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In 1794, Scottish surgeon John Hunter wrote that “Inflammation in maximum neutrophil infiltration occurs 12 hours after intraperitoneal
itself is not to be considered as a disease but as a salutary operation injection of the stimulus. The rapidity of resolution and the likelihood
consequent to some violence or some disease1.” That crucial insight that it is actively directed are emphasized by the finding that neutrophil
emphasizes that the usual outcome of the acute inflammatory program numbers decrease to 50% of the maximum with a time interval of only 8
is successful resolution and repair of tissue damage, rather than per- hours3. We argue here that events occurring early in acute inflammation
sistence of the inflammatory response, which can lead to scarring and engage an active and coordinated ‘resolution program’ involving a switch
loss of organ function. Acute inflammation is often characterized by to local production of specialized intercellular messengers, programmed
the rapid influx of blood granulocytes, typically neutrophils, followed leukocyte death by apoptosis and subsequent clearance of dying cells
swiftly by monocytes that mature into inflammatory macrophages that by phagocytes that then leave the inflamed site through lymphatics4–6.
subsequently proliferate and thereby affect the functions of resident The potential therapeutic implications of this picture of inflammation
tissue macrophages. Resolution of inflammation can occur if granulo- resolution are obvious and represent a central theme of the remainder
cytes are eliminated and the tissue mononuclear cell population (macro- of this review.
phages and lymphocytes) returns to normal preinflammation numbers
and phenotypes2. Switching eicosanoids to resolve: ‘alpha’ programs ‘omega’
As a means of more firmly defining mechanisms that regulate inflam- An informatics-based approach to systematic studies of lipid mediators
mation resolution, a series of ‘resolution indices’ have been proposed3. in the course of acute inflammatory responses has demonstrated that
These indices include the time interval between the time at which neu- prostaglandins such as prostaglandin E2 (ref. 7) are generated during
trophil infiltration is at its maximum and the time corresponding to a the initial phase of inflammation resolution. These proinflammatory
decrease in neutrophil numbers to 50% of the maximum. For example, prostaglandins are essential for the control of blood flow and vessel dila-
in self-limited experimental mouse peritonitis induced by zymosan, tion needed for leukocytes to undergo firm adhesion and diapedesis8.
Essential trafficking of lymphocytes from the post-capillary lumen to
1Center for Experimental Therapeutics and Reperfusion Injury, Department
the interstitial space is a process that is mediated in part by leukotriene
of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women’s
B4 (ref. 9). Also ‘programmed’ in this initial phase is the activation of
Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. signaling pathways for the normal self-limiting or termination at local
2Medical Research Council Centre for Inflammation Research, University of
contained sites of inflammation7,10,11. Signaling pathways12 leading to
Edinburgh, The Queen’s Medical Research Institute, Edinburgh EH16 4TJ, UK.
prostaglandins E2 and D2 in turn actively switch on the transcription
Correspondence should be addressed to C.N.S. (cnserhan@zeus.bwh.harvard.edu).
