Anda di halaman 1dari 8

See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/7400512

Serhan CN, Savill JResolution of inflammation: the beginning programs the


end. Nat Immunol 6:1191-1197

Article  in  Nature Immunology · January 2006


DOI: 10.1038/ni1276 · Source: PubMed

CITATIONS READS
1,288 846

2 authors, including:

Charles N Serhan
Brigham and Women's Hospital
722 PUBLICATIONS   59,095 CITATIONS   

SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Resolution of Lung Inflammation View project

Postoperative Pain and Neuroinflammation View project

All content following this page was uploaded by Charles N Serhan on 21 May 2014.

The user has requested enhancement of the downloaded file.


D A M P E N I N G I N F L A M M AT I O N
REVIEW
© 2005 Nature Publishing Group http://www.nature.com/natureimmunology

Resolution of inflammation: the beginning


programs the end
Charles N Serhan1 & John Savill2
Acute inflammation normally resolves by mechanisms that have remained somewhat elusive. Emerging evidence
now suggests that an active, coordinated program of resolution initiates in the first few hours after an inflammatory
response begins. After entering tissues, granulocytes promote the switch of arachidonic acid–derived prostaglandins
and leukotrienes to lipoxins, which initiate the termination sequence. Neutrophil recruitment thus ceases
and programmed death by apoptosis is engaged. These events coincide with the biosynthesis, from omega-3
polyunsaturated fatty acids, of resolvins and protectins, which critically shorten the period of neutrophil infiltration
by initiating apoptosis. Consequently, apoptotic neutrophils undergo phagocytosis by macrophages, leading to
neutrophil clearance and release of anti-inflammatory and reparative cytokines such as transforming growth factor-
β1. The anti-inflammatory program ends with the departure of macrophages through the lymphatics. Understanding
these and further details of the mechanism required for inflammation resolution may underpin the development of
drugs that can resolve inflammatory processes in directed and controlled ways.

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

NATURE IMMUNOLOGY VOLUME 6 NUMBER 12 DECEMBER 2005 1191


REVIEW

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

resolvins resolvins Neutrophil


Microbe class apoptosis
Prostaglandins
switching Lipoxins
Regulate blood flow Microbe Exudate
Change leakage permeability Macrophage
LT LXA4
Chemoattractants
peptides, and so on Pustule cAMP
PGE2
PMN activation Stops further
LX Nonphlogistic PMN recruitment
LTB4 Monocytes

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’).

1192 VOLUME 6 NUMBER 12 DECEMBER 2005 NATURE IMMUNOLOGY


REVIEW

a b
Arachidonic acid OH

C20:4 Prostaglandins Aspirin:COX-2 O(O)H


Proinflammatory mediators LOX RvE1 OH
HO
EPA HOOC
Eicosanoids Leukotrienes P450
18R-H(p)EPE COOH

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

NATURE IMMUNOLOGY VOLUME 6 NUMBER 12 DECEMBER 2005 1193


REVIEW

‘called up’ to replace losses of resident cells in


the inflammatory ‘front line’.
Does the beginning signal the end in the
cellular program of leukocyte recruitment,
Microvessel Activated Mφ death, clearance and emigration? In many
ways the answer is yes. For example, data
+
indicate that 11β-hydroxysteroid dehydro-
Resident genase 1 (ref. 47), an enzyme expressed by
cells undergo
+ apoptosis macrophages that generates cortisol from
© 2005 Nature Publishing Group http://www.nature.com/natureimmunology

