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.