of enzymes required for the generation of other classes of eicosanoids
Published online 17 November 2005; doi:10.1038/ni1276 also generated from arachidonic acid, such as lipoxins7, as well as newly
Tissue injury
Microbial invaders Cells
Fluid
Host defense
Surgical trauma
Resolution
Cyclooxygenases Eicosanoids
1&2 be Neutrophil
COX-2 PGE2
cro
Mi 15-LO
Apoptosis
Lipid mediator E series D series
© 2005 Nature Publishing Group http://www.nature.com/natureimmunology
LTB4 amplifiies
recruitment signal ‘Catabasis’
Return to
LTB4 tissue homeostasis
Post-capillar venule
Lipoxin A4 STOP
Lipoxin B4
LTB4
Platelet
Vessel lumen Leukocyte
Time
Figure 1 Temporal events and programming in resolution of acute inflammation: the function of lipid-derived mediators. ‘Triggers’ such as microbial invaders,
tissue injury and surgical trauma activate the release and formation of arachidonate-derived prostaglandins, which regulate early events in the inflammatory
response. Initial chemoattractants recruit polymorphonuclear (PMN) cells that move by diapedesis from post-capillary venules, an event that is amplified by
production of the 5-lipoxygenase pathway product leukotriene B4 (LTB4), a potent chemoattractant. During the progression of inflammatory events, platelet-
leukocyte interactions elicit the formation of lipoxins A4 and B4, which serve as ‘stop signals’ by blocking the further recruitment of polymorphonuclear cells
from the post-capillary venules. This strategic location limits the number of neutrophils required for combating microbes and/or cleaning up tissue debris. At
contained sites of inflammation, as exudates form and pustules are walled off, prostaglandins initiate many responses relevant in inflammatory events, but
most notably they signal the end by activating the transcriptional regulation of 15-lipoxygenase (15-LO) in neutrophils, which in turn leads to the temporal
dissociation and production of lipoxins from arachidonic acid, which have ‘pro-resolving’ and anti-inflammatory functions. This is referred to as class
switching of the arachidonic acid–derived eicosanoids from prostaglandins and leukotrienes to lipoxins that initiate the termination sequence. This stop in
further neutrophil entry into the exudate is also temporally associated with a switch of the families of lipid mediators generated from eicosanoids to resolvins
of the E and D series as well as protectins (Fig. 2). Clock dials indicate set points for individual neutrophils as new neutrophils ‘parachute’ into exudates.
COX-2, cyclooxygenase 2; PGE2, prostaglandin E2; LT, leukotriene; LX, lipoxin.
identified families of lipid mediators generated from omega-3 poly- exudates are not synchronized and therefore each can generate dif-
unsaturated fatty acid called resolvins (resolution-phase interaction ferent mediators at different time intervals. The mediators depend in
products) and protectins10,11,13,14, which can dominate the resolution part on the cells they come in contact with in their immediate environ-
phase (Figs. 1 and 2). ment. Once a neutrophil enters an exudate, it can, by receiving signals
The lipoxins are now appreciated for their ability to promote reso- from interactions with cells (such as other leukocytes, blood-borne
lution actively by retarding the entry of new neutrophils to sites of cell types, platelets, endothelia, mucosal epithelia20 and/or intersti-
inflammation15 and reperfusion injury16. They also reduce vascular tial cells, fibroblasts) in its immediate vicinity, carry out transcellular
permeability17, promote the nonphlogistic infiltration of monocytes biosynthesis, which generates products that neither cell type could
that seems to be required for wound healing18 and stimulate macro- make in substantial amounts alone. Polymorphonuclear cells take an
phages to ingest and clear apoptotic neutrophils19 (Fig. 1 and discussed intermediate as cell type A, transform it in cell type B and make a
below). The temporal ‘switch’ in lipid mediator class in the family of new product, thereby switching lipid mediator production from leu-
eicosanoids from pro- to anti-inflammatory eicosanoids (Fig. 2) is kotrienes to lipoxins, for example. The initiation of this termination
an active process that emphasizes the ability of leukocytes themselves sequence of events in the phagocyte seems to be a signaling circuit
to trigger a self-limiting response to acute inflammation7. The lipid comprising both extracellular chemical mediators3 and intracellular
mediator ‘switch’ also seems to be linked to a change in the phenotype signals that lead to activation of the stereotypical proinflammatory
and internal cellular ‘clock’ of individual neutrophils at the site of transcription factor NF-κB21. Hence, the beginning (‘alpha’) programs
inflammation, such as in pustules (Fig. 1). Neutrophils in pustules or the end (‘omega’).