the inactive precursor cortisone, is impor-


tant in resolution and repair. At inflamed
Granulocytes
undergo apoptosis sites, 11β-hydroxysteroid dehydrogenase 1
is expressed in the first few hours of the acute
Macrophage ‘reprogrammed’ inflammatory response and may help control
by ingesting apoptotic cells how active macrophages become in ingest-
ing apoptotic cells, a capacity accelerated by
Emigration Reparative Mφ stimulation by glucocorticoids and deficient
in knockout mice lacking 11β-hydroxyster-
oid dehydrogenase 1 (ref. 47). Macrophage
Lymphatic
Resident cells proliferate
clearance of apoptotic leukocytes, further-
more, can be enhanced by various early
inflammatory mediators48, which in turn
can be amplified by early interactions with
Figure 3 Regulation of macrophage activation by interaction with apoptotic cells. Activated apoptotic cells38. Such enhancement has been
macrophages (Mφ) can accelerate leukocyte apoptosis and trigger resident cell apoptosis. Subsequent formally demonstrated for early macrophage
phagocytosis of the apoptotic progeny deactivates or ‘reprograms’ the macrophage, which then receives exposure to cytokines, which increases the
signals to promote repair and/or emigrate. Adapted from ref. 76.
capacity of macrophages to ingest apoptotic
cells49,50. On the basis of such experimental
understood, they seem to be tightly linked to events induced by apop- data, therefore, it could be proposed that once apoptosis in leuko-
totic cell contact with monocytes and/or macrophages39. Phagocyte cytes and resident cells is engaged (an early event), subsequent uptake
recognition of cells dying by apoptosis involves a complex molecular of apoptic cells causes a switch in macrophage phenotype from acti-
array40,41. Apoptotic cells signal that they are ‘ready to be eaten’ by dis- vated or injurious to reparative or emigratory (Fig. 3).
play of apoptotic cell–associated molecular patterns such as exposure of
phosphatidylserine. Bridging molecules, including thrombospondin 1, Resolvins and protectins signal resolution
may enhance binding of apoptotic cells to phagocytes either directly The evidence that the beginning programs the end through both
or indirectly. Through such bridging molecules, phagocyte recep- chemical mediators and cellular programs of resolution of inflamma-
tors such as αvβ3 integrin, CD36 and phosphatidylserine receptor(s) tion strongly suggests the existence of what could be called ‘pro-reso-
engage apoptotic cells. Phosphatidylserine-recognition structures may lution signaling networks’. In the study of inflammation, the utility
also directly engage apoptotic cells, although these molecules require of dorsal air pouch model is well appreciated. In this model, sterile
further characterization42, as data43 have suggested that the molecule air is injected into the skin, creating a cavity that remains sterile until
originally identified as a phosphatidylserine receptor42 may in fact injection of proinflammatory stimuli such as tumor necrosis factor
have different functions. Thrombospondin-1, αvβ3 integrin, CD36 and and/or microbes that initiate acute inflammation and the formation
phosphatidylserine-recognition structures have been associated with of exudates that can be systematically analyzed for chemical media-
causing activation or secretion of TGF-β1 or both. But whether they tors, tissue trafficking events and resolution. Notably, in this model
serve this function in macrophage responses to apoptotic cells needs inflammation spontaneously resolves, meaning that with time the
further examination. exudate disappears. Systematic analysis of this phase using a lipidomic
The reparative properties of TGF-β1 also indicate a link between approach and liquid chromatography–tandem mass spectrometry has
mechanisms governing resolution of inflammation and engagement shown that during the time course of spontaneous resolution, new
of the ‘end game’: repair of damaged tissue. Lipoxin A4 increases the lipid mediators are generated10,11. These resolution-phase mediators
appearance of TGF-β1 in resolving exudates3. Lipoxin A4 is made use omega-3 polyunsaturated fatty acids as precursors to generate
during the resolution phase (Fig. 2) and hence it serves as a media- agonists for promoting resolution by stopping the further recruitment
tor of ‘pro-resolution’ responses. By its ability to enhance TGF-β, of leukocytes. The omega-3 polyunsaturated fatty acids eicosapen-
it is also involved in governing resolution and/or its turn to tissue taenoic acid (EPA) and docosahexaenoic acid (DHA) are indepen-
fibrosis. Phagocytosis of apoptotic cells not only inhibits activated dently converted to resolvins and protectins (Fig. 2b). These bioactive
macrophage killing of resident tissue cells44 but also triggers secretion substances regulate critical cellular events in resolution. The first of
of vascular endothelial growth factor, which is critical for repair of these are resolvins of the E series that are generated from the precur-
endothelial and epithelial injury45. Furthermore, in Drosophila mela- sor EPA10,11,51.
nogaster, apoptotic cells express the secretory factor wingless and can Omega-3 polyunsaturated fatty acids have long been known to be
directly stimulate cell proliferation46. These observations point to important in maintaining organ function and health52. Many reports
intimate linkage of mechanisms that promote tissue repair with cell have emphasized the importance of omega-3 supplementation in
death and clearance, as if just the right number of ‘reinforcements’ are correcting disease-mediated events52. Until the GISSI (Gruppo Italiano

