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Leukotrienes: Underappreciated Mediators of Innate Immune Responses1
Marc Peters-Golden2,*,
Claudio Canetti*,
Peter Mancuso and
Michael J. Coffey*
Departments of
*
Internal Medicine (Division of Pulmonary and Critical Care Medicine) and
Environmental Health Sciences, University of Michigan, Ann Arbor, MI 48109
Leukotrienes are bronchoconstrictor and vasoactive lipid mediatorsthat are targets in the treatment of asthma. Although they areincreasingly recognized to exert broad proinflammatory effects,their role in innate immune responses is less well appreciated.These molecules are indeed synthesized by resident and recruitedleukocytes during infection. Acting via cell surface G protein-coupledreceptors and subsequent intracellular signaling events, theyenhance leukocyte accumulation, phagocyte capacity for microbialingestion and killing, and generation of other proinflammatorymediators. Interestingly, a variety of acquired states of immunodeficiency,such as HIV infection and malnutrition, are characterized bya relative deficiency of leukotriene synthesis. The data reviewedherein point to leukotrienes as underappreciated yet highlyrelevant mediators of innate immunity.
Because myeloid cells contain substantial amounts of esterifiedarachidonic acid (AA)3 and constitutively express all of theenzymes necessary to hydrolyze it and metabolize it via the5-lipoxygenase (5-LO) pathway, they are capable of generatinglarge quantities of products termed leukotrienes (LTs) withinseconds to minutes of encountering an activating stimulus. LTsare best known as bronchoconstrictor and vasoactive mediatorsreleased by Ag-triggered mast cells that contribute to asthmaticresponses (1). However, because they are produced by all myeloidcell lineages in response to a panoply of stimuli, their broaderparticipation in a wide array of pathologic inflammatory andacquired immune responses is increasingly recognized (2, 3).Much less well appreciated is their role in innate immune responses,the homeostatic function for which inflammation evolved. Asmolecules that can be generated in response to microbial stimuliand that mediate a variety of antimicrobial functions, LTs areideally suited for such a role. Moreover, a variety of conditionsassociated with increased susceptibility to infection are characterizedby a relative deficiency of LT synthesis. This article willreview the body of evidence implicating LTs as key host-derivedmediators of antimicrobial defense.
Among the family of phospholipase A2 enzymes capable of liberatingAA from membrane phospholipids, cytosolic phospholipase A2 (cPLA2)is considered the most important for providing substrate forLT biosynthesis (4). The free fatty acid is then oxygenatedat C-5 by 5-LO in concert with the AA-binding protein, 5-LO-activatingprotein (FLAP), to generate the epoxide intermediate LTA4. Ofnote, activation of both cPLA2 and 5-LO enzymes involves increasesin intracellular calcium and is further enhanced by activationof certain protein kinases (5). LTA4 is then hydrolyzed by LTA4hydrolase to LTB4 or conjugated with reduced glutathione byLTC4 synthase to form LTC4. LTB4 is best known as a leukocytechemoattractant and activator, and LTC4 is the parent compoundof the cysteinyl LTs (cysLTs), which also include LTD4 and LTE4,and which account for the myotropic activity previously identifiedas slow-reacting substance (of anaphylaxis) and are importantin the pathogenesis of asthma. Importantly, cell specificityexists in the profile of LTs generated, with mast cells andeosinophils synthesizing primarily cysLTs, neutrophils and dendriticcells synthesizing primarily LTB4, and macrophages producinga balance of both classes of LTs (see Table I).
Table I.Synthesis and Actions of LTs in Phagocytes
The biological actions of LTs are mediated via ligation of Gprotein-coupled receptors (3, 6). In brief, LTB4 and membersof the cysLT family each interact with two distinct receptors,termed BLT1/2 and cysLT1/2, respectively. Most of the recognizedactions of LTs appear to proceed through BLT1 and cysLT1. Theseare Gq- and Gi-coupled receptors that modulate downstream signalingpathways involving phospholipase C/intracellular Ca2+/proteinkinase C, adenylyl cyclase, MAPK, PI3K, Rac, and NF-B. Virtuallyall of the actions of LTs relative to antimicrobial defenseare expected to follow from such signal transduction events.Key steps in LT biosynthesis and actions are illustrated inFig. 1.
