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American Journal of Respiratory Cell and Molecular Biology. Vol. 31, pp. 3-7, 2004
© 2004 American Thoracic Society
DOI: 10.1165/rcmb.f279

Perspective

The Alveolar Macrophage

The Forgotten Cell in Asthma

Marc Peters-Golden

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan

Address correspondence to: Marc Peters-Golden, M.D., 6301 MSRB III, 1150 W. Medical Center Drive, Ann Arbor, MI 48109-0642. E-mail: petersm{at}umich.edu

Abbreviations: 15-hydroxyeicosatetraenoic acid, 15-HETE • airway hyperresponsiveness, AHR • alveolar macrophage, AM • interferon-{gamma}, IFN-{gamma} • interleukin, IL • macrophage, m{phi} • nitric oxide, NO • prostaglandin E2, PGE2 • peroxisome proliferator activated receptor, PPAR • helper T lymphocyte, Th


   Introduction
Top
 Introduction
Experimental Approaches to...
 Roles of AMs in...
 Potential Suppressive Actions of...
 Unanswered Questions and...
 References
 
As asthma and allergic respiratory diseases have reached epidemic proportions over the last twenty years, research into the cellular and molecular pathogenesis of these disorders has exploded. Current paradigms emphasize the importance of a T lymphocyte–derived cytokine profile polarized toward type 2 molecules (Th2) that promote eosinophilic inflammation, such as interleukin (IL)-4, -5, and -13, rather than Th1 molecules such as IL-12 and interferon-{gamma} (IFN-{gamma}) (1).

A never-ending barrage of microbes, toxins, and antigens challenges the lung's gas exchange function, making the respiratory epithelial surface an enormous battleground. The alveolar macrophage (mø) (AM) is the predominant immune effector cell resident in the alveolar spaces and conducting airways, and it is responsible for activating inflammatory responses sufficient to eliminate the interlopers (2, 3). However, an excessive inflammatory response might perturb gas exchange. This means that the AM must be "ambidextrous"—capable of both enhancing and suppressing inflammatory responses—and be "smart" enough to implement the effector program appropriate to the needs of the moment. Because this cell type is not only the most abundant but was among the first pulmonary immune cells to be extensively studied ex vivo, it is rather paradoxical that the AM is the forgotten cell in asthma. This conclusion is underscored by the fact that a recent exhaustive monograph on asthmatic airway inflammation has chapters on seven specific cell types, but none on AMs (4).

Genetic factors have long been recognized to contribute to susceptibility to allergic asthma in humans (5). In animal models of allergic asthma, variations in susceptibility have also been appreciated among different species and among different strains within a given species (6). Strain variations in susceptibility most likely reflect differences at multiple genetic loci, as is almost certainly the case for variations among humans. Although the loci that confer differential susceptibility among animal strains may not be the same as those that do so among humans, such strain differences provide an attractive experimental model for identifying mechanisms and molecules of potential relevance in humans.

In this issue of the AJRCMB, Careau and Bissonnette have exploited differences between rat strains and present interesting data suggesting that AMs contribute to genetic susceptibility to allergic asthma (7). Especially intriguing is the fact that, in this experimental model, AMs do so by suppressing airway hyperresponsiveness (AHR). In this Perspective, I review selected methodologic advances in studying AMs, and discuss some of the possible mechanisms by which AMs may exert anti-asthmatic effects as well as the possible therapeutic implications of this line of research.


   Experimental Approaches to Investigating AM Function
Top
 Introduction
 Experimental Approaches to...
Roles of AMs in...
 Potential Suppressive Actions of...
 Unanswered Questions and...
 References
 
Bronchoalveolar lavage followed by adherence purification affords an attractive means to obtain a reasonably large number of pure and viable AMs for functional studies. Although this time-honored experimental approach—initially reported in animals in 1961 (8) and first applied to humans in 1967 (9)—has taught us much of what we know about the AM, it also imposes a number of limitations. Among these are the facts that lavage selects for the AM subset that is least firmly adherent to the respiratory epithelium and that removal of cells from their native milieu necessarily limits the ability of ex vivo approaches to discern in vivo function.

The development and application of two newer experimental methods have begun to advance our ability to understand the functional roles of AMs in vivo, and nicely complement the older ex vivo approach. The first of these involves the in vivo administration of liposome-encapsulated chloromethylene diphosphonate (clodronate), which is ingested by møs and causes their apoptosis and subsequent elimination. This method was first utilized in 1984 to deplete splenic møs (10), and was first applied to AMs with intratracheal injection of liposomal clodronate in 1989 (11). Numerous studies have reported ~ 85% depletion of lavageable AMs within 3 d of clodronate administration. The second of these methods involves adoptive transfer of møs—either genetically engineered cells (12) or cells from an animal donor (13, 14)—to a recipient animal via intratracheal delivery. As might be expected, some investigators have employed both depletion of resident AMs as well as adoptive transfer of donor cells.