1194 VOLUME 6 NUMBER 12 DECEMBER 2005 NATURE IMMUNOLOGY


REVIEW

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/
ated biosynthesis and their essential link to cellular trafficking51 as
well as their involvement in regulating inflammation disorders such 1. Majno, G. The Healing Hand: Man and Wound in the Ancient World (Harvard
as inflammatory bowel disease58,59. Mapping of the resolution phase University Press, Cambridge, Massachusetts, 1975).
of acute inflammatory responses seems to be organ specific as to 2. Gallin, J.I., Snyderman, R., Fearon, D.T., Haynes, B.F. & Nathan, C. Inflammation:
Basic Principles and Clinical Correlates (Lippincott Williams & Wilkins, Philadelphia,
the timing of expression and relationship between lipid mediator 1999).
classes3,7,60. 3. Bannenberg, G.L. et al. Molecular circuits of resolution: Formation and actions of

NATURE IMMUNOLOGY VOLUME 6 NUMBER 12 DECEMBER 2005 1195


REVIEW

resolvins and protectins. J. Immunol. 174, 4345–4355 (2005). cytosis of apoptotic cells is associated with reduced p130Cas expression, loss
4. Nathan, C. Points of control in inflammation. Nature 420, 846–852 (2002). of paxillin/pyk2 phosphorylation and high levels of active Rac. J. Immunol. 167,
5. Lawrence, T., Willoughby, D.A. & Gilroy, D.W. Anti-inflammatory lipid mediators 976–986 (2001).
and insights into the resolution of inflammation. Nat. Rev. Immunol. 2, 787–795 35. Voll, R.E. et al. Immunosuppressive effects of apoptotic cells. Nature 390, 350–
(2002). 351 (1997).
6. Savill, J. Apoptosis in resolution of inflammation. J. Leukoc. Biol. 61, 375–380 36. Fadok, V. et al. Macrophages that have ingested apoptotic cells in vitro inhibit
(1997). proinflammatory cytokine production through autocrine/paracrine mechanisms
7. Levy, B.D., Clish, C.B., Schmidt, B., Gronert, K. & Serhan, C.N. Lipid mediator involving TGF-β, PGE2 and PAF. J. Clin. Invest. 101, 890–898 (1998).
class switching during acute inflammation: signals in resolution. Nat. Immunol. 37. Huynh, M-L. N., Fadok, V.A., Henson, P.M. Phosphatidylserine-dependent ingestion
2, 612–619 (2001). of apoptotic cells promoted TGF-β1 secretion and the resolution of inflammation.
8. Williams, T.J. & Peck, M.J. Role of prostaglandin-mediated vasodilatation in inflam- J. Clin. Invest. 109, 41–50 (2002).
mation. Nature 270, 530–532 (1977). 38. Lucas, M., Stuart, L.M., Savill, J. & Lacy-Hulbert, A. Apoptotic cells and innate
© 2005 Nature Publishing Group http://www.nature.com/natureimmunology