FIGURE 1. Synthesis and antimicrobial mechanisms of action of LTs. Microbes as well as opsonins IgG and C can trigger release of AA from membrane phospholipids and its metabolism to LTs. Neutrophils produce primarily LTB4 and macrophages produce both classes of LTs. The expression and catalytic activity of these biosynthetic enzymes are influenced by relevant exogenous factors, with cytokines and leptin generally augmenting (indicated by "+") and NO and PGE2 generally inhibiting (indicated by "–") LT production. By ligating BLT1/2 and cysLT1/2, LTB4 and cysLTs activate Gq and Gi proteins to generate increased intracellular Ca2+ and decreased cAMP, respectively; subsequent signal transduction events include activation of a number of downstream protein kinases. Resultant functional responses include recruitment of circulating leukocytes as well as activation of both recruited and resident leukocytes to ingest and kill microbes. Generation of cytokines serves to further amplify LT production and actions. PKC, Protein kinase C; ROIs, reactive oxygen intermediates.
Activation of LT synthesis during infection with bacteria, fungi,viruses, and protozoa has been observed in vivo in patientsand animal models and in vitro in isolated leukocytes. For example,elevated levels of LTs have been reported in lung lavage fluidof patients with bacterial (7) and respiratory syncytial viral(8) pneumonia, peripheral blood of patients infected with Vibriocholerae (9), gastric fluid of patients infected with Helicobacterpylori (10), and nasal secretions of patients with rhinovirus(11). In vitro LT generation has likewise been observed in responseto bacteria (12, 13), Mycobacterial species (14), Toxoplasmagondii (15), Pneumocystis carinii (16), Histoplasma capsulatum(17), influenza (18), and EBV (19). Although microbial activationof LT biosynthesis has been most extensively investigated inphagocytes, it has also been described in mast cells (20) andeosinophils (21).
The capacity of microbes to stimulate LT generation can bestbe understood by considering the molecules through which theyinteract with leukocytes and the effects of receptor ligationon requisite signal transduction pathways. Leukocytes interactwith microorganisms through cell surface receptors for eitheropsonin molecules or intrinsic pathogen-associated molecularpatterns (PAMPs).
The best-studied opsonins are IgG and complement. Interactionof IgG-opsonized microbes with phagocyte Fc receptors triggersAA release and LT synthesis (12, 13), and this is to be expectedin view of the well-documented capacity of Fc ligation to increaseintracellular calcium and activate a myriad of kinases (22).By contrast, ingestion of targets opsonized by complement peptidesC3b and C3bi via complement receptor (CR) 1, CR3, and CR4 failsto trigger AA release or LT synthesis, yet can enhance AA releasein response to other stimuli (23).
Ligation of pattern recognition receptors by PAMPs activatesintracellular signaling cascades that culminate in the inductionof NF-B-dependent genes and the synthesis of inflammatory mediators,such as TNF- and NO, that participate in antimicrobial defense.Zymosan, a carbohydrate component of yeast cell wall, is wellknown to trigger increases in intracellular calcium, releaseof AA, and LT biosynthesis (24, 25, 26). This substance is aligand for multiple receptors, and both the mannose receptor(27) and TLR2 (28) may mediate LT synthesis. Gram-negative LPSare important PAMPs which signal via TLR4. The effects of LPSon LT biosynthesis are complex. Because LPS/TLR4 signaling doesnot result in increases in intracellular calcium (26), it isnot sufficient to trigger LT synthesis. However, brief exposureof leukocytes to LPS can prime them for enhanced LT synthesisin response to an activating stimulus (29). Prolonged exposureof leukocytes to LPS, however, impairs their capacity for LTsynthesis in response to activating stimuli, as a consequenceof generation of inhibitory substances such as NO (30, 31, 32)(see below) and PGE2 (31).
