INSIGHTS | PERSPECTIVES
Neutrophils take a round-trip
Imaging sheds light on neutrophil dynamics
in sterile inflammation
By Hannah Garner and Karin E. de Visser
Inflammation is a body’s response to harmful stimuli that aims to elimi- nate the trigger that caused the ini- tial injury and enable tissue repair. Inflammation can be either pathogen- associated or sterile. Sterile inflammation can be triggered by acute conditions,
such as trauma, toxin exposure, and isch-emia-reperfusion injury, but it is also an
important component of life-threatening
chronic inflammatory conditions, such as
atherosclerosis, cancer, and asbestosis (1).
Regardless of etiology, the mechanisms resolving inflammatory responses constitute highly
coordinated and active
processes that are vital
for restoring tissue homeostasis. Although the
cellular and molecular
signals that drive the initiation of sterile inflammation are well studied
(1), we have a relatively
poor understanding of the mechanisms
through which sterile inflammation is resolved, thus limiting our ability to therapeutically tackle harmful inflammation.
On page 111 of this issue, Wang et al. (2)
shed light on a provocative aspect of reso-
lution by key orchestrators of the inflam-
matory process: neutrophils.
Neutrophils are the first immune cells
to arrive at sites of inflammation, where
they play a critical role in the elimina-
tion of inflammatory stimuli and tissue
repair. Considered relatively short-lived
cells, neutrophils are believed to undergo
apoptosis at the site of inflammation, af-
ter which they are cleared by other leu-
kocytes with phagocytic activity, such as
macrophages ( 3). These processes are not
only believed to be vital to ensure that the
noxious armory within neutrophils is con-
tained and disposed of safely but is also
thought to provide critical signals that
promote successful resolution of inflam-
mation. In the past 10 years, a paradigm
shift has emerged that challenges the idea
that neutrophils always die at the site of
inflammation. Several groups have dem-
onstrated, with human cells in vitro ( 4, 5),
zebrafish ( 6, 7), and mouse models ( 8, 9),
that some neutrophils have the capacity to
actively leave the site of inflammation and
migrate into the surrounding healthy tis-
sue or vasculature, a process referred to as
reverse migration (see the figure) ( 10).
Wang et al. bring new insight into this
fascinating and relatively unexplored property of neutrophil behavior in a mouse
model of thermal hepatic injury combined
with intravital imaging techniques, visualizing neutrophil function and fate during
sterile inflammation in vivo and in real
time. The authors show
that critical components
for successful resolution
of inflammation, such as
clearing debris from the
injury site and revascularization of damaged
tissue, are delayed in the
absence of neutrophils.
Using intravital microscopy to track neutrophil
dynamics in the hours after injury, the
authors provide conclusive evidence for
neutrophils leaving the injury site and reentering the vasculature. But what is the
fate of these reverse-migrating neutrophils? To address this, the authors used a
transgenic mouse model in which neutrophils express photoactivatable green fluorescent protein (GFP), which facilitates the
temporal and spatial visualization of neutrophils in situ. After induction of liver injury in these mice, neutrophils at the injury
site were photoactivated and tracked over
time. On the basis of kinetic analysis of the
injury-derived GFP-expressing neutrophils,
the authors propose that the neutrophils
follow a preprogrammed pathway through
the lungs to the bone marrow, where they
undergo apoptosis. The authors demonstrate that this process was C-X-C motif
chemokine receptor 4 (CXCR4)–dependent,
a mechanism that is reminiscent of neutrophil fate under homeostatic conditions
where senescent neutrophils up-regulate
CXCR4 to return to the bone marrow for
their safe removal ( 11).
Wang et al. add important insight to the
growing body of work that suggests that
neutrophils have the capacity to reenter
of neutrophils is a
Division of Tumor Biology & Immunology, Netherlands Cancer
Institute, Amsterdam. Email: firstname.lastname@example.org
nity reorganization as microbes struggle
to adjust to the environmental conditions
(see the figure). These phases are followed
by surges in breakdown of previously inaccessible soil carbon pools as the reorganized
microbial community takes advantage of
the warmer conditions. If these findings
hold more widely across major terrestrial
ecosystems, then a much greater portion
of the global soil carbon store could potentially be vulnerable to decomposition and
release as CO2 under global warming than
Melillo et al. make a persuasive argument
for the importance of considering the complexity and dynamism of the underground
world to understand climate change. Further work would benefit from widening this
focus to encompass the complexity above
ground and the intricate linkages between
above- and belowground domains. Plants
regulate the amount and type of carbon inputs to soil over a range of time scales and
via various distinct pathways, and these
inputs are sensitive to various environmental factors, including temperature (1, 10).
These plant-soil interactions represent a
key frontier for development in the global
vegetation models that are used to predict
feedbacks between terrestrial ecosystems
and climate change ( 10, 11).
Myriad linkages between plant and soil
processes are included in current global
vegetation models, but many of these interactions have not been rigorously evaluated against data from field experiments
( 11). With complementary aboveground
data, the warming experiment described
by Melillo et al. could add further scientific value as a real-world test bed for
the scientific ideas and hypotheses about
plant-soil interactions coded in the model
algorithms ( 11). However, perhaps the
most critical future activity in the case of
this experiment may at first glance seem
like the least inspiring: to keep the study
going. Experience shows that this kind of
tedious repetition and painstaking replication has produced, and will likely continue
to produce, some of our most valuable and
exciting scientific insights. j
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2. D. B. Richter etal .,Soil Sci.Soc.Am.J. 71, 266 (2007).
3. J. M. Melillo et al., Science 358, 101 (2017).
4. C. Le Quéré et al., Earth Syst. Sci. Data 8, 605 (2016).
5. M. Cao, F. I. Woodward, Glob. Chang. Biol . 4, 185 (1998).
6. E.A.Davidson,I.A.Janssens, Nature 440,165(2006).
7. J. C. Carey etal ., Proc.Natl.Acad.Sci.U.S.A. 113, 13797
8. B.Bond-Lamberty,A. Thomson, Nature 464,579(2010).
9. R. T. Conant et al ., Glob. Chang. Biol . 17, 3392 (2011).
10. F. S. Chapin III et al ., J. Ecol . 97, 840 (2009).
11. N. J. Ostle et al., J. Ecol. 97, 851 (2009).
42 6 OCTOBER 2017 • VOL 358 ISSUE 6359