9. Pouliot, M., Fiset, M.E., Masse, M., Naccache, P.H. & Borgeat, P. Adenosine up- immune stimuli combine to regulate macrophage cytokine secretion. J. Immunol.
regulates cyclooxygenase-2 in human granulocytes: impact on the balance of eico- 171, 2610–2615 (2003).
sanoid generation. J. Immunol. 169, 5279–5286 (2002). 39. Byrne, A. & Reen, D.J. Lipopolysaccharide induces rapid production of IL-10 by
10. Serhan, C.N. et al. Novel functional sets of lipid-derived mediators with anti- monocytes in the presence of apoptotic neutrophils. J. Immunol. 168, 1968–1997
inflammatory actions generated from omega-3 fatty acids via cyclooxygenase2- (2002).
nonsteroidal anti-inflammatory drugs and transcellular processing. J. Exp. Med. 40. Savill, J., Dransfield, I., Gregory, C. & Haslett, C. A blast from the past: Clearance
192, 1197–1204 (2000). of apoptotic cells regulates immune responses. Nat. Rev. Immunol. 2, 965–975
11. Serhan, C.N. et al. Resolvins: a family of bioactive products of omega-3 fatty acid (2002).
transformation circuits initiated by aspirin treatment that counter pro-inflammation 41. Lauber, K., Blumenthal, S.G., Waibel, M. & Wesselborg, S. Clearance of apoptotic
signals. J. Exp. Med. 196, 1025–1037 (2002). cells: Getting rid of the corpses. Mol. Cell 14, 277–287 (2004).
12. Gilroy, D.W. et al. Inducible cycloxygenase may have anti-inflammatory properties. 42. Fadok, V. et al. A receptor for phosphatidylserine-specific clearance of apoptotic
Nat. Med. 5, 698–701 (1999). cells. Nature 405, 85–90 (2000).
13. Hong, S., Gronert, K., Devchand, P., Moussignac, R.-L. & Serhan, C.N. Novel 43. Bose, J. et al. The phosphatidylserine receptor has essential functions during
docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine embryogenesis but not in apoptotic cell removal. J. Biol. 3, 15 (2004).
brain, human blood and glial cells: autacoids in anti-inflammation. J. Biol. Chem. 44. Duffield, J.S., Ware, C.F., Ryffel, B. & Savill, J. Suppression by apoptotic cells
278, 14677–14687 (2003). defines tumour necrosis factor-mediated induction of glomerular mesangial cell
14. Marcheselli, V.L. et al. Novel docosanoids inhibit brain ischemia-reperfusion-medi- apoptosis by activated macrophages. Am. J. Pathol. 159, 1397–1404 (2001).
ated leukocyte infiltration and pro-inflammatory gene expression. J. Biol. Chem. 45. Golpon, H.A. et al. Life after corpse engulfment: phagocytosis of apoptotic cells
278, 43807–43817 (2003). leads to VEGF secretion and cell growth. FASEB J. 18, 1716–1718 (2004).
15. Serhan, C.N. et al. Design of lipoxin A4 stable analogs that block transmigration 46. Ryoo, H.D., Gorenc, T. & Steller, H. Apoptotic cells can induce compensatory cell
and adhesion of human neutrophils. Biochemistry 34, 14609–14615 (1995). proliferation through the JNK and the wingless signaling pathways. Dev. Cell 7,
16. Chiang, N. et al. Leukotriene B4 receptor transgenic mice reveal novel protective 491–501 (2004).
roles for lipoxins and aspirin-triggered lipoxins in reperfusion. J. Clin. Invest. 104, 47. Gilmour, J.S. et al. Local amplification of glucocorticoids by 11β-hydroxysteroid
309–316 (1999). dehydrogenase type 1 promotes macrophage phagocytosis of apoptotic leukocytes.
17. Takano, T., Clish, C.B., Gronert, K., Petasis, N. & Serhan, C.N. Neutrophil-mediated J. Immunol. (in the press).
changes in vascular permeability are inhibited by topical application of aspirin- 48. Ren, Y. et al. Non-phlogistic clearance of late apoptotic neutrophils by macro-
triggered 15-epi-lipoxin A4 and novel lipoxin B4 stable analogues. J. Clin. Invest. phages: Efficient phagocytosis independent of β2 integrins. J. Immunol. 166,
101, 819–826 (1998). 4743–4750 (2001).
18. Maddox, J.F. & Serhan, C.N. Lipoxin A4 and B4 are potent stimuli for human 49. Erwig, L.P., Kluth, D.C. & Walsh, G.M. Rees, A.J. Initial cytokine exposure deter-
monocyte migration and adhesion: selective inactivation by dehydrogenation and mines function of macrophages and renders them unresponsive to other cytokines.
reduction. J. Exp. Med. 183, 137–146 (1996). J. Immunol. 161, 1983–1988 (1998).
19. Godson, C. et al. Cutting edge: Lipoxins rapidly stimulate nonphlogistic phagocy- 50. Erwig, L.P., Stewart, K. & Rees, A.J. Macrophages from inflamed but not normal
tosis of apoptotic neutrophils by monocyte-derived macrophages. J. Immunol. 164, glomeruli are unresponsive to anti-inflammatory cytokines. Am. J. Pathol. 156,
1663–1667 (2000). 295–301 (2000).
20. Colgan, S.P., Serhan, C.N., Parkos, C.A., Delp-Archer, C. & Madara, J.L. Lipoxin A4 51. Arita, M. et al. Stereochemical assignment, anti-inflammatory properties, and
modulates transmigration of human neutrophils across intestinal epithelial mono- receptor for the omega-3 lipid mediator resolvin E1. J. Exp. Med. 201, 713–722