   Roles of AMs in Immune and Inflammatory Responses: Lessons from In Vivo Depletion and Adoptive Transfer Experiments
Top
 Introduction
 Experimental Approaches to...
 Roles of AMs in...
Potential Suppressive Actions of...
 Unanswered Questions and...
 References
 
Not surprisingly, in vivo depletion studies have confirmed that AMs are important for pulmonary innate immune responses such as microbial clearance (15). By contrast, such studies have generally indicated that AMs downregulate acquired immune responses, because AM depletion has been shown to enhance antigen presentation by dendritic cells (16) and humoral immune responses to inhaled antigens (17). Tang and coworkers (18) examined the influence of local AMs on such processes in a murine ovalbumin sensitization and challenge model of allergic asthma. Depletion of resident AMs with clodronate before airway antigen challenge resulted in enhanced antigen-induced AHR in association with enhanced eosinophilic inflammation and increased lavage levels of IL-4 and IL-5, whereas lavage levels of IFN-{gamma} were diminished. These results suggest that AMs in vivo promoted a Th1 response.

A difference in susceptibility to ovalbumin-induced asthma between the Brown Norway and Sprague Dawley strains of rat is well established. As is true for BALB/c mice, Brown Norway rats resemble atopic humans in that they are much more prone to develop antigen-specific IgE, Th2 cytokine production, eosinophilic inflammation, early- and late-phase bronchoconstrictor responses, and AHR than are Sprague Dawley rats (19, 20).

To directly examine the in vivo contribution of AMs to antigen-induced asthma in these two strains, Careau and Bissonnette (7) effected an 85% depletion of lavageable AMs from both Brown Norway and Sprague Dawley rats 3 d after intratracheal clodronate, then subjected them to aerosolized antigen challenge and examined AHR to aerosolized methacholine. They found that AM depletion increased AHR in Sprague Dawley rats, but had no effect in Brown Norway animals. Intratracheal transfer of AMs from one strain into the other before allergen challenge was then undertaken. The transfer of Brown Norway AMs into Sprague Dawley animals had no effect on AHR. However, the transfer of Sprague Dawley AMs into Brown Norway animals significantly reduced AHR. Taken together, these data strongly suggest that, although AMs did not mediate susceptibility to AHR in Brown Norway rats, they did mediate the resistance to AHR observed in Sprague Dawleys.


   Potential Suppressive Actions of AMs in Allergic Asthma
Top
 Introduction
 Experimental Approaches to...
 Roles of AMs in...
 Potential Suppressive Actions of...
Unanswered Questions and...
 References
 
By what mechanisms might Sprague Dawley AMs confer resistance to AHR? Generally speaking, these AMs might exert their suppressive actions by elaboration of soluble molecules (Table 1) and/or by mechanisms that require cell-cell contact or interactions (see Figure 1). These authors did not directly examine the effects of AM depletion and transfer on airway inflammation per se. However, because AHR generally correlates reasonably well with airway inflammation (1), it is likely that the protection conferred by resistant AMs involved a downregulatory effect on inflammation, although additional effects on smooth muscle responses are possible as well. A suppressive effect on allergic inflammation might involve either specifically polarizing the immune response toward a Th1 phenotype or nonspecifically dampening immune responses and/or leukocyte activation. It is instructive that virtually all the factors elaborated by AMs that are candidate anti-asthmatic substances (discussed below) are also capable of promoting asthmatic inflammation or responses, emphasizing the context dependence of their roles. Moreover, their levels in the asthmatic lung are often elevated as compared with controls, rather than depressed; this apparent paradox may represent an attempt to counterbalance inflammation and restore homeostasis.


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  		TABLE 1. Candidate anti-asthmatic substances elaborated by AMs

 


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  		Figure 1. Potential mechanisms by which AMs can mediate suppression of AHR. AMs from Sprague Dawley rats are capable of conferring resistance to antigen-induced AHR when transferred into the lungs of otherwise susceptible Brown Norway rats. This could result from elaboration of mediators (such as those listed in Table 1) that suppress one or more of the pathogenic components contributing to AHR. Such elaboration could itself require cell–cell interactions such as ingestion of apoptotic inflammatory or structural cells.

 
AM-mediated protection against AHR could reflect their direct elaboration of Th1 cytokines such as IFN-{gamma}, IL-12, and IL-18. AMs from humans without asthma have been reported to produce more IL-12 (21) and more IL-18 (22) than those from humans with atopic asthma. By contrast, AMs from antigen-unsensitized Sprague Dawley rats elaborate less IL-12 than do cells from Brown Norway rats (23). However, it is not known if this is also the case for AMs from antigen-sensitized Sprague Dawleys, such as those capable of conferring resistance in the study by Careau and Bissonnette (7).

