Effects of sepsis on neutrophil chemotaxis

Raju C. Reddy and Theodore J. Standiford

Department of Internal Medicine, Division of Pulmonary
and Critical Care Medicine, University of Michigan
Medical Center, Ann Arbor, Michigan, USA
Correspondence to Raju C. Reddy, MD, University of
Michigan Medical Center, Division of Pulmonary and
Critical Care Medicine, 109 Zina Pitcher Place, 4062
BSRB, Ann Arbor, MI 48109-2200, USA
Tel: +1 734 615 2871; fax: +1 734 615 2111;
e-mail: rajuc@umich.edu
Current Opinion in Hematology 2010,
17:1824
Purpose of review
Neutrophil recruitment to sites of infection is a critical element of the innate immune
response. In patients with sepsis, this response is dysregulated, with exuberant
inflammation being followed by a state of profound immune suppression, including
inhibition of neutrophil recruitment. This review examines mechanisms underlying
suppression of neutrophil migration during sepsis.
Recent findings
Mechanisms governing neutrophil chemotactic function in sepsis are complex. Bacterial
products, cytokines, and chemokines can modulate neutrophil migratory responses
during sepsis via induction of cytoskeletal changes, inhibition of polymorphonuclear
leukocyte (PMN)endothelial cell interactions, and alterations in G protein-coupled
receptor expression or signaling. Impaired chemotactic responses can occur as a result
of dysregulated PMN Toll-like receptor signaling. Other recently identified inhibitory
mechanisms include exposure to elevated temperatures, activation of the anti-
inflammatory nuclear transcription factor peroxisome proliferator-activated receptor-g,
and suppression of PMNendothelial interactions due to nitric oxide and its
metabolites. Finally, circulating microparticles released in sepsis exert important
immunomodulatory effects on PMN adherence and transmigration.
Summary
Neutrophil recruitment is a coordinated process that is altered at multiple stages during
sepsis, culminating in defective innate immunity and increased risk of infection in these
patients. Defining mechanisms involved and strategies to interrupt these deleterious
responses requires further investigation.

Keywords
immunosuppression, nitric oxide, peroxisome proliferator-activated receptor-g,
systemic inflammatory response syndrome, Toll-like receptors

Curr Opin Hematol 17:1824

2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
1065-6251

ance, as an increase in mortality is observed in severe

Introduction
Sepsis is a progressive, injurious inflammatory response to
infection [1]. Burns, trauma, and major surgery can
promote analogous clinical responses, referred to as the
systemic inflammatory response syndrome (SIRS) [2].
Growing evidence indicates that the failure to maintain
the necessary balance between excessive and inadequate
inflammation is a fundamental pathologic feature of
sepsis [3,4]. Neutrophils are key cells in the innate
response, releasing important regulatory cytokines and
chemokines, engulfing invading microbes, and releasing
antimicrobial proteins and oxidants required for microbial
killing. Neutrophil migration in severe sepsis is impaired,
resulting in an inadequate recruitment of polymorpho-
nuclear leukocytes (PMNs) to sites of microbial invasion
[5,6,7,8]. Sepsis is also characterized by deleterious
accumulation of neutrophils in vital organs, culminating
in PMN-mediated organ failure [3]. Impaired recruit-
ment of PMNs in sepsis is of considerable clinical import-
1065-6251 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
sepsis patients who display impaired PMN chemotactic
responses [5,6]. This review will cover recent advances in
our knowledge of how sepsis modulates neutrophil
migration and the molecular mechanisms involved.
Overview of sepsis
Host immune responses in sepsis can be conceptualized
as occurring in distinct, but overlapping, phases. The
initial response in sepsis, referred to as SIRS, is charac-
terized by the release of a number of proinflammatory
mediators, including early response cytokines such as
tumor necrosis factor-a (TNFa), interleukin (IL)-1b,
leukocyte-active chemokines, leukotrienes, adhesion
molecules, reactive oxygen species, and nitric oxide
[4,9]. SIRS is counter-regulated by the release of inhibi-
tory molecules, including anti-inflammatory cytokines
[e.g. IL-10 and transforming growth factor-b (TGFb)],
suppressors of pathogen recognition signaling cascades,
DOI:10.1097/MOH.0b013e32833338f3

Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 Effects of sepsis on neutrophil chemotaxis Reddy and Standiford 19