layers. J. Clin. Invest. 92, 75–82 (1993). (2005).
21. Lawrence, T., Bebien, M., Liu, G.Y., Nizet, V. & Karin, M. IKKα limits macrophage 52. Burr, G.O. & Burr, M.M. A new deficiency disease produced by the rigid exclusion
NF-kappaB activation and contributes to the resolution of inflammation. Nature of fat from the diet. J. Biol. Chem. 82, 345–367 (1929).
434, 1138–1143 (2005). 53. GISSI-Prevenzione Investigators. Dietary supplementation with n-3 polyunsatu-
22. Savill, J. Apoptosis in post-streptococcal glomerulonephritis. Kidney Int. 60, rated fatty acids and vitamin E after myocardial infarction: results of the GISSI-
1203–1214 (2001). Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto
23. Metchnikoff, E. Lectures on the Comparative Pathology of Inflammation (Kegan, miocardico. Lancet 354, 447–455 (1999).
Paul, Trench and Trubner, London, 1893). 54. Marchioli, R. et al. Early protection against sudden death by n-3 polyunsaturated
24. Hurley, J.V. in Acute inflammation (ed. Hurley, J.V.) 109–117 (Churchill Livingstone, fatty acids after myocardial infarction: time-course analysis of the results of the
London, 1983). Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-
25. Newman, S.L., Henson, J.E. & Henson, P.M. Phagocytosis of senescent neutrophils Prevenzione. Circulation 105, 1897–1903 (2002).
by human monocyte-derived macrophages and rabbit inflammatory macrophages. 55. Gilroy, D.W. & Perretti, M. Aspirin and steroids: new mechanistic findings and
J. Exp. Med. 156, 430–442 (1982). avenues for drug discovery. Curr. Opin. Pharmacol. 5, 405–411 (2005).
26. Savill, J.S., Wyllie, A.H., Henson, J.E., Walport, M.J. & Henson, P.M. Haslett, C. 56. Maderna, P., Yona, S., Perretti, M. & Godson, C. Modulation of phagocytosis of
Macrophage phagocytosis of aging neutrophils in inflammation. Programmed cell apoptotic neutrophils by supernatant from Dexamethasone-treated macrophages
death in the neutrophil leads to its recognition by macrophages. J. Clin. Invest. 83, and annexin-dervied peptide Ac2–261. J. Immunol. 174, 3727–3733 (2005).
865–875 (1989). 57. Ward, C. et al. Prostaglandin D2 and its metabolites induce caspase-dependent
27. Bellingan, G.J. et al. In vivo fate of the inflammatory macrophage during the resolu- granulocyte apoptosis that is mediated via inhibition of IκBα degradation using a
tion of inflammation: Inflammatory macrophages do not die locally but emigrate to peroxisome proliferator-activated receptor-γ-independent mechanism. J. Immunol.
the draining lymph nodes. J. Immunol. 157, 2577–2585 (1996). 168, 6232–6243 (2002).
28. Lee, A., Whyte, M.K. & Haslett, C. Inhibition of apoptosis and prolongation of 58. Arita, M. et al. Resolvin E1, a novel endogenous lipid mediator derived from omega-
neutrophil functional longevity by inflammatory mediators. J. Leukoc. Biol. 54, 3 eicosapentaenoic acid, protects against TNBS-induced colitis. Proc. Natl. Acad.
283–288 (1993). Sci. USA 102, 7671–7676 (2005).
29. Ward, C. et al. 1999. NK-κB activation is a critical regulator of human granulocyte 59. Wallace, J.L. & Fiorucci, S. A magic bullet for mucosal protection...and aspirin is
apoptosis in vitro. J. Biol. Chem. 274, 4309 (1999). the trigger! Trends Pharmacol. Sci. 24, 323–326 (2003).
30. Jonsson, H., Allen, P. & Peng, S.L. Inflammatory arthritis requires Foxo3a to prevent 60. Fukunaga, K., Kohli, P., Bonnans, C., Fredenburgh, L.E. & Levy, B.D. Cyclooxygenase
Fas ligand-induced neutrophil apoptosis. Nat. Med. (2005). 2 plays a pivotal role in the resolution of acute lung injury. J. Immunol. 174,
31. Brown, S.B. Savill, J. Phagocytosis triggers macrophage release of Fas-ligand and 5033–5039 (2005).
induces apoptosis of bystander leukocytes. J. Immunol. 162, 480–485 (1999). 61. Gilroy, D.W., Lawrence, T., Perretti, M. & Rossi, A.G. Inflammation resolution: new
32. Meagher, L.C., Cousin, J.M. & Seckl, J.R. Haslett, C. Opposing effects of gluco- opportunities for drug discovery. Nat. Rev. Drug Discov. 3, 401–416 (2004).
corticoids on the rate of apoptosis in neutrophilic and eosinophilic granulocytes. 62. Clària, J. & Serhan, C.N. Aspirin triggers previously undescribed bioactive eico-
J. Immunol. 156, 4422 (1996). sanoids by human endothelial cell-leukocyte interactions. Proc. Natl. Acad. Sci.
33. Liu, Y. et al. Glucocorticoids promote nonphlogistic phagocytosis of apoptotic leu- USA 92, 9475–9479 (1995).
kocytes. J. Immunol. 162, 3639–3646 (1999). 63. Schottelius, A.J. et al. An aspirin-triggered lipoxin A4 stable analog displays a
34. Giles, K.M. et al. Glucocorticoid augmentation of macrophage capacity for phago- unique topical anti-inflammatory profile. J. Immunol. 169, 7063–7070 (2002).

