ATVB in Focus
Series Editor: Alain Tedgui
Mechanisms of Resolution of Inflammation
A Focus on Cardiovascular Disease
Benjamin H. Maskrey, Ian L. Megson, Phillip D. Whitfield, Adriano G. Rossi
Abstract—The inflammatory response is an integral part of the innate immune mechanism that is triggered in response to
a real or perceived threat to tissue homeostasis, with a primary aim of neutralizing infectious agents and initiating repair
to damaged tissue. By design, inflammation is a finite process that resolves as soon as the threat of infection abates and
sufficient repair to the tissue is complete. Resolution of inflammation involves apoptosis and subsequent clearance of
activated inflammatory cells – a tightly regulated event. Chronic inflammation is a characteristic feature in virtually all
inflammatory diseases, including atherosclerosis, and it is becoming increasingly clear that derangement of the
processes usually involved in resolution of inflammation is an underlying feature of chronic inflammatory conditions.
This review will draw on evidence from a range of diseases in which dysregulated inflammation is important, with
particular emphasis on cardiovascular disease. (Arterioscler Thromb Vasc Biol. 2011;31:1001-1006.)
Key Words: atherosclerosis ? eicosanoids ? lipids ? NO ? resolution of inflammation
perceived threat to tissue homeostasis.1The acute inflamma-
tory process is characterized by rapid recruitment of granu-
locytes (ie, neutrophils, eosinophils, and basophils) to the
inflammatory site; the relative contribution of these cell types
is dependent on the location of the inflammatory site in
question. The migration of granulocytes to inflammatory loci
is a necessary requirement for the neutralization and removal
of deleterious agents; these cells play a key role in the defense
against bacterial, fungal, and viral infections and in resistance
to parasitic invasion and the allergic response. Resolution of
inflammation is perceived to occur by elimination of granu-
locytes and the eventual return of tissue mononuclear cell
(macrophage and lymphocyte) numbers to basal levels.2For
effective resolution to occur, cessation of proinflammatory
signaling is a prerequisite that pre-empts removal of infiltrat-
ing granulocytes. During spontaneous resolution, neutrophils
undergo apoptosis, a highly regulated cell death mechanism
that prevents the release of histotoxic cellular contents.3
Alterations in neutrophil cell surface markers and morpho-
logical changes during apoptosis correlate with increased
recognition by professional phagocytes, such as macro-
phages, that mediate effective clearance of dying cells.3,4It is
accepted that the resolution process is active, rather than
passive, and is controlled by a range of tightly regulated
biochemical and cellular mechanisms.2The acute inflamma-
tory response is self-limiting and normally results in tissue
nflammation is a primary component of the immune
system that is triggered by any stimulus that poses a real or
restoration and the return of tissue homeostasis. Persistent
inflammatory stimuli or dysregulation of mechanisms of the
resolution phase results in chronic inflammation,2recognized
to be a key underlying factor in the progression of a range of
diseases, including atherosclerosis,5,6arthritis,7and chronic
neurodegenerative diseases, such as Alzheimer’s disease.8
Atherogenesis is widely recognized to be an inflammatory
process in the vascular wall, with early atherogenic events
characterized by lipoprotein accumulation, leukocyte recruit-
ment (especially monocytes and macrophages), and expres-
sion of proinflammatory cytokines, such as interleukin
(IL)-1? and tumor necrosis factor (TNF) ?.5,9Recent stud-
ies10–12examining the mechanism of resolution in the context
of atherosclerosis indicate that failure of resolution mecha-
nisms may underlie the inflammatory processes involved.
Atherosclerosis constitutes the underlying pathological fea-
tures associated with many cardiovascular diseases, including
coronary artery disease, myocardial infarction, stroke, and
ischemic gangrene.9Evidence is accumulating that, as well as
being involved in the formation of atherosclerotic plaques,
intensified inflammation can promote plaque rupture, with
the resulting ischemic consequences.9,12Therefore, because
of the dysregulated inflammatory nature of atherosclerosis, an
understanding of the mechanisms involved in the resolution
of inflammation may reveal novel therapeutic targets with
important clinical applications. In addition, it may lead to the
identification of clinically relevant biomarkers of an aberrant
resolution process, in a similar vein to the use of C-reactive
Received on: November 18, 2010; final version accepted on: December 16, 2010.
