Introduction
Sepsis is defined as a life-threatening organ dysfunction that is caused by a dysregulated host response to infection [1]. Globally, it is estimated that there are 31.5 million sepsis and 19.4 million severe sepsis cases per year, and up to 5.3 million deaths annually [2]. In 2017, the world health organization (WHO) declared sepsis as a disease of global health priority, needing special attention due to its high prevalence and mortality worldwide [3]. In sepsis, the host immune response that is triggered by microbial infection fails to return to normal homeostasis, involving both sustained excessive inflammation and immune suppression [4]. Identification of host immune regulators participating in disturbing host immune response may point toward novel therapeutic leads in sepsis.
The CXC chemokine ligand 16 (CXCL16) is an unusual chemokine that exists in both transmembrane and soluble forms [5]. The protein structure of CXCL16 comprises a small C-terminal intracellular domain and an extracellular N-terminal chemokine domain bound to the transmembrane region through a heavily glycosylated mucin-like stalk [6]. CXCL16 is mainly produced by macrophages and dendritic cell, but is also produced by lymphocytes, fibroblasts, smooth muscle cells, and endothelial cells [7]. Surface-expressed CXCL16 can mediate adhesion to cells expressing its specific receptor CXCR6, while the soluble form of CXCL16 shed from the surface can act as a chemotactic gradient for leukocytes expressing CXCR6 [8]. CXCL16 expression has been related to a variety of human inflammatory diseases including rheumatoid arthritis [9], systemic lupus erythematosus (SLE) [10], lung cancer [11], thyroid cancer [12], hepatocellular carcinoma [13], lung injury [14], Salmonella enterica serovar Enteritidis [7], and human immunodeficiency virus (HIV) infection [15]. Besides, several studies support usage of soluble CXCL16 as a biomarker of Inflammation, atherosclerosis, and acute coronary syndromes in humans [16-18]. However, little is known about the expression and function of CXCL16 in sepsis.
In order to investigate the potential role of CXCL16 in sepsis, we accompanied human clinical studies with in vivo mice experiments. Firstly, we analyzed the extent of soluble CXCL16 over time in the patients with sepsis and its correlation with disease outcome. Furthermore, we examined the impact of CXCL16 on host immune responses, tissue injury, and mortality in the cecal ligation and puncture (CLP) model of polymicrobial sepsis by administration of recombinant CXCL16 protein or neutralizing anti-CXCL16 antibody. We here reported that CXCL16 might be an important inflammatory mediator in the pathogenesis of sepsis.