Figure 1 Schematic depicting pathophysiological phases in sepsis, including mediators involved, biological effects, and clinical
manifestations

CARS, compensatory anti-inflammatory response syndrome; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage
colony-stimulating factor; IL, interleukin; NO, nitric oxide; PPARg, peroxisome proliferator-activated receptor-g; SIRS, systemic inflammatory response
syndrome; TLR, Toll-like receptor; TNF, tumor necrosis factor. Adapted with permission from [11].

immunomodulatory eicosanoids, and hormones. This Neutrophil origin and mobilization

counter-regulatory phase is referred to as the compensa-
tory anti-inflammatory response syndrome (CARS) [9,10].
Molecules released during CARS are believed to limit
systemic inflammation, and the expression of these
mediators is induced by both microbial-derived and
host-derived signals. Historically, therapeutic interven-
tions in sepsis have targeted selected mediators of SIRS.
However, many randomized, controlled trials directed
against these mediators have failed to improve outcomes
in patients with sepsis, and in some cases have resulted in
detrimental effects. The failure of these trials has brought
the functional importance of CARS in sepsis to light [10].
Molecules expressed during SIRS and CARS are depicted
in Fig. 1 [11].
Overview of neutrophil recruitment and
migration
Recruitment of neutrophils to sites of inflammatory or
infectious insult is one of the initial and most critical arms
of the innate immune response. Four distinct phases of
neutrophil recruitment have been described: mobiliz-
ation, margination (movement to the vessel periphery)
and rolling, adherence, and transmigration through the
vessel wall along chemotactic gradients. All phases of
PMN migration are altered during sepsis [7,8].
Neutrophils originate from bone marrow stem cells under
the influence of granulocyte colony-stimulating factor
(G-CSF) [12]. G-CSF also stimulates release of mature
neutrophils from the marrow under baseline conditions,
with release being further stimulated by inflammation-
associated cytokines. In the absence of inflammation,
neutrophils circulate for a brief period (6 h) before
becoming senescent and being cleared by liver, spleen,
and bone marrow [13]. Once neutrophils have reached the
site of infection, however, their otherwise short lifetime is
extended by inflammatory mediators such as granulocyte-
macrophage colony-stimulating factor (GM-CSF), chemo-
kines, and other chemoattractant molecules [14].
Margination and rolling
Movement of neutrophils to the vessel wall allows low-
affinity interactions between neutrophils and the endo-
thelial layer [15]. The primary molecular effectors of these
interactions are L-selectin, constitutively expressed on
circulating leukocytes, and E-selectin and P-selectin,
expressed on endothelial cells after activation by chemo-
kines and other inflammatory mediators.
Adhesion
The combination of low-affinity contact between neu-
trophils and endothelial cells and chemokine activation

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 20 Myeloid biology

induces molecules that mediate high-affinity adhesion.
The relevant adhesion molecules on neutrophils are the
integrins, two-chain heterodimers with a number of vari-
ants for each subunit. The aLb2-integrin, also known as
CD11a/CD18, is expressed on the surface of most leuko-
cytes, whereas the aMb2-integrin, also known as CD11b/
CD18, is mobilized to the cell surface of monocytes and
neutrophils following activation by microbial components,
inflammatory cytokines, or chemokines. These integrins
interact with adhesion molecules on the surface of the
endothelial cell to provide the firm anchorage that charac-
terizes adhesion, with the most important endothelial
adhesion molecules being intercellular adhesion mol-
ecule-1 (ICAM-1) and vascular cell adhesion molecule-1
(VCAM-1).
Transmigration and chemotaxis
The final stage in neutrophil recruitment is passage across
the endothelium through tight junctions into infected
tissues. This process is guided by concentration gradients
of chemoattractants, which include both microbial com-
ponents, such as formyl-methionyl-leucyl-phenylalanine
(fMLP), and host-derived chemoattractants, including
complement components (e.g. C5a), eicosanoids (e.g.
leukotriene B4 and platelet-activating factor), and che-
mokines [16]. Many of these chemoattractants act
through G protein-coupled receptors (GPCRs), with cells
migrating in the direction of highest receptor occupancy
[17].
Mechanisms influencing neutrophil migration
in sepsis
Multiple mechanisms contribute to sepsis-induced sup-
pression of neutrophil recruitment, although our under-
standing of this complex process remains incomplete.
Key events, including recent findings, are summarized in
this review and illustrated schematically in Fig. 2.
Alterations in neutrophil rigidity and sequestration
Factors released during sepsis result in marked increase in
the rigidity of neutrophil cell membranes. As a result of
altered deformability, neutrophils sequester in capillary
beds, especially those of the lung. Sequestered neutrophils
neither migrate through endothelium nor complete their
passage through the capillary. The occlusion of vasculature
by PMN limits blood flow, resulting in tissue ischemia,
which contributes to multiple organ failure [18,19]. Rigid-
ity increases with sepsis severity [19], whereas a progress-
ive decrease in rigidity signals recovery [18]. This
increased rigidity, which can be induced in vitro by
exposure to fMLP or TNFa [18], is associated with
accumulation of F-actin immediately below the cell mem-
brane but not with cytoskeletal rearrangement [20]. A