It has been proposed that lymphocyte Th1 versus Th2 responses are ultimately dictated by two distinct types of møs, termed M-1 and M-2 (24). Murine peritoneal møs from prototypical Th1 strains (such as C57BL/6 mice) have a greater capacity to convert arginine to nitric oxide (NO) than do cells from Th2 strains (such as BALB/c mice), which preferentially convert arginine to ornithine. These two metabolites have opposing effects on lymphocyte proliferation, and perhaps cytokine profiles. It is interesting in this regard that Sprague Dawley rat AMs have a greater ex vivo capacity for NO synthesis than do Brown Norway AMs (25), consistent with M-1 and M-2 profiles, respectively. The significance of NO will be considered further below.

A class of molecules termed "regulatory cytokines" has generalized suppressive effects on inflammatory and immune responses (26). The best-studied representatives of this group are transforming growth factor-ß and IL-10. These can inhibit either Th1 or Th2 responses, depending on the context. Although well known to be the products of regulatory T cells, they are also elaborated by structural cells as well as various leukocyte populations including AMs (27, 28).

Contradictory roles in allergic asthma have been attributed to NO (27), already mentioned above. On the one hand, it has been suggested to promote Th2 responses (28, 29) and its levels in exhaled breath condensate seem to reflect uncontrolled asthmatic inflammation (30, 31). On the other, it can suppress various inflammatory responses, including synthesis of leukotrienes (32) and of numerous cytokines (33, 34), as well as smooth muscle contractile responses (35). Because NO can interact with reactive oxygen species to form additional bioactive products such as peroxynitrite, the pleiotropic effects of NO may depend, at least in part, on the redox state of target tissues. Rodent AMs are an abundant source of NO, and it is increasingly clear that under appropriate circumstances, this can be demonstrated for human AMs as well (36). Because the capacity for NO synthesis of Sprague Dawley AMs exceeds that of Brown Norway AMs (25), this gas is a plausible candidate for mediating the suppressive actions of the former in models of allergic asthma.

CO is another gaseous molecule that possesses broad anti-inflammatory actions. Its administration to mice after allergen sensitization and challenge reduced eosinophilic inflammation and lavage levels of several inflammatory mediators (37). Interestingly, expression of its enzymatic source, heme oxygenase I, has been reported to be elevated in AMs recovered from sputum of individuals with uncontrolled asthma, as compared with cells from control subjects without asthma, individuals with well controlled asthma, and individuals with asthma treated with systemic corticosteroids (38).

Prostaglandin E2 (PGE2) also has been observed to have contradictory actions relevant to asthma. Because of its edemagenic actions, this prostanoid has long been viewed as a proinflammatory substance, and conflicting effects on eosinophilic inflammation have been reported (39–41). Yet it has bronchodilatory and bronchoprotective actions (42, 43), inhibits a broad array of pro-inflammatory leukocyte functions (44, 45), and inhibits diverse functions of smooth muscle cells (46) and fibroblasts (47); this is reviewed in Ref. 48. Although immunologic dogma holds that it promotes Th2 cytokine secretion by lymphocytes in vitro (49), recent in vivo studies suggest that, in the lung, endogenous PGE2 may suppress Th2 cytokine secretion and allergic asthmatic responses (50, 51). It is not known whether Sprague Dawley and Brown Norway AMs differ in their capacity for synthesis of this prostanoid.

The arachidonate 15-lipoxygenase product 15-hydroxyeicosatetraenoic acid (15-HETE) and the PGD2 degradation product 15-deoxy-PGJ2 both exert a variety of anti-asthmatic effects. For example, 15-HETE has been shown to reduce AHR in humans in vivo (50) and to inhibit leukotriene synthesis and cytokine production in vitro (51). In vitro, 15-deoxy-PGJ2 inhibits IL-5 generation by T cells (52) and IL-8 generation by epithelial cells (53). When added to cells exogenously, both 15-HETE and 15-deoxy-PGJ2 are capable of ligating the nuclear hormone receptor, peroxisome proliferator–activated receptor-{gamma} (PPAR-{gamma}), which can in turn inhibit activation of the transcription factor nuclear factor-{kappa}B. A variety of PPAR-{gamma} ligands have also been shown to inhibit inflammatory manifestations and AHR in allergic asthma models in vivo (52, 54, 55). However, whether these lipids reach high enough concentrations to act as endogenous PPAR-{gamma} ligands is quite controversial (54). Furthermore, although AMs from rats and humans can synthesize both 15-HETE and PGD2, these appear to be minor eicosanoid products of isolated AMs ex vivo, and can be generated in much greater quantities by airway epithelial cells and mast cells, respectively. Whether they are also minor products of AMs in vivo and whether they may be synthesized to a greater degree by Sprague Dawley than Brown Norway rat AMs is uncertain.