From the Lipidomic Research Facility (B.H.M., and P.D.W.) and Free Radical Research Facility (I.L.M.), Highland Diabetes Institute, Centre for
Health Science, Inverness, Scotland; and MRC Centre for Inflammation Research (A.G.R.), Queen’s Medical Research Institute, University of Edinburgh
Medical School, Edinburgh, Scotland.
Correspondence to Benjamin H. Maskrey, PhD, Lipidomic Research Facility, UHI Department of Diabetes and Cardiovascular Science, Highland
Diabetes Institute, Centre for Health Science, Old Perth Road, Inverness IV2 3JH, Scotland. E-mail Ben.Maskrey@uhi.ac.uk
© 2011 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.orgDOI: 10.1161/ATVBAHA.110.213850
protein for the detection of cardiovascular disease.13This
review will discuss a range of mechanisms involved in the
resolution of inflammation, with particular emphasis on
atherosclerosis and cardiovascular diseases. The following
list of mechanisms is by no means exhaustive; instead, we
focused on a few topics undergoing research that we believe
merit further investigation.
Granulocyte Apoptosis: Inhibition of
Apoptosis of inflammatory cells is a non-inflammatory mech-
anism of cell removal and plays a critical role in successful
resolution of the inflammatory response. Recent studies14
have highlighted the importance of cyclin-dependent kinase
(CDK) inhibitor drugs, such as R-roscovitine, as potential
therapeutic agents with anti-inflammatory properties that
promote resolution. The CDKs are traditionally viewed as
cell cycle regulators and are differentially activated during
the progression of the cell cycle.15Given that neutrophils are
terminally differentiated cells, inhibition of CDKs might be
expected to have little impact in these cells. However, in
addition to expressing functional CDKs, a range of pharma-
cological CDK inhibitor drugs promotes caspase-dependent
neutrophil apoptosis (Figure 1).16Furthermore, R-roscovitine
overrides powerful TNF-? and lipopolysaccharide-induced
prosurvival signals to promote neutrophil apoptosis.17CDK
inhibitor drug–induced apoptosis is triggered by downregu-
lation of transcription of the prosurvival protein myeloid cell
leukemia-1, with no effects observed on early parameters of
neutrophil nuclear factor ?B activation. Studies16using in
vivo mouse models of the resolution phase of inflammation
have highlighted the therapeutic potential of these com-
pounds through dramatic enhancement of the resolution of
inflammation. In a resolving model of carrageenan-induced
pleural inflammation, intraperitoneal administration of
R-roscovitine enhanced the resolution of the established
inflammation. Total inflammatory cell numbers were signif-
icantly decreased, with a dose of 100 mg/kg reducing inflam-
matory cell levels to near baseline at 24 hours after treatment.
The powerful pro-resolution properties of R-roscovitine have
been demonstrated in bleomycin-induced lung injury and in a
model of passively induced arthritis; in these models, treat-
ment administered after the inflammatory response was
established resulted in successful reduction of inflammation
and promotion of resolution, further highlighting the potential
of R-roscovitine as a novel therapeutic agent in this field. In
addition, R-roscovitine promoted human eosinophil apoptosis
by loss of mitochondrial membrane potential and downregu-
lation of Mcl-1.18This ability of CDK inhibitors to promote
eosinophil apoptosis, in addition to neutrophil apoptosis, has
therapeutic potential for the resolution of eosinophilic-driven
allergic diseases, such as asthma and eczema. However, the
profound pro-resolution effects of CDK inhibitor drugs in
acute inflammation models require further investigation in
more chronic inflammation models, especially in cardiovas-
cular disease models.
