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(Journal of Leukocyte Biology. 2001;70:163-170.)
© 2001 by Society for Leukocyte Biology

Functional heterogeneity in liver and lung macrophages

Debra L. Laskin*, Barry Weinberger{dagger} and Jeffrey D. Laskin{dagger}

* Rutgers University and
{dagger} University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey

Correspondence: Dr. Debra Laskin, Rutgers University, Department of Pharmacology and Toxicology, 160 Frelinghuysen Rd., Piscataway, New Jersey. E-mail: laskin{at}eohsi.rutgers.edu


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ABSTRACT
 
Although initially considered merely "scavenger cells" that participate in immunologic responses only after B and T lymphocytes have performed their biological tasks, more recent evidence suggests that macrophages play a key role in host defense as well as in the maintenance of normal tissue structure and function. For macrophages to perform their biological functions, they must be activated. This involves up-regulation of an array of signaling pathways resulting in altered gene expression and increased biochemical and functional activity. Macrophages have been identified in almost all tissues of the body. However, the basal activity of these cells, as well as their ability to respond to inflammatory mediators, varies considerably with their location. In addition, even within a particular tissue, there is evidence of macrophage heterogeneity. The largest populations of macrophages in the body are located in the liver and lung. Because of the unique attributes of these tissues, hepatic and pulmonary macrophages play essential roles not only in nonspecific host defense but also in the homeostatic responses of these tissues. In this review, the functional and biochemical activities of macrophages localized in the liver and lungs are compared. Evidence suggests that these represent distinct cell populations with unique functions and responsiveness to inflammatory agents.

Key Words: mononuclear phagocytes • Kupffer cells • alveolar macrophages • subpopulations


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INTRODUCTION
 
Macrophages are derived from bone marrow precursors and blood monocytes. Mature macrophages localize in tissues and constitute the mononuclear-phagocyte or reticuloendothelial system. They are present in connective tissue and around the basement membrane of small blood vessels and are particularly concentrated in the liver (Kupffer cells), alveolar spaces of the lung (alveolar macrophages), and linings of splenic and lymph node medullary sinusoids, where they are strategically localized to filter foreign material. Other examples of macrophages are Langerhan’s cells in the skin, mesangial cells in the kidney glomerulus, brain microglia, and osteoclasts in bone. In general, macrophages are characterized morphologically by an enlarged horseshoe-shaped nucleus, significant rough-surfaced endoplasmic reticulum, and large numbers of mitochondria and cytoplasmic vacuoles, although these characteristics vary depending on the tissue origin of the cell. Macrophages are motile cells that typically appear at inflammatory sites within 24–48 h. They are relatively long-lived cells that exhibit continuous secretory activity during inflammatory processes, enabling them to destroy a range of cells, antigens, and pathogens [1 , 2 ]. Macrophages are also highly phagocytic cells, readily engulfing and digesting a variety of substances including viruses, bacteria, effete red blood cells, tissue and cellular debris, and some tumor cells [3 ]. Despite their origin from a common bone marrow progenitor population [4 ], macrophages display considerable tissue heterogeneity. Moreover, even within tissues, there appear to be subpopulations of macrophages that exhibit unique characteristics. These findings suggest that the microenvironment of a tissue regulates the phenotype of these cells. This is most clearly evident in macrophages localized in the liver and the lungs, and these macrophages are the focus of this review.


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LIVER MACROPHAGES
 
Macrophages were first identified in the liver histologically in the late nineteenth century by the German pathologist, von Kupffer. These cells, later referred to as Kupffer cells, are the most abundant mononuclear phagocytes in the body. They are predominantly localized in the lumen of hepatic sinusoids and are anchored to the endothelium by long cytoplasmic processes [5 ]. The major function of Kupffer cells is to clear particulate and foreign materials from the portal circulation, primarily through the process of phagocytosis. Kupffer cells possess both Fc and C3 receptors and are known to phagocytize a wide variety of both opsonized and nonopsonized particles [6 ]. Kupffer cells play a central role in the uptake and detoxification of endotoxin from the portal circulation [7 ]. Like other mononuclear phagocytes, they have the capacity to act as antigen-presenting cells for the induction of T-lymphocyte responses [8 ]. When activated by antigens or inflammatory stimuli, Kupffer cells release superoxide anions, hydrogen peroxide, nitric oxide, hydrolytic enzymes, and eicosanoids, each of which can aid in antigen destruction [9 10 11 ]. Kupffer cells also release a number of different immunoregulatory and inflammatory cytokines, including interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-{alpha}, platelet-activating factor, transforming growth factor-ß and interferon (IFN)-{gamma} [9 10 11 ].