An in vivo role for LTs in antimicrobial defense was first suggestedby Demitsu et al. (33), who showed that i.p. administrationof LTB4 facilitated resolution of experimental bacterial peritonitis.An important role for endogenous LTs in host defense was firstdemonstrated by Bailie et al. (34), who reported that 5-LO-deficientmice exhibited impaired survival and pulmonary bacterial clearancein a model of K. pneumoniae pneumonia. Subsequent studies havedocumented a protective function of endogenous LTs in animalmodels including bacterial peritonitis (20), fungal pneumonia(35), and viral CNS infection (36). The effector functions involvedin innate immune responses that are influenced by LTs includedirect effects on leukocyte accumulation as well as their capacityfor microbial phagocytosis and killing and indirect effectsmediated by elaboration of other inflammatory molecules. TableI summarizes the relevant effects of both cysLTs and LTB4 inboth macrophages and neutrophils, and antimicrobial actionsare further illustrated in Fig. 1.
Leukocyte accumulation.
LTs induce leukocyte recruitment to an inflammatory site bothby stimulating chemotaxis and by promoting firm adhesion toendothelial cells. LTB4 has long been known to induce neutrophilmigration in vivo and in vitro (37), and is now recognized toparticipate in the in vivo trafficking of CD4 and CD8 T lymphocytes(38). cysLTs participate in dendritic cell trafficking to sitesof Ag stimulation (39) as well as to lymph nodes (40). The abilityof cysLTs to promote microvascular leak (41) may contributeto neutrophil recruitment to sites of inflammation (42). Inaddition to their ability to increase leukocyte recruitment,LTs also contribute to leukocyte accumulation in tissues byenhancing their survival via inhibition of apoptosis (43, 44).
Phagocytosis.
Wirth and Kierszenbaum first noted the capacity of exogenousLTB4 (45) and LTC4 (46) to enhance macrophage phagocytosis ofT. cruzii in 1985. Increased phagocytosis of IgG-opsonized bacteriahas also been observed for macrophages in response to both classesof LTs (12), and for neutrophils in response to LTB4 (47). Animportant role for specific endogenous 5-LO products in Fc-mediatedphagocytosis was established in these studies by the use of5-LO null mice, 5-LO and FLAP inhibitors, and specific receptorantagonists (see Table I). CR-mediated phagocytosis in neutrophilswas also augmented by LTB4 (47). It seems highly likely thatthe ability of LTs to enhance phagocytosis reflects the factthat the requisite signal transduction events downstream fromopsonin or microbial recognition receptors are themselves amplifiedby ligation of the LT receptors. An alternative paradigm isexemplified by the fact that LTB4 enhanced the activation ofthe non-receptor protein tyrosine kinase Syk, a process evokedby IgG ligation of Fc and which is essential for phagocytosis,but was not capable of directly activating Syk in the absenceof Fc ligation (48).
Microbial killing.
In addition to their effects on phagocytosis, LTs have beenshown to augment killing of a variety of microorganisms, includingbacteria (33, 34), mycobacteria (14), fungi (49), and parasites(50, 51). Phagocytic cells utilize a myriad of microbicidalmechanisms to kill ingested microorganisms and many of theseare activated or amplified by LTs. Lysosomal enzyme releasewas stimulated by LTB4 (52). LTB4 also induced the release ofthe antimicrobial peptide -defensin by human neutrophils (53).Both LTB4 and cysLTs induced NO generation in human neutrophils(54, 55) and 5-LO inhibitors decreased NO formation by elicitedmacrophages (56). Finally, the rapid generation of reactiveoxygen intermediates upon assembly of the NADPH oxidase complexhas been reported to be triggered by both LTB4 (57) and cysLTs(55) in human neutrophils, as well as in alveolar macrophages(C. H. Serezani, D. M. Aronoff, S. Janear, P. Mancuso, and M.Peters-Golden, unpublished observations). Again, the intracellularsignals required for NADPH oxidase activation appear to intersectwith those generated by LT receptor ligation.
Generation of other inflammatory mediators.
In addition to their direct actions on leukocyte effector functionsdiscussed above, 5-LO metabolites also promote innate immuneresponses indirectly by stimulating the elaboration of otherinflammatory mediators, such as cytokines and chemokines, whichthemselves activate leukocyte recruitment and antimicrobialmechanisms. Examples of this phenomenon include the abilityof LTB4 to induce lung generation of TNF- (58), MCP-1 by monocytes(59), and IL-8 by neutrophils (60), and of cysLTs to stimulateproduction of IL-5, TNF- and MIP-1 by mast cells (61).