Lipoxin A4 is a dual 5- and 15-lipoxygenation product of arachidonic acid that has largely anti-inflammatory actions in a variety of in vitro and in vivo models. Administration of a stable lipoxin A4 analog has recently been reported to inhibit allergic asthma in a murine model (55). Although reported to be generated in small quantities by isolated human AMs (56), greater quantities might be expected to be synthesized in vivo via interactions between the arachidonate 5-lipoxygenase pathway of AMs and the 15-lipoxygenase pathway of airway epithelium. Once again, no information is available about possible differences in lipoxin A4 synthetic capacity between cells from the two rat strains.

In any inflammatory process, leukocytes undergo programmed cell death, and these apoptotic cells must be ingested and cleared. Phagocytosis of apoptotic cells by møs leads to their elaboration of suppressive molecules such as PGE2 and transforming growth factor-ß, which contributes to an anti-inflammatory milieu (57). This is in striking contrast to the pro-inflammatory consequences of mø phagocytosis of microbes via classical opsonin receptors, such as the Fc{gamma} receptor for IgG. It is remarkable that this cell is able to execute a proinflammatory program when ingesting an opsonized microbe and an anti-inflammatory program when ingesting an apoptotic body. Interestingly, AMs from human subjects with asthma have been reported to exhibit impaired Fc{gamma} receptor–mediated phagocytosis, which was associated with reduced surface expression of Fc{gamma} receptor I (58). As recognition and ingestion of apoptotic cells is not believed to involve Fc{gamma} receptors, there is no reason to expect that this particular defect should influence AM clearance of apoptotic cells. Nevertheless, it is interesting to consider whether variations in apoptotic cell ingestion might influence susceptibility to asthma and be differentially distributed among different individuals or different rat strains. For example, it is plausible to imagine that Sprague Dawley AMs have a greater capacity to either ingest apoptotic eosinophils or to elaborate anti-inflammatory mediators after their ingestion, than do Brown Norway cells.


   Unanswered Questions and Therapeutic Implications
Top
 Introduction
 Experimental Approaches to...
 Roles of AMs in...
 Potential Suppressive Actions of...
 Unanswered Questions and...
References
 
Although the data of Careau and Bissonnette certainly suggest that the AM may be an important and overlooked conductor in the symphony (cacophony?) that is allergic asthma, their findings provide only the faintest hint of its role. But the roadmap to be followed to clarify the regulatory role, mechanisms, and relevance of this most abundant respiratory immune cell is readily apparent, and is outlined by the following series of questions. (i) What aspects of the allergic asthmatic response—generation of a primary immune response, the nature of the airway inflammatory response (including Th2 polarization), epithelial injury, and/or smooth muscle contractile responses—are targeted by the suppressive actions of transferred AMs? (ii) Are the suppressive actions of AMs mediated by soluble AM-derived factors, or do they involve cell–cell interactions? If the former, are the suppressive molecules elaborated constitutively or only after antigen sensitization and challenge? Defining the identity of candidate molecules should be feasible by employing gene array analysis of AMs and by studying the suppressive capacity of AMs whose candidate mediators have been functionally deleted using pharmacologic, antibody neutralization, or transgenic strategies. (iii) Is the capacity for suppression limited to AMs, or can bone marrow or circulating precursors carry out a similar effect? (iv) Are the suppressive effects of transferred AMs transient or long-lived? (v) Do the mechanisms or molecules responsible for the suppressive effects of Sprague Dawley AMs also underlie resistance to allergic asthma observed in other animal strains (e.g., Lewis rats and C57BL/6 mice), and do they contribute to differences in asthmatic susceptibility among humans?

Any possible therapeutic implications of this research will surely hinge on the answers to the above questions. If soluble factors mediate the anti-asthmatic actions of AMs, then the direct administration of such molecules or analogs thereof, or of substances that increase their expression, may have therapeutic potential. On the other hand, if AM suppression requires direct cell-cell contact and especially if it results in a long-lived change in the inflammation program of susceptible individuals, efforts to administer resistant cells (natural or genetically engineered) themselves (via the airways or via a bone marrow transplantation) may be worth the obvious obstacles. Finally, the possibility that AMs may downregulate other types of inflammatory and pathologic pulmonary responses besides allergic asthma can now be considered.


   Acknowledgments
 
This article was supported by NIH grants RO1 HL058897 and P50 HL 56402.


   Footnotes
 
Conflict of Interest Statement: M.P.-G. has no declared conflicts of interest.

Received in final form April 6, 2004


   References
Top
 Introduction
 Experimental Approaches to...
 Roles of AMs in...
 Potential Suppressive Actions of...
 Unanswered Questions and...
 References
 

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