Discussion
Over the past years, the chemokine has emerged to be an important
inflammatory mediator of various human diseases. In the present report,
we identified CXCL16 to be centrally involved in the pathogenesis of
sepsis. We made the following key observations: I. Sepsis patients had a
marked and sustained elevation of soluble CXCL16. II. Admission levels
of soluble CXCL16 levels correlated with disease severity and mortality
in human patients with sepsis. III. CXCL16 was found to be an
independent predictor of 28-day mortality in the patients with sepsis on
day of ICU admission. IV. CXCL16 supplementation in the presence of
sepsis could worsen outcome of CLP-induced nonsevere sepsis. V.
Neutralization of the CXCL16 activity with antibody against CXCL16 could
produce substantial survival benefit in CLP-induced severe sepsis.
It has been suggested that soluble CXCL16 could serve as a reliable
marker of inflammation. 16 Indeed, soluble levels of
serum CXCL16 were correlated significantly with the disease activity of
patients with inflammatory bowel disease (IBD) [22]. Consistent with
this pro-inflammatory profile, soluble CXCL16 levels were independently
associated with coronary atherosclerosis, particularly acute coronary
syndromes. 16 In patients with an acute coronary
syndrome, CXCL16 levels obtained within 24 hours of admission are
associated with long-term mortality after adjustment for other risk
factors [23]. Furthermore, admission level of CXCL16 is
independently related to adverse clinical outcomes in patients with an
acute coronary syndrome, mainly driven by an association to
cardiovascular death [18]. Therefore, CXCL16 measurement may enhance
risk stratification in patients with acute coronary syndrome. However,
to our knowledge CXCL16 has never been evaluated in the patients with
sepsis. This study revealed dramatically increased soluble CXCL16 levels
in septic patients on day of ICU admission as compared to healthy
controls. Further, we observed that admission levels of soluble CXCL16
significantly differed between survivors and non-survivors in the
patients with sepsis. Moreover, admission levels of CXCL16 were
positively correlated with SOFA score and different laboratory outcome
parameters such as WBC, CRP, IL-6, IL-8, IL-27 and TNF-α. We therefore
tested for an additive prognostic value of soluble CXCL16 levels in
septic patients. We demonstrated, for the first time, the association
between increased admission levels of soluble CXCL16 and higher risk of
death in the patients with sepsis. Although the AUC of CXCL16 was lower
than that of SOFA score in predicting 28-day mortality, it was superior
to PCT and CRP for predicting 28-day mortality in septic patients. In
the logistic regression analysis, CXCL16 was found to be independent
predictors of 28-day mortality in septic patients. These findings
suggest that CXCL16 might be added to the list of risk markers that
could identify a group of septic patients presenting with higher risk of
mortality beyond that of other risk indicators, such as soluble ST2
[24], presepsin [25], soluble IL-7 receptor [26], and
apoptosis inhibitor of macrophage (AIM) [27].
CXCL16 up-regulation has been shown to participate in the inflammatory
response elicited during bacterial and viral infections, which was
associated with either beneficial or detrimental effects [6, 7]. To
further investigate the role of CXCL16 in the pathogenesis of sepsis, we
established a clinically relevant murine model of sepsis induced by CLP.
Consequently, we found that supplementation with recombinant CXCL16
decreased survival and increased tissue inflammation and tissue injury
in mice after non-severe CLP, while neutralization of CXCL16 resulted in
substantial survival benefit after severe-CLP. Interestingly, CXCL16 is
dispensable for controlling bacterial infection in CLP-induced
polymicrobial sepsis. These results are consistent with a previous study
showing that neutralization of CXCL16 resulted in reduced cerebrospinal
fluid pleocytosis in an animal model of pneumococcal meningitis, but it
did not influence bacterial outgrowth in the central nervous system
irrespective of the time of administration [28]. In a murine model
of collagen-induced arthritis (CIA), treatment with anti-CXCL16
monoclonal antibody has also been shown to significantly reduce the
clinical arthritis score and reduce infiltration of inflammatory cells
and bone destruction in the synovium of mice with CIA [9].
Neutralizing CXCL16 by injection of anti-CXCL16 antibody ameliorated the
extent of hepatic inflammation and steatosis development in experimental
metabolic injury [29]. Furthermore, administration of anti-CXCL16
antibody could ameliorate colonic inflammation in the experimental model
of colitis [22]. In fact, sepsis was associated with a complex
network of pro- and anti-inflammatory modulators, the balance of which
determines the outcome of the sepsis. Taken together, sepsis was
associated with elevated production of CXCL16, and CXCL16 had a limited
antibacterial role in sepsis. However, CXCL16 could cause aberrant
inflammatory response (increase of leukocyte infiltration including
monocytes/macrophages, neutrophils and lymphocytes, and elevation of
inflammatory cytokines/ chemokines including IL-6, TNF-α, KC and IL-27),
resulting in exaggerated inflammation, which can cause tissue injury and
increased lethality. Therefore, targeting CXCL16 might therefore
represent a promising novel therapeutic approach for the treatment of
sepsis.
Some limitations of this study should be noted. First, this is a
single-center study with a limited sample size, and our results should
be validated in a larger ideally multicentric study. Second, the AUC of
CXCL16 was lower than that of SOFA score in predicting 28-day mortality
of septic patients, suggesting that incremental further studies are
required to investigate whether the combination of CXCL16 with other
risk biomarkers might provide additional prognostic value in septic
patients. Finally, further investigation using CXCL16 knockout mice is
required to elucidate the underlying molecular mechanisms by which
CXCL16 amplifying local and systemic inflammation during sepsis.
Collectively, we here firstly establish that human septic patients had a
stable and sustained elevation of soluble serum CXCL16 levels, which
correlate with disease severity and mortality. Measuring admission
levels of soluble serum CXCL16 could represent a promising biomarker for
risk stratification and evaluation of prognosis in the patients with
sepsis. In complementary experimental studies, administration with
recombinant CXCL16 could aggravate nonsevere sepsis, while anti-CXCL16
treatment could ameliorate severe sepsis. Targeting the chemokine CXCL16
is a promising strategy in the treatment of sepsis. Taken together,
CXCL16 emerges as a promising biomarker for disease severity and as a
potential target for therapeutic intervention in human sepsis.