a b
Arachidonic acid OH
Microbial
EETs
NPD1
P450
Anti-Inflammatory
Anti-inflammatory
Anti-Inflammatory
Lipoxins
Pro-resolution
Proresolution
Pro-resolution Protectins
OH COOH
Protectins
Eicosapentanoic acid Neuroprotectins COOH
Neuroprotectins OH
HO
C20:5
© 2005 Nature Publishing Group http://www.nature.com/natureimmunology
OH
OH
Resolvins HO RvD1
OH
E series COOH Epoxidation
OH COOH
RvD1 COOH OH
HO 17R-resolvin D series
RvE1 Acetylated COX-2 RvD2
OH OH
HO
Docosahexanoic acid Aspirin:COX-2 LOX
Resolvins OH
COOH
C22:6
D series OH DHA HOOC RvD3 OH
LOX O(O)H HO HOOC
17-H(p)DHA
Docosanoids OH
Nonenzymatic Protectins OH
RvD4 OH OH
COOH 17S-resolvin
oxidation 17S-ResolvinDDseries
series
Neuroprotectin D1 NPD1 Lipoxygenase
Lipoxygenase mechanism
mechanism
Neuroprostanes OH
Figure 2 Function of essential polyunsaturated fatty acids in the production of families of bioactive lipid mediators. (a) Arachidonic acid is the
precursor of eicosanoids, which have distinct functions as proinflammatory mediators. A series of prostaglandins and leukotrienes has specific actions
pivotal to the progression of inflammation71,72. Arachidonic acid–derived epoxyeicosatetraenoic acid (EET) generated by cytochrome P450 enzymes
may also be important here73,74. Through cell-cell interactions, exemplified by platelet leukocytes in the vasculature and/or polymorphonuclear cell–
mucosa interactions, lipoxins are generated that serve as ‘stop signals’ and promote resolution and serve as endogenous anti-inflammatory mediators
self-limiting the course of inflammation. The essential omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid (C20:5 and C22:6) are
converted to new families of lipid mediators that are pivotal in promoting resolution (as in b). Resolvins of the E series such as RvE1 are generated
from eicosapentaenoic acid, and resolvins of the D series such as RvD1 as well as the protectins such as neuroprotectin D1 (NPD1) are generated
from DHA, for which neural systems are enriched10,11,13,14,75. (b) Aspirin affects the formation of resolvin E1 by acetylating cyclooxygenase 2 in
vascular endothelial cells that, in a ‘stereoselective’ way, can generate 18R-H(p)EPE (hydroperoxyeicosapentaenoic acid) that is picked up through
transcellular metabolism by leukocytes and converted by a lipoxygenase-like mechanism to resolvin E1. The complete stereochemistries of resolvin
E1 and one of its receptors have been identified51. Notably, biosynthesis of resolvin E1 can also be initiated by P450-like enzymes in microbes10.
Aspirin also affects the formation of D-series resolvins and catalytically switches cyclooxygenase 2 to a 17R-lipoxygenase-like mechanism that serves
to generate 17R-series resolvin D11. Aspirin also affects the formation of protectins and neuroprotectins by a similar mechanism and generates
compounds carrying the 17R epimer at the alcohol at carbon 17 in neuroprotectin D1 and other protectins. LOX, lipoxygenase; H(p)DHA, hydroperoxy-
docosahexaenoic acid.
The cellular program in resolution the process of egress from the inflamed local tissue site to the nearest
Neutrophils are present mainly in injured, inflamed tissues from opening to the draining lymphatics22, the usual fate of inflammatory
which their effective elimination is a prerequisite for resolution of macrophages27.
the inflammatory response6. The cellular mechanisms involved in This multicellular ‘waste elimination program’ offers key thera-
this process seem likely to mediate clearance of other inflammatory peutic targets. For example, constitutive neutrophil apoptosis, nor-
cells as well, such as certain lymphocytes, macrophages and excess mally relatively rapid, can be slowed by a wide range of inflammatory
resident tissue cells that have been driven to proliferate in response mediators28, which in turn may engage activation of NF-κB29 and
to the inflammation repair response22. In the late nineteenth century, other ‘prosurvival’ transcription factors such as Foxo3a30. These pro-
it was discovered that intact extravasated neutrophils can be cleared survival and activation factors would wreak havoc if left unregulated.
from peripheral tissues by being ‘ingested’ (phagocytosis) by other Hence, mechanisms must exist that can override such survival signals.