Modulation of LT synthesis by other mediators of innate immunity
LT synthetic capacity is under genetic control (62), but itis also subject to regulation by a vast array of endogenous(cytokines, hormones, small molecules, reactive species) andexogenous (toxins, pharmacologic agents, dietary factors) factors.Only a few of these with particular relevance to innate immunitywill be discussed here.
Colony-stimulating factors.
In addition to their originally recognized roles in myelopoiesis,G-CSF and GM-CSF are also recognized to up-regulate leukocytefunctional responses, such as the recruitment, survival, phagocytosis,and microbicidal activities of neutrophils, monocytes, and macrophages(63). A role in LT synthesis is demonstrated by the facts thatmacrophages from GM-CSF-deficient mice exhibit reduced LT synthesis(64), and exogenous addition of CSFs has been shown to enhancethe capacity for LT biosynthesis in vitro (65, 66) and in vivo(49, 67).
Nitric oxide.
Despite its participation in microbial killing, NO has the capacityto down-regulate inflammatory responses by reducing cytokineproduction (68) and neutrophil recruitment (69). Interestingly,NO has also been shown to reduce LT synthetic capacity in culturedalveolar macrophages (30, 70) and mast cells (32). Such an impairmentin macrophage LT synthesis in vitro and in vivo (71), attributableto LPS induction of NO generation, may contribute to the increasedsusceptibility to secondary infection (72) observed in patientswho survive an episode of sepsis.
Leptin.
Leptin is a 16-kDa protein synthesized by adipocytes that wasinitially recognized for its role in the regulation of foodintake and energy balance, but which has more recently beenrecognized to also influence inflammatory and immune processes(73). Macrophage LT synthesis was recently found to be reducedin leptin-deficient mice, and this defect was associated withimpaired innate immune responses following intrapulmonary challengewith K. pneumoniae (74); the addition of exogenous leptin invitro restored cellular LT synthetic capacity and the relevantenzymatic mechanisms have recently been identified (75).
It is increasingly apparent that a plethora of clinical circumstancesare associated with an acquired defect in LT synthesis (TableII). Many of these circumstances are exceedingly common andwell recognized. Others, such as vitamin D3 deficiency, arecommon but less well appreciated (76). Most of these impairLT biosynthesis in cells throughout the body, whereas the effectof cigarette smoking is limited to lung cells (77). Many ofthese conditions are clearly associated with increased susceptibilityto infections. Although the causal importance of a relativeLT deficiency in such susceptibility remains to be established,it is possible that defects in LT synthesis represent a commonpathway to impaired innate immunity. As examples of this phenomenon,HIV infection and malnutrition will be considered further.
Table II.Conditions associated with acquired defects in LT synthetic capacity
HIV infection.
Peripheral blood neutrophils (49, 78), monocytes (67), and alveolarmacrophages (79) from patients with HIV infection have all beenreported to manifest a profound defect in their capacity forstimulated LT generation. This defect was confined to the 5-LOpathway and was associated with reduced expression of 5-LO andFLAP. As the defect extends to neutrophils, which cannot bedirectly infected with the virus, it is likely that the dysregulationof 5-LO metabolism is the consequence of an altered milieu.Indeed, the impairments in cellular LT biosynthesis and FLAPexpression were quantitatively related to the decrement in CD4lymphocyte count (79); moreover, macrophages from CD4-depletedmice also demonstrated reduced FLAP expression and decreasedcellular LT synthesis (80). These studies suggest that optimalFLAP expression and LT synthetic capacity in myeloid cells invivo depends on mediators elaborated by CD4 cells. In vivo datain humans support a role in this regard for CSFs. When subjectswith end-stage AIDS (CD4 counts <100/cm2) were treated systemicallyfor 5 days, GM-CSF (67) and G-CSF (49) were found to augmentLT synthesis as well as 5-LO and FLAP expression in monocytesand neutrophils, respectively. In neutrophils, these effectswere paralleled by increased capacity to kill fungi. That theaugmented microbicidal activity was due to the increment inLT synthesis was indicated by the fact that it was completelyabrogated by inclusion of a LT synthesis inhibitor (49).