Although the liver tissue is uniform at the level of histology, it is heterogeneous with respect to morphometry and histochemistry. This heterogeneity appears to be related to the blood supply. Thus cells located in the upstream or periportal regions of the liver lobule differ from those in the downstream or centrilobular (perivenous) regions in several key enzymes, receptors, and subcellular structures and therefore have different functional capacities [12 , 13 ]. Kupffer cells have been reported to be about twofold more abundant in periportal than centrilobular regions of the liver lobule [13 , 14 ]. Moreover, in situ experiments have demonstrated that Kupffer cells in periportal regions are larger, possess greater lysosomal enzyme activities, and are more phagocytic than cells in centrilobular regions but generate less superoxide anion [5 , 14 , 15 ]. These data suggest that Kupffer cell functional heterogeneity and size are related to the location of these cells within the liver acinus [14 ]. Subpopulations of Kupffer cells that differ in size have also been isolated from the livers of rodents and characterized. Whereas the majority of Kupffer cells of all sizes display an endogenous peroxidase pattern characteristic of resident tissue macrophages and show positive staining for macrophage markers such as nonspecific esterase (NSE), ED1, and ED2, heterogeneity in intensity of staining has been observed [16 ]. In general, the intensity of staining for these markers decreases with decreasing cell size, suggesting that these cells display a more immature phenotype [14 ]. Phenotypic heterogeneity of human liver macrophages has also been observed histologically, using monoclonal antibodies that recognize the macrophage antigens CD68 and 25-F9. Whereas most macrophages in normal human liver are positive for CD68, fewer mature macrophages express the macrophage differentiation antigen 25-F9 [17 , 18 ]. Moreover, although some cells are doubly positive for these antigens, others are only CD68 positive. Quantitative analysis has confirmed these differences, suggesting that liver macrophage maturation is heterogeneous.

Functional heterogeneity has also been described in macrophages of different sizes isolated from rat livers. Thus large macrophages are more phagocytic and generate increased quantities of lysosomal enzymes, TNF-{alpha}, IL-1, and prostaglandin E (PGE), when compared with small liver macrophages [5 , 13 , 14 , 19 20 21 22 23 24 25 ]. In contrast, the smaller macrophages express greater quantities of Ia antigen, release more nitric oxide and superoxide anion, and exhibit increased cytotoxic activity towards tumor cells [14 , 15 , 19 , 25 26 27 28 ]. These cells also appear to be more susceptible to activation [20 , 23 , 29 ]. These observations suggest that there is a relationship between Kupffer cell functionality, maturation, and size. The findings that large liver macrophages located in periportal regions appear to provide more scavenger functions and are less active in inflammatory reactions may in part explain the relative immunological tolerance of the liver for immunogens entering from the portal vein [19 ]. Figure 1 is a schematic summarizing the relationship between size, maturation, function, and location of macrophages in the liver.



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  		Figure 1. Schematic diagram illustrating liver macrophage heterogeneity. Phenotypic and functional characteristics of liver macrophages (Kupffer cells) are related to their location within the hepatic sinusoid.


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LUNG MACROPHAGES
 
Like Kupffer cells in the liver, pulmonary macrophages play an important role in nonspecific host defense, as well as in specific immune responses in the lung. This is mediated through their phagocytic, microbicidal, and secretory functions [30 ]. At least two different subpopulations of macrophages, alveolar macrophages and interstitial macrophages, are localized in distinct anatomical compartments in the lung, including the air spaces and lung connective tissue, respectively [31 , 32 ]. Alveolar macrophages reside within the alveolus and are often seen protruding from the alveolar epithelial walls into the lumen of the lungs. They occupy a relatively unique position within the body because they are exposed directly to a relatively hyperoxic environment and are in intimate contact with both air- and blood-borne materials. Alveolar macrophages are strategically located to function as a primary defense of the lung against inhaled particulate matter, microorganisms, and environmental toxins [30 , 33 , 34 ]. Damage to these cells is an important factor in increased host susceptibility to airborne bacterial infection and toxicants [31 ]. Interstitial macrophages are also quite prominent in the lung, constituting approximately 40% of the total macrophages in tissue [35 ]. Morphometric studies show that the number of macrophages within the interstitium of normal lung approximates or exceeds the number of alveolar macrophages [30 , 32 ]. Moreover, because interstitial macrophages are in direct contact with matrix and other pulmonary connective-tissue components, the release of mediators or enzymes by these cells may have greater biological and/or pathological effects than those released by macrophages in the alveolar compartment.