inflammation-associated cells (the macrophages, or ‘big eaters’, of the One possible mediator of such signals may be the macrophage, whose
inflammatory response)23. Nevertheless, for many years it was assumed arrival on the inflammatory scene can cause the release of ‘death cyto-
that neutrophils entering inflamed sites underwent eventual ‘disinte- kines’ such as Fas ligand, which can trigger apoptosis in neighboring
gration’ or necrosis24. It was later discovered, however, that isolated neutrophils31. Another very different kind of mediator of leukocyte
neutrophil cultures that have been ‘aged’ overnight in the laboratory apoptosis and phagocytic clearance is the class of anti-inflammatory
become susceptible to phagocytosis by macrophages25. By 1989, it was drugs, such as glucocorticoids, that are effective in inducing eosinophil
understood that the events reported earlier24,25 were actually explained apoptosis32 while also promoting apoptosis of dying leukocytes by
by neutrophils’ spontaneously undergoing a physiological process of maturing monocytes33,34.
programed death called ‘apoptosis’26. It is apoptosis of neutrophils, Alternatively, uptake of apoptotic cells may also stimulate mac-
in fact, that causes specific recognition and clearance by inflamma- rophages to release mediators that suppress the inflammatory
tory macrophages, an essential step in inflammation reduction that is response35,36. In particular, strong in vitro and in vivo evidence37,38
found in a wide range of inflammatory sites6,22. In addition to clear- points to macrophage secretion of the anti-inflammatory cytokine
ing dead neutrophils, the process of phagocytosis could serve a dual transforming growth factor-β1 (TGF-β1), which can suppress proin-
purpose by initiating a key signal to the inflammatory macrophage flammatory signaling from Toll-like receptors. Although the molec-
(and perhaps the closely related phagocytic dendritic cell) to begin ular mechanisms involved in TGF-β1 suppression remain poorly
per lo Studio della Sopravvivenza nell’Infarto miocardico) studies53,54, Prospects for pro-resolution therapies
the possible effect of polyunsaturated fatty acids on the resolution of Well established and commonly used drugs affect the resolution of
inflammation was much debated. The main mechanism of action for inflammation12,61. Aspirin, which is well appreciated for its ability to
polyunsaturated fatty acids was thought to be by blockade, through inhibit the biosynthesis of lipid mediators such as prostaglandins55,
substrate competition, of the formation of proinflammatory media- actually triggers the generation of epimeric forms of arachidonic
tors. In fact, during the course of inflammation and its active resolu- acid62, EPA and DHA-derived mediators10,11,13 that are themselves
tion, omega-3 polyunsaturated fatty acids are used to generate new anti-inflammatory and ‘pro-resolving’. For example, the epimeric
lipid mediators that inhibit inflammation10,11. A systematic analysis forms of lipoxins or the aspirin-triggered 15-epi-lipoxins have shared
for defining the indices of resolution using an approach combining actions in vitro and in vivo15–19, including disease models63–65, as is
© 2005 Nature Publishing Group http://www.nature.com/natureimmunology
trafficking proteomic and lipid mediator informatics–mass spectrom- the case with EPA-derived resolvins and DHA-derived resolvins of the
etry has shown that representatives of each family of lipid mediators D series (17R resolvins and/or protectins, as well as neuroprotec-
(lipoxin A4, resolvin E1 and neuroprotectin D1; Fig. 2a) act at different tins)13,66. In the presence of aspirin, acetylation of cyclooxygenase 2
steps in defined resolution indices. Each of the lipid mediators defined leads to the generation of 17R-hydroperoxy precursors that are trans-
is anti-inflammatory when given in vivo but, more notably, each can formed to epimeric forms of these compounds. They have essentially
promote resolution by shortening resolution indices such as the time similar biological actions, but when generated in the presence of aspi-
interval between maximum neutrophil infiltration and the drop to rin they carry an alcohol group: the 17R configuration, rather than
half-maximum neutrophil infiltration and thus increase the rate of the 17S configuration. Hence, they are considered aspirin-triggered
return of involved tissue to homeostasis (a series of events also called lipid mediators. There is also evidence that glucocorticoids enhance
‘catabasis’)3. the uptake of apoptotic neutrophils33. The active process of ‘catabasis’
Resolution of acute inflammation specifically involves mobilization seems to be ‘programmed’ at the level of lipid mediators and pro-
of different fatty acid precursors that appear in exudates (arachidonic tein mediators3 in both intracellular and extracellular events that are
acids, EPA and DHA) in a temporally orchestrated way (Fig. 1). Each involved in dampening inflammation and promoting its resolution.