NO Signaling in the Resolution
The inorganic free radical, NO, is a key mediator in a wide
range of biological processes, including regulation of inflam-
mation. During the inflammatory response, activated inflam-
matory cells generate reactive oxygen and nitrogen species,
including NO; of particular interest in the context of this
review is the ability of NO to regulate apoptosis of a range of
cells, including the inflammatory cells themselves.19Depend-
ing on local concentrations and the cell type, NO can
demonstrate both pro-apoptotic and anti-apoptotic properties
(Figure 1). For example, in murine peritoneal macrophages,
high concentrations of NO generated from L-arginine by NO
synthase (NOS) induce apoptosis.20Conversely, pre-
treatment with low concentrations of NO protects a murine
macrophage cell line (RAW 264) from cytotoxic concentra-
tions of NO.21Given the pro-apoptotic potential of NO, its
presence might be of particular relevance during the resolu-
tion phase of inflammation. In the presence of NOS inhibi-
tors, activated murine macrophages display a reduced ability
to induce mesangial cell apoptosis.22Treatment with the NOS
inhibitor, N?-nitro-L-arginine methyl ester, reduces protein
A–induced apoptosis of tumor cells, further supporting a role
Figure 1. The impact of NO and CDKi in the apoptotic signaling
pathway. Bcl indicates B-cell lymphoma; Bim, Bcl2-interacting
mediator of cell death; Mcl, myeloid cell leukemia; MPO, myeloper-
oxidase; NF, nuclear factor; O2
oxynitrite; PD, protectins; RSNO, S-nitrosothiol; Rv, resolvins.
•?, superoxide anion; ONOO, per-
1002Arterioscler Thromb Vasc Biol
for NO in apoptosis regulation and promotion of the resolu-
tion phase of inflammation.23In atherosclerosis, recruitment
of inflammatory cells is a major contributing factor to plaque
formation. Because of its proapoptotic properties, NO has the
potential to promote the resolution of inflammation during
the atherosclerotic process and might, therefore, be a prom-
ising target for therapeutic manipulation.24,25Hypercholester-
olemic rabbits treated with the NOS substrate, L-arginine,
have elevated numbers of apoptotic cells, particularly mac-
rophages, in the intimal lesions.26Furthermore, regression of
atheroma was also observed in this model, reinforcing its
potential as a therapeutic target.
In addition to the generation of NO, activated inflamma-
tory cells are likely to produce peroxynitrite, which is the
product of the rapid reaction of NO with the superoxide
anion. Like NO, peroxynitrite possesses a pro-apoptotic role
in human neutrophils and induces rapid apoptosis via activa-
tion of caspases 2 and 3.27However, apoptosis of monocyte-
derived macrophages is only induced by peroxynitrite release,
with NO proving ineffective in promoting apoptosis. The
ability of macrophages to “resist” NO-induced apoptosis
could indicate an ability of these cells to survive within the
inflammatory milieu to affect phagocytosis of apoptotic cells
and, therefore, contribute to the resolution of inflammation.
In addition to their apoptotic properties, reactive species
derived from NO that are generated under inflammatory
conditions are able to nitrate a range of molecules, including
unsaturated fatty acids.28The products of these reactions are
highly electrophilic species that are able to interact with
cysteine and histidine residues on proteins and, thus, induce
post-translational modifications and alterations in protein
activity and localization. These alterations can include induc-
tion of protein nuclear respiratory factor (Nrf2)/protein
Kelch-like ECH-associated protein (Keap1),29and peroxi-
some proliferator-activated receptor-? signaling.30,31Nitrated
fatty acids demonstrate anti-inflammatory properties and
inhibit endothelial TNF-?–induced vascular cell adhesion
molecule 1 expression and monocyte rolling and adhesion,
suggesting their role as a new class of lipid-derived anti-
inflammatory mediators.32Furthermore, subcutaneous ad-
ministration of nitro-oleic acid to apolipoprotein E–deficient
mice reduces atherosclerotic lesions and decreases infiltration
of inflammatory cells into the vessel wall.33
Bioactive Lipid Mediators in the Resolution
Lipid mediators derived from arachidonic acid (AA; 20:4,
omega-6 [?-6]) are known to regulate the inflammatory
process and generate pro-inflammatory, anti-inflammatory,
and proresolving mediators (Figure 2).34–36Indeed, synthesis
of the cyclooxygenase (COX)–generated eicosanoid, prosta-
glandin E2, regulates blood flow and vasodilatation.37How-
ever, temporal analysis of eicosanoid generation in inflam-
matory exudates reveals a switch toward a lipid profile that
actively promotes resolution after initial activity involving
the proinflammatory mediator, prostaglandin E2.38Exposure
of human peripheral blood polymorphonuclear neutrophils
(PMNs) to prostaglandin E2results in the diversion of
eicosanoid generation away from the proinflammatory 5-li-
poxygenase (LO) product, leukotriene B4, to the 15-LO
product, lipoxin A4(LXA4), which promotes resolution.