An early report noted that Pneumocystis pneumonia in patientswith HIV infection was associated with less lung neutrophiliathan observed in patients with this infection and other statesof immunosuppression (81), and it is possible that the bluntedneutrophil accumulation in HIV-infected individuals relatesto this alveolar macrophage defect in LTB4 biosynthesis. Indeed,subsequent studies have explicitly documented unexpectedly lowlocal levels of LTB4 in bacterial pneumonia (82) as well asfungal meningitis (83) in HIV-positive individuals. It is alsoattractive to consider that this state of LT deficiency alsocontributes to impaired microbicidal capacity in HIV infection.
Malnutrition.
Malnutrition is a vitally important cause of immunosuppressionthat affects both individuals in the developing world and thosein industrialized countries. Both macronutrient (protein) andmicronutrient (vitamin) deficiencies have been associated withimpaired innate immunity. Experimental protein-calorie malnutritionin rats resulted in impaired production of LTB4 by alveolarmacrophages (84). In studies of undernourished hospitalizedpatients, LT synthesis by granulocytes was decreased as comparedwith cells from healthy controls (85). It is established thatserum leptin levels decline rapidly during periods of caloricinsufficiency (86), and it is likely that leptin deficiencyduring malnutrition is an important cause of defective LT synthesisand its associated immunosuppression. Deficiency of vitaminD3 is known to be associated with an increased incidence ofinfections (87); of note, dietary vitamin D3 deficiency in ratsresulted in reduced LT synthetic capacity by macrophages (88),while exogenous vitamin D3 increased FLAP expression and 5-LOmetabolism (89).
We are aware of no evidence that anti-LT drugs used in the treatmentof asthma have been associated with an increased incidence ofinfections of the respiratory tract or other organs. For a varietyof reasons, however, this experience does not represent an adequatetest of the role of LTs in innate immunity in vivo. First, thegreat bulk of such patients has been treated with cysLT1 antagonists;since the antimicrobial actions of cysLTs are narrower thanthose of LTB4, this approach may underestimate the impact thatmight be observed with drugs inhibiting LTB4 synthesis or actions.Second, the incomplete abrogation of LT synthesis or actionsachieved by currently available pharmacologic agents in a patientpopulation known to be overproducing LTs would be expected torender these patients only relatively, but not absolutely, deficientin LTs. Finally, asthmatics do not have an intrinsically highsusceptibility to bacterial or fungal infection. For all ofthese reasons, substantial blockade of LTs, especially LTB4,in a patient population with a recognized predilection for suchinfections might be necessary to reveal an important role forthese molecules in innate immune responses. Future applicationof more potent LT biosynthesis inhibitors or LTB4 antagonistsin patients with disorders such as chronic obstructive lungdisease, cystic fibrosis, acute lung injury, or organ transplantationmay yet disclose such a role.
It is also of interest to ask whether commonly used medicationsmight have unintended effects on LT synthesis and, thereby,on innate immunity. Increases in intracellular levels of cAMPcan inhibit LT synthesis by a variety of enzymatic mechanisms(90), and commonly used cAMP-elevating drugs such as -adrenergicagonists, theophylline, and phosphodiesterase inhibitors havebeen reported to inhibit LT synthesis by leukocytes (91). Althoughits clinical significance is unclear, in vivo cAMP elevationhas been reported to impair pulmonary bacterial clearance inan animal model of pneumonia (92). It must be noted, however,that elevated intracellular cAMP can itself suppress antimicrobialfunctions of phagocytes (93); therefore, the contribution ofreduced LT biosynthesis in this context is uncertain. By contrast,nonsteroidal anti-inflammatory drugs are capable of increasingLT synthesis in vivo, in part by diverting AA from the inhibitedcyclooxygenase to the 5-LO pathway; interestingly, these medicationshave been associated with enhanced microbial clearance in animalmodels of infection (94), but once more the relative contributionof decreased generation of cAMP-elevating PGE2 vs increasedgeneration of 5-LO products cannot be distinguished. Finally,the antifungal agent amphotericin B has been reported to inhibitneutrophil 5-LO metabolism (95), and one wonders whether thispotentially undesirable action extends to other antimicrobials.