In normal lung tissue, alveolar macrophages are considered the end stage of development of blood monocytes. A number of studies have suggested that interstitial macrophages are actually an intermediary stage in the maturation of alveolar macrophages [36 , 37 ]. Morphologic studies have shown that alveolar macrophages are large, mature cells, with an increased cytoplasm/nucleus ratio which resembles other tissue macrophages, whereas interstitial macrophages are smaller, more uniform in size, have blunt pseudopodia, contain few intracytoplasmic lamellar inclusions or lysosomes, and in general more closely resemble peripheral blood monocytes [38 39 40 41 42 43 44 ]. Based on these observations, it has been suggested that the pulmonary interstitium provides an environment for late-stage maturation or preconditioning of blood monocytes prior to their entrance into the air space [36 ]. Nevertheless, there is considerable evidence to support the concept that alveolar and interstitial macrophages represent distinct cell populations with unique functional attributes and that each population has the capacity to contribute to pulmonary inflammatory and immune responses [45 ]. Thus, although alveolar macrophages exhibit greater functional activity related to inflammation and antimicrobial defense including increased chemotaxis, phagocytosis, cytotoxicity, and release of reactive oxygen and nitrogen intermediates, PGE, TNF-{alpha}, and IFN, interstitial macrophages express greater quantities of C3 receptor and intercellular adhesion molecule 1, are more active in secreting IL-1 and IL-6 and exhibit greater Ia antigen expression along with a stronger accessory function [36 , 40 , 45 46 47 48 49 50 51 52 53 54 55 56 ]. These capabilities demonstrate that interstitial macrophages display pronounced immunoregulatory capacity and suggest that they are more involved in specific immune responses. Interstitial macrophages have also been reported to exhibit a significantly greater proliferative capacity when compared with alveolar macrophages [40 ], and this capacity is thought to play a role in maintaining the lung macrophage pool under homeostatic and pathologic conditions [57 ]. Figure 2 summarizes the differences between alveolar and interstitial macrophages.



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  		Figure 2. Schematic diagram illustrating lung macrophage heterogeneity. Phenotypic and functional characteristics of lung macrophages are related to their location within the alveolus or interstitium.

Alveolar macrophages are the best studied of the lung macrophages, in part because of their ease of isolation by bronchoalveolar lavage. A number of studies have demonstrated that these cells are not homogeneous and can be separated into subpopulations with distinct morphologic and functional properties on the basis of adherence to the alveolar walls, flow-cytometric parameters, expression of surface receptors, and density [36 , 38 , 43 , 58 59 60 61 62 63 64 65 66 67 ]. Most studies have focused on cells grouped by density. In general, alveolar macrophages of higher density are smaller and appear less mature when compared with lower-density cells [64 ]. However, these cells are more functionally active. Thus, high-density alveolar macrophages exhibit increased NSE staining and express greater numbers of C3 and immunoglobulin (Ig) receptors, as well as Ia antigen [54 , 58 ]. They are also more phagocytic and chemotactic, and they generate increased amounts of superoxide anion, lysozyme, IL-1, TNF-{alpha}, neutrophil chemotactic factor, and PGE when compared with low-density alveolar macrophages [43 , 45 , 50 , 59 , 65 66 67 68 69 70 71 72 73 74 75 76 77 ]. High-density alveolar macrophages also exhibit greater cytotoxicity towards neoplastic cells and more effectively support T-cell proliferation [43 , 66 , 77 , 78 ]. In contrast, low-density alveolar macrophages, which have been characterized cytochemically as more mature cells [78 ], display increased procoagulant activity and ectoenzyme function [64 , 79 80 81 82 ]. Several investigators have suggested that morphologic and cytochemical maturation is associated with decreasing cell density and increasing cell size [59 , 60 , 64 , 79 , 83 ]; thus, density centrifugation has been proposed as a method to separate alveolar macrophages at different stages of maturation. However, it is also possible that heterogeneity in alveolar macrophages reflects the existence of macrophage subpopulations with functionally distinct roles in airway immunity and is derived from distinct bone marrow precursors [84 ].

