated mice at the site of infection, accompanied by elevated production of neutrophil chemokine chemokine (C-X-C motif) ligand 1 and macrophage chemokine C-C motif chemokine ligand 2 in the peritoneal cavity. Depletion of neutrophils or macrophages reversed interleukin-34-mediated protection against polymicrobial sepsis. CONCLUSIONS: We reported for the first time a potential therapeutic role for interleukin-34 in sepsis and suggested that interleukin-34 is a novel target for the development of therapeutic agents against sepsis.