Figure 2 Schematic depicting stages of polymorphonuclear leukocyte recruitment and how these various stages are altered by
mediators expressed in sepsis

CXCR2, CXC chemokine receptor 2; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor;
GPCR, G protein-coupled receptor; HO-1, heme oxygenase-1; ICAM, intercellular adhesion molecule; Ig, immunoglobulin; NO, nitric oxide; PMN,
polymorphonuclear leukocyte; PPARg, peroxisome proliferator-activated receptor-g; TLR, Toll-like receptor; TNF, tumor necrosis factor; VCAM,
vascular cell adhesion molecule. , selectins; , Ig superfamily members; , integrins.

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causal connection between submembrane F-actin and
sequestration is demonstrated by the finding that only
neutrophils with submembrane F-actin rims are lost during
passage through the lungs of rats with bacterial pneumonia
[21].
Alterations in Toll-like receptor expression and
signaling
Toll-like receptors (TLRs) are a family of cell surface and
intracellular pathogen recognition receptors that are
required for the generation of immune responses to micro-
bial pathogens. PMNs express several TLRs, including
TLR2, which is activated by pathogen-associated molecu-
lar patterns (PAMPs) expressed by Gram-positive bacteria,
and TLR4, which is activated by lipopolysaccharide
released from Gram-negative bacteria [22]. Stimulation
of either TLR2 or TLR4 enhances random motility of
neutrophils via the extracellular-signal regulated kinase
mitogen-activated protein kinase (ERKMAPK) signaling
pathway, but directed motility (chemotaxis) requires
further stimulation with a chemoattractant such as fMLP
[23]. Neutrophils can also be activated in a TLR-depen-
dent fashion by host-derived inflammatory mediators
released in sepsis, referred to as danger-associated molecu-
lar patterns (DAMPs) or alarmins. Observations made in
animal models of sepsis and in neutrophils isolated from
patients with septic shock indicate that neutrophil expres-
sion of TLR2 and TLR4 is diminished [24]. Moreover,
microarray analysis of PMNs isolated from septic patients
within 24 h of onset reveals a global suppression of immune
regulation and inflammatory response gene clusters,
particularly genes regulated in a TLR or nuclear factor
(NF)-kB-dependent fashion [25]. Conversely, the expres-
sion of selected suppressive genes is enhanced, including
the NF-kB inhibitor alpha, NFkBIA. Sepsis also induces
the upregulation of cytokines or proteins that inhibit down-
stream TLR signaling cascades. In particular, IL-10 pro-
duced by macrophages and other cells can substantially
diminish TLR activation and PMN responses to chemoat-
tractants in a paracrine fashion [26], whereas we have found
that the expression of the IL-1 receptor-associated kinase
IRAK-M is upregulated in PMNs isolated from patients
with sepsis (unpublished observations).
Alteration of G protein-coupled receptor expression and
downstream signaling events in sepsis
A paramount feature of the septic response is the exuber-
ant release of leukocyte chemoattractants that function
through activation of the GPCR. Exposure to high levels of
ligand can result in functional desensitization of receptor
responsiveness, which can occur as a result of downregula-
tion of GPCR cell surface expression [27]. Decreased
expression of the CXC chemokine receptor 2 (CXCR2)
on neutrophils isolated from sepsis patients has been
observed [28]. This rapid downregulation is due, in part,
to internalization and recycling of occupied receptors [27].
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Effects of sepsis on neutrophil chemotaxis Reddy and Standiford 21
In addition, decreased CXCR2 expression appears to be
partially mediated by activation of TLR2, as treatment of
PMNs with the TLR2 agonist lipoteichoic acid reduced
CXCR2 expression and chemotactic responses in vitro,
whereas neutrophil CXCR2 expression is well maintained
in septic mice deficient in TLR2 [29].
Receptor desensitization can also occur as a consequence of
differential ligand binding to high and low-affinity recep-
tors. For instance, Herrmann et al. [30] have recently
reported that stimulation of PMNs with fMLP at low
concentration (10 7 mol/l) results in binding to its high-
affinity receptor, leading to chemotactic responses without
