blood vessels and return to the bone mar-
row from an injury site ( 10). These insights
stimulate additional questions and open
further research avenues into the com-
plex resolution phase. It remains largely
unclear what proportion of neutrophils
from the inflammatory site migrate back
to the bone marrow compared to those
that undergo apoptosis in situ, and it is
yet to be fully established whether the phe-
nomenon of neutrophil reverse migration
to lungs and bone marrow is a universal
mechanism that can be observed during
inflammation of other organs, with di-
verse inflammatory stimuli and in chronic
conditions. Another aspect of this process
that has not been fully elucidated by the
current and previous studies is its (patho)
physiological relevance. Is reverse migra-
tion of neutrophils a physiological mech-
anism, facilitating neutrophil clearance
from the inflammatory site, or do the neu-
trophils that have undergone reverse mi-
gration from sites of sterile inflammation
convey a message to distant organs, such
as the lung and bone marrow? The find-
ings of Wang et al. and studies in zebra-
fish models indicate that reverse migration
of neutrophils is a physiological aspect of
resolution of inflammation ( 6, 7, 12). These
findings tempt the speculation that return-
ing neutrophils “educate” other immune
cells at distant sites to further contribute
to the resolution of the sterile inflamma-
tory condition, or even to prepare the host
for future sterile injuries. However, at pres-
ent, these conjectures are not supported by
experimental evidence. Paradoxically, pre-
vious studies have suggested that reverse-
migrated neutrophils cause tissue damage
at distant sites, and researchers have hy-
pothesized that this process may contrib-
ute to turning local inflammation into
systemic inflammation ( 8–10), as is seen in
patients that develop acute respiratory dis-
tress syndrome upon severe trauma ( 13).
Here, Wang et al. did not report second-
organ tissue injury after thermal hepatic
injury; thus, more experimental work is
required to understand which features of
sterile inflammation, such as the type or
location of injury, dictate the occurrence of
distant organ injury as a consequence of
Insights into the resolution process of
sterile inflammation may open new opportunities for the treatment of chronic
inflammatory conditions. However, therapeutic manipulation of neutrophil reverse
migration necessitates greater understanding of the molecular mechanisms that
underlie this behavior and further understanding of the abovementioned paradox
that is present within the field. In light of
Wang et al., it could be anticipated that
therapeutic acceleration or amplification
of this process may be an attractive approach to treat conditions of nonresolving
inflammation. However, as other studies
have implied neutrophil reverse migration
to be pathological ( 8, 9), enhancing this
process could have detrimental effects.
Rather, in this context, inhibition of reverse migration could represent an innovative strategy to minimize distant tissue
damage or contribute to the suppression
of systemic inflammation. Indeed, neutrophilic systemic inflammation is implicated
in many chronic, sterile inflammatory
conditions, including autoimmune diseases such as systemic lupus erythematosus and cancer. There is a growing body
of evidence that cancer-induced systemic
neutrophilic inflammation promotes lung
metastasis ( 14). It is appealing to hypothesize that neutrophils leaving the primary
tumor site by means of reverse migration
may contribute to the establishment of a
metastasis-permissive niche. Given the
growing appreciation of the role of neutrophils in pathological settings, the findings
of Wang et al. further our understanding
of neutrophil dynamics and ultimately
may contribute to therapeutic strategies to
fight nonresolving inflammation. j
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Neutrophils reverse migrate along a preprogrammed path through
the lungs to the bone marrow, where they undergo apoptosis.
recruited to a site
of sterile injury in
found in the
Direct migration from
injury to bone marrow?
6 OCTOBER 2017 • VOL 358 ISSUE 6359 43
Neutrophils take a round-trip in sterile inflammation
Upon sterile injury initiation in the liver (in a mouse model), neutrophils are recruited from the bone marrow to
the liver, where they play a critical role in tissue repair. They then undergo reverse migration, which is important
for the resolution of sterile inflammation. The possible human injury scenario is shown.