precursor in turn is transformed through enzymatic mechanisms to ‘Catabasis’ is the return from the disease state (in this context) and the
separate families of bioactive compounds that serve as local chemi- march toward homeostasis. Active events, rather than passive events (as
cal mediators. Production of these bioactive compounds has notable previously thought), govern this process at the cellular and tissue level
implications regarding the ‘programming and circuitry’ of lipid to generate specific mediators that can dampen the magnitude of the
mediators in resolution; for example, regulation of the duration and leukocytic infiltrate during inflammation and expedite its resolution
magnitude of inflammation (discussed below). This model suggests and return to tissue homeostatis.
that deficiencies in polyunsaturated fatty acid substrates, as might
occur with certain diets or with supplementation deficient in EPA Conclusions
or DHA, might lead to ineffective resolution of inflammation. That The resolution of inflammation can now be regarded as an integral
possibility is being tested in a laboratory setting. At least one sup- component of the program of acute inflammation. The numerous
porting model, mouse peritonitis, has demonstrated that a program and variable processes of inflammation resolution are governed by
of events leading to inflammation resolution, involving cellular traf- interacting programs of chemical mediators and, in cases in which
ficking and clearance of apoptotic cells, is regulated in an active way leukocyte apoptosis is present, by clearance of dead cells by phago-
by both lipid-derived mediators3 as well as protein-derived mediators, cytes. Although much new information has been obtained over the
such as annexins55. past few years, many issues still require detailed characterization,
The potential links between pro-resolution mediators and the including why defective macrophage clearance of apoptotic cells
cellular programs of resolution need to be characterized further. may sometimes be associated with inflammatory disease67,68 while
Lipoxin A4 and annexin 1, for example, share the ability to regulate at other times it is not69,70. New therapeutic targets are being investi-
uptake of apoptotic neutrophils by macrophages19,56. Furthermore, gated, and potential pro-resolution properties of existing drugs have
prostaglandin D2 and its metabolites not only promote lipoxin for- been identified. These discoveries may bring profound advances in
mation but also over-ride granulocyte survival signals, which lead therapies aimed at reducing inflammation and may represent the
to inhibition of degradation of the inhibitor of NF-κB IκBα and beginning of the end for disease processes characterized by persistent
triggering of caspase-dependent granulocyte apoptosis57. Indeed, inflammation.
links between lipid mediators and leukocyte clearance by apopto-
ACKNOWLEDGMENTS
sis have been emphasized by results indicating that release from
We thank M.H. Small, C. Gilchrist and C. Law for assistance in manuscript
apoptotic cells of lysophosphatidylcholine can specifically sum- preparation, and K. Gotlinger for assistance with the illustrations. Supported by
mon phagocytes to sites of resolution41. A priority for future work the National Institutes of Health (P50-DE016191 and GM38765 to C.N.S.), the
will therefore be to define cellular mechanisms by which resolvins Wellcome Trust (064487 to J.S.) and the Medical Research Council (J.S.).
and protectins shorten the period of neutrophil infiltration 3 in
COMPETING INTERESTS STATEMENT
self-limited inflammation. The identification of the resolvin E1 The authors declare that they have no competing financial interests.
receptor and its presence on leukocytes and dendritic cells and
the importance of these cells in inflammatory responses empha- Published online at http://www.nature.com/natureimmunology/
size the communication between early initial events in lipid-medi- Reprints and permissions information is available online at http://npg.nature.com/
reprintsandpermissions/
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