Lastly, in view of the fact that a relative state of LT deficiencycharacterizes many conditions associated with increased susceptibilityto infection, the possibility that stimulation of innate immunitymight be accomplished by augmenting tissue levels of LTs meritsconsideration. In fact, it can be suggested that enhancing levelsof LT biosynthesis may indirectly contribute to the immunostimulationresulting from administering cytokines such as CSFs (Ref. 96 and see above). Alternatively, tissue levels of LTs at a siteof infection might be amplified by their direct administration.In this scenario, LTB4 would be the preferred candidate forexogenous delivery because of its broader antimicrobial activityand lesser propensity for myotropic and edemagenic effects thancysLTs. LTB4 was recently administered as an i.v. bolus to normalsubjects and was shown to dose-dependently increase plasma levelsof the antibacterial peptide -defensin and the chemokine MIP-1(53). Local LTB4 administration has been shown to reduce theperitoneal burden of bacteria in an animal model of peritonitis(33), and it has also been administered to the human lung viaaerosol (97) or via a bronchoscope (98) and resulted in neutrophilinflux without evidence of lung injury or other adverse effects.As compared with administration of a protein, direct administrationof a lipid such as LTB4 has the advantages of being less immunogenic,shorter-lived, and less expensive.
A growing body of evidence reviewed herein supports the conclusionthat LTs are important participants in innate immune responses.Notable features of these mediators include their ability tobe synthesized both rapidly and in delayed fashion by a varietyof cell types, their diverse antimicrobial actions, and theirnetwork of interactions with many other relevant mediators.As compared with cytokines and chemokines, however, their rolein antimicrobial defense has been largely overlooked. This likelyreflects the commonly held but narrow view that lipid mediatorsare exclusively pathogenic and the corresponding ethos mandatingtheir pharmacologic blockade that has dominated the pharmaceuticalindustry. A more enlightened contemporary perspective is neededto recognize the potential homeostatic functions of selectedlipids, such as LTB4 in innate immunity, and to seek to exploitthese for therapeutic gain.
Acknowledgments
We thank David Aronoff for critical review of this manuscript.
Footnotes
The costs of publication of this article were defrayed in partby the payment of page charges. This article must thereforebe hereby marked advertisement in accordance with 18 U.S.C.Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health GrantHL58897 and Conselho Nacional de Pesquisa-Brazil.
2 Address correspondence and reprint requests to Dr. Marc Peters-Golden,Department of Internal Medicine, Division of Pulmonary and CriticalCare Medicine, 6301 MSRB III, 1150 West Medical Center Drive,Ann Arbor, MI 48109-0642. E-mail address: petersm{at}umich.edu
3 Abbreviations used in this paper: AA, arachidonic acid; LO,lipoxygenase; LT, leukotriene; cPLA2, cytosolic phospholipaseA2; FLAP, 5-LO-activating protein; cysLT, cysteinyl LT; BLT,B leukotriene; PAMP, pathogen-associated molecular pattern;CR, complement receptor.
Received for publication September 20, 2004.
Accepted for publication October 18, 2004.
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Top
Abstract
Introduction
B. Virtually all of the actions of LTs relative to antimicrobial defense are expected to follow from such signal transduction events. Key steps in LT biosynthesis and actions are illustrated in Fig. 1. 
receptors triggers AA release and LT synthesis (12, 13), and this is to be expected in view of the well-documented capacity of Fc
and NO, that participate in antimicrobial defense. Zymosan, a carbohydrate component of yeast cell wall, is well known to trigger increases in intracellular calcium, release of AA, and LT biosynthesis (24, 25, 26). This substance is a ligand for multiple receptors, and both the mannose receptor (27) and TLR2 (28) may mediate LT synthesis. Gram-negative LPS are important PAMPs which signal via TLR4. The effects of LPS on LT biosynthesis are complex. Because LPS/TLR4 signaling does not result in increases in intracellular calcium (26), it is not sufficient to trigger LT synthesis. However, brief exposure of leukocytes to LPS can prime them for enhanced LT synthesis in response to an activating stimulus (29). Prolonged exposure of leukocytes to LPS, however, impairs their capacity for LT synthesis in response to activating stimuli, as a consequence of generation of inhibitory substances such as NO (30, 31, 32) (see below) and PGE2 (31). 
by mast cells (61). 