Treatment with the stable LXA4analogue, 15-epi-LXA4,
decreases PMN infiltration in the exudates. LXA4and LXB4
are generated from AA by transcellular metabolism during
inflammatory responses by sequential oxygenation from cell-
specific LO enzymes present in the inflammatory milieu.35,39
In addition, acetylation of COX-2 by aspirin modulates its
structure and shifts its enzymatic activity away from its
normal prostaglandin endoperoxide synthase activity to an
LO-like process.40This results in the generation of the LX
epimer, 15-epi-LXA4, also known as aspirin-triggered lipoxin
(ATL).40Exposure of monocyte-derived macrophages to
LXA4or its stable synthetic analogues induces rapid phago-
cytosis of apoptotic PMNs in a concentration-dependent
manner.41In a murine model of thioglycollate-induced peri-
tonitis, intraperitoneal injection of LXA4, LXB4, 15-epi-
LXB4, or the stable synthetic analogue, 15(R/S)-methyl-
LXA4, all stimulate monocyte-derived macrophage
phagocytosis of PMNs within 15 minutes in a protein kinase
C- and phosphatidylinositol 3-kinase-dependent manner, sug-
gesting a role for these lipids as rapidly acting endogenous
proresolution agents.42In healthy human patients after an
acute dermal inflammatory response created by cantharidin,
treatment with low-dose aspirin triggers ATL synthesis and
reduces PMN and macrophage accumulation.43Furthermore,
LXA4reduces microvascular permeability in inflammatory
Figure 2. Formation of bioactive lipid mediators. The precursor
?-6 fatty acid AA and the ?-3 fatty acids eicosapentaenoic acid
(EPA) and DHA can generate a range of both proinflammatory
and anti-inflammatory lipid mediators via actions of LO, COX-2,
or aspirin-acetylated COX-2 enzymes. AA forms a range of pro-
inflammatory mediators, such as the prostaglandins (PGs), via
COX-2, and the leukotrienes (LTs), via multiple LO action. An
array of anti-inflammatory and proresolving mediators, including
resolvins, protectins, and maresins, is generated from EPA and
DHA by LO. The 13-electrophilic oxo derivative (EFOX) is
formed by COX-2 action, although its anti-inflammatory proper-
ties have only been documented in vitro (distinguished from
other lipid mediators by a dashed line). In the presence of aspi-
rin, acetylated COX-2 generates an epimeric range of ATLs,
resolvins, protectins, and an alternative 17-EFOX product.
Maskrey et alResolution of Inflammation
rat mesenteric arteries, supporting its proresolution proper-
ties.44In a randomized human trial45of healthy patients who
received aspirin or placebo, platelet reactivity, as assessed by
plasma thromboxane B2levels, was inversely related to
plasma ATL concentration, which might account for the
anti-inflammatory and antineutrophil actions of aspirin. In
neutrophils, myeloperoxidase suppresses the apoptotic
process via modulation of Mac-1 signaling, thereby pro-
longing inflammation. In myeloperoxidase-treated neutro-
phils, the addition of ATL downregulated Mac-1 expression
and promoted apoptosis via decreased expression of Mcl-1
and the promotion of mitochondrial dysfunction.46Further-
more, the proresolution effects of ATL were demonstrated in
vivo in models of myeloperoxidase-sustained acute lung
injury, in which ATL administration accelerated resolution.
