Thus, neutralization of JAM-C contributed to not only the improvement of local inflammation but also systemic inflammation in septic mice as illustrated inFig 7. == Figure 7. significantly reduced the frequencies of CXCR4+aged neutrophils. Treatment with anti-JAM-C Ab significantly reduced systemic injury markers (ALT, AST and LDH) as well as systemic and lung inflammatory cytokines (IL-6 and IL-1) and chemokine (MIP-2). The blockade of JAM-C improved lung histology and reduced neutrophil contents in lungs of septic mice. Thus, reduction of the pro-inflammatory aged neutrophils Varenicline by blockade of JAM-C has a novel therapeutic potential in sepsis-induced ALI. Keywords:Neutrophil Aging, Junctional Adhesion Molecule-C (JAM-C), CXCR4, Sepsis, Apoptosis, Transmigration, Acute Lung Injury == INTRODUCTION == Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response Varenicline to infection Varenicline [1], remains a considerable challenge to critical care medicine. According to the new clinical criteria of sepsis as represented by an increase in the Sequential Organ Failure Assessment (SOFA) score of 2 points or more, in-hospital mortality rate of sepsis is recorded as over 10% [1]. However, it grows up to greater than 40% when septic shock develops [2]. In the United States, more than 1 million cases of septicemia are reported annually [3,4]. Despite resources incurred in treatment, over 200,000 patients die annually due to hSNFS this condition, making septicemia as one of the leading causes of death in the United Varenicline States [3]. Due to this unacceptably high mortality rate and frequent admission of septic patients in the intensive care unit [2], scientists and the clinicians are desperately looking for an effective strategy to treat sepsis [2]. Although more than 100 clinical trials tested for sepsis resulted in failure in the past [5], additional efforts and novel therapeutic ideas should be implemented to reduce sepsis-induced death. Neutrophil infiltration in the lungs is a pathological hallmark of sepsis-induced acute lung injury (ALI), or acute respiratory distress syndrome (ARDS) [6]. Therefore, controlling neutrophil recruitment and activation is considered to be one of the main therapeutic strategies to treat ALI in sepsis [7]. Neutrophils are produced in the bone marrow and released into the circulation as the first responders of the innate immune system during acute inflammatory conditions [8]. After the sequential processes between the circulatory neutrophils and the vascular endothelium represented by capture, rolling, adhesion, crawling and transmigration [9], they infiltrate into the inflamed tissues and eliminate invading pathogens by releasing proteolytic enzymes such as myeloperoxidase (MPO) and reactive oxygen species (ROS), forming neutrophil extracellular traps (NETs), and promoting phagocytosis [7,10,11]. However, overwhelming migration and exaggerated function of activated neutrophils in the inflamed tissues not only kill the bacteria but also cause surrounding tissue injury and unrestrained inflammation, resulting in organ dysfunction and death [12,13]. Thus, regulating the function of neutrophils and their uncontrolled infiltration into tissues could serve as an effective therapeutic tool during sepsis. Under steady-state conditions, the heterogeneity of neutrophils arises from their ageing and replenishment by nave bone marrow-derived neutrophils. A growing body of literatures demonstrated the phenotype of aged neutrophils which express CXCR4 at a high level on their cell surface compared to freshly isolated neutrophils [1417]. The chemokine receptor CXCR4 expressed on the surface of aged neutrophils helps their clearance in the bone marrow [16,17]. Recently, the CXCR4+neutrophils are shown as a pro-inflammatory phenotype of neutrophils whilst in circulation [15]. CXCR4+aged neutrophils represent an excessively active subset exhibiting enhanced M2-integrin activation and NET formation under inflammatory conditions [15]. The NET forming neutrophils were previously shown to be deleterious in sepsis [18], thus suggesting the fact that CXCR4+neutrophils could be detrimental in sepsis as CXCR4+neutrophils form excessive NET [15]. Zhanget al.also have shown that the neutrophil ageing is driven by the microbiota via Toll-like receptor (TLR) and myeloid differentiation factor 88 (MyD88)-mediated signaling pathways [15]. Depletion of the microbiota significantly reduced the number of circulating aged neutrophils and dramatically improved the pathogenesis and inflammation-related organ damage in endotoxin-induced septic shock [15]. Therefore, the above literatures clearly suggest that, i) CXCR4+neutrophils are named aged neutrophils, ii) sepsis can increase the contents of CXCR4 expressing aged neutrophils, and iii) CXCR4+neutrophils display pro-inflammatory roles in sepsis. Junctional adhesion molecule-C (JAM-C) is a glycoprotein which belongs to the immunoglobulin superfamily with two extracellular immunoglobulin-like domains, one transmembrane segment, and a short cytoplasmic tail [19]. JAM-C is expressed in a wide variety of cells including endothelial cells, fibroblasts, intestinal epithelial cells and smooth muscle cells [20]. JAM-C promotes neutrophil transendothelial migration (TEM) from circulation to the inflamed tissues by binding to its receptor integrin M2(Mac-1) [21]. By contrast, the cleavage of endothelial JAM-C promotes.