release of oxidants. Conversely, exposure to this chemoat-
tractant at higher concentrations (10 5 mol/l) activates its
low-affinity receptor, resulting in stimulation of oxidative
burst while blocking high-affinity receptor-mediated che-
motactic responses, including fMLP-induced calcium flux.
A final means by which the presence of GPCR ligands in
high concentrations can mitigate chemotactic responses
is via phosphorylation of agonist-occupied GPCR by
GPCR kinases (GRKs) [31]. An increase in the expres-
sion of selected GRKs (GRK2 and GRK5) is found in
PMNs isolated from sepsis patients [32]. Induction of
PMN GRKs can be reproduced in vitro by treatment with
inflammatory stimuli released in the setting of sepsis.
A number of inhibitors of GPCR-mediated signaling have
been described. Recent studies have shown that the
receptor for activated C kinase 1 (RACK1) modulates
chemotaxis by competitively binding to G protein bg and
thereby blocking binding to the G-protein targets such as
phosphatidylinositol 3-kinase g and phospholipase C
[33]. The role of this GPCR inhibitor as a mediator of
impaired PMN chemotactic responses has not been
described but is worthy of further investigation.
Another novel mechanism for inhibition of chemoattrac-
tant-mediated signaling is exposure to elevated tempera-
tures similar to those associated with infection [34]. In a
murine model of skin infection, raising the body tempera-
ture from baseline to 408C strongly reduced subsequent
neutrophil infiltration. Neutrophil chemotaxis toward
GM-CSF or IL-8, but not adhesion and spreading, was
likewise inhibited by elevated temperatures in vitro,
which was associated with a reduction in chemoattrac-
tant-induced downstream activation of NF-kB. These
results suggest that sepsis-induced fever may be one of
the mechanisms contributing to impaired chemotactic
responses in this syndrome.
Nitric oxide as a mediator of sepsis-induced impairment
in neutrophil chemotaxis
Sepsis results in a dramatic increase in the elaboration of
nitric oxide, which is largely attributed to inflammatory
 22 Myeloid biology
cytokine and endotoxin-mediated upregulation of indu-
cible nitric oxide synthase (iNOS or NOS-2) [35]. Nitric
oxide has been identified as an important modulator of
neutrophil migration, although data exist to support both
stimulatory and inhibitory effects of nitric oxide on PMN
migration [36,37]. This molecule directly inhibits leuko-
cyteendothelial cell interactions, primarily by inhibiting
leukocyte b2-integrins and selectins, as well as endo-
thelial cell ICAM-1 and VCAM-1 [38,39]. Mestriner et al.
[40] demonstrated that acute-phase protein a-1 dose-
dependently inhibited neutrophil migration into the rat
peritoneal cavity following carrageenan injection or cecal
ligation and puncture (CLP), and that this effect could be
eliminated either by pharmacological inhibition of iNOS
or by genetic deficiency of this enzyme.
Nitric oxide can also interact with other molecules gener-
ated during the septic response including reactive oxygen
species. For instance, nitric oxide reacts with the super-
oxide anion to form peroxynitrite, which has been shown
to inhibit PMN migration by blocking leukocyteendo-
thelial cell interactions in a P-selectin-dependent fashion
and by inhibiting actin polymerization required for neu-
trophil locomotion [4143]. Moreover, nitric oxide
induces the expression of the microsomal enzyme heme
oxygenase-1 (HO-1). Metabolites of HO-1 disrupt PMN
rolling and adhesion [4446]. Importantly, inhibition of
HO-1 during experimental sepsis (CLP) restores PMN
responses in septic animals.
Peroxisome proliferator-activated receptor-g activation
suppresses neutrophil chemotaxis
Two recent studies [47,48] highlight the importance of
peroxisome proliferator-activated receptor-g (PPARg) as
a negative regulator of neutrophil migration. PPARs are a
family of nuclear hormone receptors that play a promi-
nent role in regulating fundamental aspects of cellular
activation, proliferation, and differentiation. The ligand-
activated nuclear transcription factor PPARg not only
stimulates transcription of certain target genes involved
in adipocyte differentiation and glucose metabolism but
also downregulates activity of key proinflammatory trans-
cription factors, including NF-kB and signal transducer