1196 VOLUME 6 NUMBER 12 DECEMBER 2005 NATURE IMMUNOLOGY


REVIEW

64. Fiorucci, S. et al. A beta-oxidation-resistant lipoxin A4 analog treats hapten-induced phenotyope. J. Immunol. 174, 3220–3226 (2005).
colitis by attenuating inflammation and immune dysfunction. Proc. Natl. Acad. Sci. 71. Samuelsson, B., Dahlén, S.E., Lindgren, J.Å., Rouzer, C.A. & Serhan, C.N.
USA 101, 15736–15741 (2004). Leukotrienes and lipoxins: structures, biosynthesis, and biological effects. Science
65. Karp, C.L. et al. Defective lipoxin-mediated anti-inflammatory activity in the cystic 237, 1171–1176 (1987).
fibrosis airway. Nat. Immunol. 5, 388–392 (2004). 72. Funk, C.D. Prostaglandins and leukotrienes: Advances in eicosanoid biology.
66. Mitchell, S. et al. Lipoxins, aspirin-triggered epi-lipoxins, lipoxin stable analogues, Science 294, 1871–1875 (2001).
and the resolution of inflammation: stimulation of macrophage phagocytosis of 73. Capdevila, J.H., Falck, J.R., Dishman, E. & Karara, A. in Arachidonate Related
apoptotic neutrophils in vivo. J. Am. Soc. Nephrol. 13, 2497–2507 (2002). Lipid Mediators (eds. Murphy, R.C. & Fitzpatrick, F.A.) 385–394 (Academic, San
67. Taylor, P.R. et al. A hierarchical role for classical pathway complement proteins in Diego, 1990).
the clearance of apoptotic cells in vivo. J. Exp. Med. 192, 359–366 (2000). 74. Node, K. et al. Anti-inflammatory properties of cytochrome P450 epoxygenase-
68. Hanayama, R. et al. Autoimmune disease and impaired uptake of apoptotic cells derived eicosanoids. Science 285, 1276–1279 (1999).
in MFG-E8-deficient mice. Science 304, 1147–1150 (2004). 75. Mukherjee, P.K., Marcheselli, V.L., Serhan, C.N. & Bazan, N.G. Neuroprotectin D1: a
© 2005 Nature Publishing Group http://www.nature.com/natureimmunology

69. Devitt, A. et al. Persistence of apoptotic cells without autimmune disease or inflam- docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial
mation in CD14−/− mice. J. Cell Biol. 167, 1161–1170 (2004). cells from oxidative stress. Proc. Natl. Acad. Sci. USA 101, 8491–8496 (2004).
70. Stuart, L.M., Takahashi, K., Shi, L., Savill, J. & Ezekowitz, R.A.B. Mannose-binding 76. Hughes, J.A. & Savill, J. Apoptosis in glomerulonephritis. Cur. Opn. Neph. & Hyper.
lectin-deficient mice display defective apoptotic cell clearance but no autoimmune 14, 389–395 (2005).

NATURE IMMUNOLOGY VOLUME 6 NUMBER 12 DECEMBER 2005 1197

View publication stats

Anda mungkin juga menyukai