Recent studies47,48have identified a new family of lipid
mediators generated from the ?-3 fatty acids, eicosapenta-
enoic acid (20:5), and docosahexaenoic acid (DHA; 22:6)
(Figure 2). These mediators, including the resolvins, protec-
tins, and maresins, display potent, specialized, proresolving
properties and were identified by lipidomic analysis of
resolving self-limited inflammatory exudates.49,50Resolvins
are biosynthesized from either eicosapentaenoic acid or DHA
(designated as E or D series, respectively) and bear similarity
to lipoxins in that they can also be generated by the
“alternative” acetylated COX-2 pathway in the presence of
aspirin, thus producing “aspirin-triggered” forms.48Like the
D-series resolvins, protectins and maresins are generated
from DHA. Protectins contain a conjugated-triene structure
and possess potent anti-inflammatory properties.51Protectin
D1 inhibits TNF-?–induced leukocyte trafficking to a murine
air pouch inflammatory site51and regulates PMN infiltration
in a murine model of peritonitis.52In addition, maresin 1 is a
recently identified macrophage-derived dihydroxy lipid me-
diator that demonstrates comparable phagocytosis-enhancing
properties to both resolvin E1 and protectin D1.53The
generation of these compounds produces a range of specific
member compounds that are stereospecific in their formation
and action.49Furthermore, these compounds act as specific
receptors and demonstrate high potency. For example, resol-
vin E1 binds the G-protein couple receptor CMKLR1 (for-
merly termed ChemR23)54; and the ip administration of 300
ng resolvin E1 or protectin D1 promotes phagocyte removal
during a zymosan-induced model of peritonitis.55
In an apolipoprotein E–deficient murine model of athero-
sclerosis, macrophage-specific overexpression of 12/15-LO,
an essential enzyme in LX, resolvin, and protectin generation,
has been shown to protect against atherosclerotic lesion
development.10On further examination of the mechanism for
protection, levels of plasma cholesterol or lipoprotein were
unaltered, but expression of proinflammatory cytokines, such
as IL-17 and chemokine (C-C motif) ligand-5, were down-
regulated, indicating an inflammatory component in this
disease. LXA4, resolvin D1, and protectin D1 reduce inflam-
matory cytokine expression and elevate macrophage uptake
of apoptotic thymocytes. Furthermore, protectin D1 down-
regulates the expression of the adhesion molecules, vascular
cell adhesion molecule 1 and membrane cofactor protein-1,
which are known to regulate leukocyte recruitment during
atherogenesis. In addition, patients with symptomatic periph-
eral artery disease demonstrate reduced plasma levels of ATL
compared with healthy volunteers.11The migration of vascu-
lar smooth muscle cells is an important feature of atheroscle-
rotic lesion formation, and receptors for both ATL and
resolvin E1 (LXA4 receptor and ChemR23, respectively)
have been detected in human vascular smooth muscle cells. In
addition, treatment with ATL and resolvin E1 inhibits plate-
let-derived growth factor–stimulated chemotaxis of vascular
smooth muscle cells via decreased activation of platelet-
derived growth factor receptor-?, further implicating the
inflammatory aspect of this disease and identifying another
potential therapeutic target.
A recent study56has uncovered a novel range of bioactive
lipid mediators generated by the action of COX-2 on the ?-3
polyunsaturated fatty acids, DHA, and docosapentaenoic acid
(22:5) that possess anti-inflammatory properties in vitro. In
activated macrophages, COX-2 generates a range of electro-
philic oxo derivatives; this generation increases further after
modulation of COX-2 activity by aspirin acetylation. Because
of the highly electrophilic nature of these electrophilic oxo
derivative compounds, they readily form adducts with cys-
teine and histidine protein residues in vivo, in a similar
manner to nitrated fatty acids. Treatment of RAW 264 cells
with a range of electrophilic oxo derivative compounds
results in a concentration-dependent decrease in the expres-
sion of IL-6, membrane cofactor protein-1, IL-10, and induc-
ible NOS, nitrite, and nitrate, suggesting a broad spectrum of
anti-inflammatory effects. However, the generation and role
of these compounds in inflammatory models have yet to be
Atherosclerosis is a chronic inflammatory disease, with
dysregulation of the inflammatory process and failure of
effective resolution being features throughout its life cycle,
from initiation of lipoprotein accumulation and leukocyte
recruitment to plaque formation and rupture. Although the
formation of atherosclerotic plaques per se is not necessarily
deleterious, plaque rupture is the trigger for a range of
potentially fatal cardiovascular events. Because of the role of
continual and intense local inflammatory processes in plaque
rupture, an understanding of the mechanisms that control
inflammation and promote its successful resolution in athero-
sclerosis will have significant importance in the development
of new clinically relevant therapeutic targets, with the poten-
tial to reduce the prevalence of fatal cardiovascular events.
Recent studies that have elucidated the structure and role of
the novel proresolving ?-3–derived lipids in the resolution of
inflammation are particularly exciting and highlight a fruitful
area of research that has led to the development of novel
therapeutic agents that are undergoing clinical evaluation.
Sources of Funding
This study was supported by the European Regional Development
Fund, Highlands and Islands Enterprise, and the Scottish Funding
Council (Drs Maskrey, Megson, and Whitfield); and in part by
grant G060481 from the Medical Research Council Programme
1004Arterioscler Thromb Vasc Biol
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