and activator of transcription 6 (STAT6), by competing
for common coactivators [49]. We have shown that
PPARg expression is increased in neutrophils isolated
either from septic mice or from humans with sepsis [48].
Induction of neutrophil PPARg expression could be repli-
cated in vitro by exposure to either TNFa or IL-4, cyto-
kines elaborated in sepsis. Treatment with either the
synthetic PPARg agonist troglitazone or the natural ago-
nist 15-deoxy-D12,14-prostaglandin J2 (15d-PGJ2) inhibited
neutrophil chemotaxis in response to IL-8 or fMLP, which
occurred in association with reduced fMLP-induced phos-
phorylation of ERK-1/2 and alterations in F-actin assem-
bly. Moreover, the reduced ex-vivo chemotaxis of PMNs
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
isolated from septic mice was reversed by treatment with
the PPARg antagonist GW9662.
Napimoga et al. [47] studied the influence of PPARg on
PMN adhesion responses in mesenteric postcapillary
venules using a carrageenan-induced peritonitis model
in vivo [48]. Importantly, treatment with 15d-PGJ2
inhibited both PMN rolling and tight adherence to endo-
thelium, which was attributable, in part, to suppression of
mesenteric ICAM-1 expression. A role for nitric oxide in
mediating these effects was indicated by the inability of
15d-PGJ2 to block migration when nitric oxide synthase
was inhibited or iNOS was genetically absent. In-vitro
neutrophil chemotaxis was likewise inhibited by 15d-
PGJ2 or rosiglitazone, an effect that was again blocked by
specific inhibitors of either PPARg or by a specific
inhibitor of iNOS. It is uncertain whether nitric oxide
is acting intracellularly or as an extracellular autocrine
mediator in this setting.
Role of microparticles in regulating polymorphonuclear
leukocyte chemotactic responses in sepsis
Circulating microparticles are membrane-coated particles
released from activated or apoptotic cells, including leu-
kocytes, platelets, erythrocytes, and endothelial cells
[50]. Microparticle release is enhanced in patients with
sepsis and can exert both beneficial and detrimental
effects on inflammatory responses in sepsis, including
neutrophil recruitment [51,52]. Microparticles released
from neutrophils enhance PMN chemotaxis to IL-8,
which is mediated by L-selectin and P-selectin glyco-
protein ligand-1 present on the surface of these micro-
particles [53]. Interestingly, treatment of PMNs with
the NOS inhibitor NG-nitro-L-arginine methyl ester
(L-NAME) stimulated the release of microparticles from
these cells, indicating that nitric oxide tonically sup-
presses neutrophil microparticle formation and release.
Conversely, it has recently been shown that neutrophil-
derived microparticles can also inhibit, rather than facili-
tate, neutrophil chemotaxis [54]. This inhibitory effect
appears to be mediated by the action of the anti-inflam-
matory protein annexin 1, which is bound to the surface of
microparticles. Collectively, the aforementioned studies
indicate that microparticles can exert varied effects on
PMN migratory responses depending upon the cell of
microparticle origin and the nature of the molecules
present on the surface of these structures.
Conclusion
Sepsis represents a severe derangement of the immune
response to infection, resulting in end-organ injury and
a profound state of immune suppression. Recruitment
of neutrophils to sites of infection, a crucial component
of the innate immune response, is substantially impaired
in sepsis. Recently explored mechanisms include
 Effects of sepsis on neutrophil chemotaxis Reddy and Standiford 23
downregulation or inhibition of cell surface GPCR and
TLRs that activate neutrophils. Factors that mediate
these deleterious responses include anti-inflammatory
cytokines, activation of the nuclear transcription factor
PPARg, and nitric oxide and its metabolites. Strategies to
interrupt dysregulated PMN migratory response in sepsis
are desperately needed.
Acknowledgements
This study is supported by National Institutes of Health grants HL093196
(R.C.R.), HL25243, and P50 HL074024 (T.J.S.). The authors would like
to thank Robin Kunkel for her assistance in preparation of the schematics
included in this review.
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been highlighted as:
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