As observed in alveolar macrophages, considerable heterogeneity with respect to size, morphology, function, and antigen expression has also been observed within the interstitial macrophage population [32 , 39 ]. Separation of interstitial macrophages by density has yielded results similar to those reported for alveolar macrophages. Thus, higher-density interstitial macrophages exhibit increased chemotaxis, phagocytosis, and Fc receptor expression, as well as increased prostaglandin biosynthesis, when compared with lower-density fractions [45 , 46 , 54 ]. As suggested for alveolar macrophages, these differences may reflect distinct maturational stages of these cells, although differences could also be related to the anatomical location of cells within the tissue.


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ARE LIVER AND LUNG MACROPHAGES DIFFERENT?
 
Although only a few studies have directly compared liver and lung macrophages, these clearly indicate that significant heterogeneity exists between these two populations. Thus, whereas normal Kupffer cells are highly phagocytic, alveolar macrophages produce significantly greater quantities of reactive-oxygen species and reactive-nitrogen intermediates (Table 1 ). This difference most likely reflects the nature of the mediators and pathogens to which these cells are exposed in vivo, as well as the needs of the tissue. For example, the liver is the major site for clearance of gut-derived endotoxin. Thus, Kupffer cells localized in hepatic sinusoids have developed a highly efficient phagocytic capacity to remove endotoxin from the portal circulation. Moreover, since Kupffer cells are continuously exposed to endotoxin, they are in a chronic state of low-level activation. In this regard, resident Kupffer cells have been reported to constitutively express enzymes such as cyclooxygenase-2 and nitric oxide synthase-2, which mediate the formation of inflammatory prostaglandins and reactive-nitrogen intermediates, respectively [85 ]. In contrast to interstitial macrophages, alveolar macrophages are primed by exposure to inhaled pathogens and particulates to generate increased quantities of cytotoxic mediators that aid in their destruction. The relative functional capacities and antigenic differences between alveolar macrophages and Kupffer cells are shown in Table 1 . For comparison purposes, we also included peritoneal macrophages. Although all three macrophage populations exhibit characteristic features of mononuclear phagocytes, levels of these activities vary considerably, demonstrating clearly that functional, antigenic, and morphologic heterogeneity exists both within and between tissues. A question arises, however, as to whether heterogeneity observed within the macrophage family stems from differences in the stage of differentiation or activation state of a single highly dynamic macrophage/monocyte lineage or the existence of multiple distinct macrophage/monocyte lineages. Whereas animals studies have supported the concept that macrophage subpopulations arise from distinct bone marrow precursors [4 ], in humans, this remains to be determined [86 ].


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  		Table 1. Comparison of Kupffer Cells, Alveolar Macrophages, and Peritoneal Macrophages


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SUMMARY AND CONCLUSIONS
 
The role of macrophages in host defense and tissue injury is now well established, not just in the liver and lungs but also in almost all other tissues of the body [1 , 2 , 87 , 88 ]. Although there is considerable evidence demonstrating macrophage heterogeneity between tissues, accumulated data suggest that there is also heterogeneity within each tissue. A question arises about the relationship among cell size, density, and function. Based on the literature surveyed, it appears that smaller, denser macrophages might play a more prominent role in immune regulation while larger, less dense cells are engaged in anti-inflammatory/antimicrobial activity. Whether this is true for tissues other than the liver and lung remains to be determined. For the future, a focus on understanding the functional importance of macrophage subpopulation heterogeneity will be important in designing new and potentially more effective approaches to limiting inflammation and cytotoxicity.


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ACKNOWLEDGEMENTS
 
This work was supported by NIH grants ES04738, ES06897, and GM34310 and by a Career Development Award from the Burroughs Wellcome Fund awarded to D. L. L.

Received November 14, 2000; revised March 31, 2001; accepted April 3, 2001.


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