TRANSATLANTIC AIRWAY CONFERENCE Altered Macrophage Function in Chronic Obstructive Pulmonary Disease Pieter S. Hiemstra1 1

Department of Pulmonology, Leiden University Medical Centre, Leiden, The Netherlands

Abstract The observation that macrophages are increased in chronic obstructive pulmonary disease (COPD) and are associated with COPD severity has led to a large number of studies on macrophage function in COPD. These studies have provided evidence that these cells contribute to tissue injury through the release of various mediators, including proteases such as matrix metalloprotease-12. In addition, it was found that macrophages in COPD have an impaired ability to clear respiratory pathogens and apoptotic cells. Macrophage phagocytic function in COPD can be restored at least in part, as shown by in vitro studies. In a search to further understand this altered function of macrophages in COPD, several studies

have used a range of markers to phenotype macrophages in COPD. Macrophages constitute a heterogeneous cell population, and, currently, proinflammatory M1 and anti-inflammatory M2 and M2-like cells are considered to represent the extremes of a pattern of macrophage polarization. In COPD, there is no clear evidence for a predominance of one of these phenotypes, and an intermediate phenotype may be present. Future studies are needed to establish the nature of this apparent COPD-specific macrophage subset, and to link macrophage dysfunction to COPD phenotypes. Keywords: chronic obstructive pulmonary disease; macrophages; inflammation; phagocytosis

(Received in original form May 22, 2013; accepted in final form August 12, 2013 ) Correspondence and requests for reprints should be addressed to Pieter S. Hiemstra, Ph.D., Department of Pulmonology, Leiden University Medical Center, Albinusdreef 2, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail: [email protected] Ann Am Thorac Soc Vol 10, Supplement, pp S180–S185, Dec 2013 Copyright © 2013 by the American Thoracic Society DOI: 10.1513/AnnalsATS.201305-123AW Internet address: www.atsjournals.org

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease that is characterized by an inflammatory response to inhaled noxious particles and gases. Analyses of lung tissue and airway secretions from patients with COPD have demonstrated increased numbers and/or altered activation of cells of both the innate and adaptive immune system (1, 2). In most patients, cigarette smoke is the initial trigger for activation of cells of the innate immune system, such as epithelial cells and macrophages. These cells are activated by cigarette smoke exposure through a variety of mechanisms, including direct activation of these cells that may involve pattern recognition receptors, as well as indirect activation through the generation of danger signals resulting from tissue injury (so-called damage-associated molecular patterns).

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Various studies have provided evidence for altered numbers and/or activation of macrophages in the lungs from patients with COPD. Macrophages are increased in lung tissue from patients with COPD (3), and the number of macrophages is associated with the degree of COPD (4, 5). This increase in macrophage numbers may be the result of increased recruitment, local proliferation, and/or local survival of macrophages (6). In this review, the focus will be on the role of macrophages in tissue injury and defense against respiratory infections in COPD. Macrophages constitute a heterogeneous population of cells of the innate immune system that display a variety of functions (6). They are essential for host defense against infection through their capacity to phagocytose and subsequently kill ingested

micro-organisms. In addition, they produce a range of pro- and anti-inflammatory mediators and effector molecules, including cytokines, proteases and protease inhibitors, and reactive oxygen intermediates (ROIs) and reactive nitrogen intermediates (RNIs). In this way, macrophages contribute not only to inflammation and tissue injury, but also to wound repair and the control and resolution of inflammation. Macrophages contribute to the control and resolution of inflammation by releasing a range of anti-inflammatory mediators, and by removing apoptotic cells by a specialized form of phagocytosis, called efferocytosis (7, 8). This process restricts, for example, the unwanted effect of neutrophils releasing toxic mediators after cell death. Finally, macrophages contribute to adaptive immunity through their ability to present antigen, but their ability to

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TRANSATLANTIC AIRWAY CONFERENCE stimulate T cells is limited compared with dendritic cells. This range of macrophage functions is explained by the fact that diversity and plasticity are characteristics of macrophages. In the lung, distinct populations of macrophages can be distinguished based on their anatomical location, such as with alveolar macrophages and interstitial macrophages. However, macrophage diversity is more complex, and distinct functional macrophage phenotypes develop as a result of the response of mononuclear phagocytes to local microenvironmental signals that allow them to adapt to this local environment (9, 10). It has been shown that IFN-g alone, or in combination with Toll-like receptor (TLR) ligands, stimulates the classical pathway of M1 activation, resulting in proinflammatory macrophages characterized by high production of proinflammatory cytokines, ROIs, and RNIs, and by strong microbicidal and tumoricidal activity. IL-4 and IL-13 drive the pathway of alternative M2 activation, resulting in macrophages that are considered to have anti-inflammatory, wound-healing properties, with high expression of scavenger and mannose receptors, and good phagocytic activity for micro-organisms and apoptotic cells (efferocytosis). In addition, the related M2-like macrophages share many properties with M2 cells, and are characterized by high production of IL-10. Similar overlapping phenotypes have been derived by exposure of human monocytes to granulocyte/macrophage colony– stimulating factor (GM-CSF; resulting in M1 cells) or M-CSF (resulting in M2 cells) (11). These distinct phenotypes resemble the T helper type 1–2 polarization of T cells, but it needs to be noted that these M1 and M2 phenotypes are largely based on in vitro studies, and are characterized by plasticity. Therefore, it is likely that many intermediate phenotypes can be distinguished in vivo. Furthermore, there are differences between murine and human M1- and M2-polarized subsets (6). Nevertheless, distinct macrophage phenotypes are associated with a diversity of diseases and animal models of diseases, as illustrated by the association of allergy and asthma with M2 polarization of macrophages. Novel therapies that target macrophage polarization are being developed, and existing interventions have now been shown to affect this polarization (10). Hiemstra: Macrophage Function in COPD

Macrophages and Tissue Injury in COPD Both neutrophils and macrophages produce a range of proteases and ROIs that can contribute to the protease–antiprotease imbalance, a mechanism that has long dominated research on the pathogenesis of COPD. Neutrophils produce the elastindegrading enzyme, elastase, and its activity is restricted by protease inhibitors, such as a1-antitrypsin (a1-AT). A deficiency of a1-AT is associated with early onset emphysema, and, furthermore, a1-AT and related serine protease inhibitors are inactivated by exposure to ROIs, thus shifting the balance toward excess protease activity. Although this does suggest a major involvement of neutrophils, these inflammatory cells are not correlated with emphysema, whereas macrophages and T lymphocytes are (4). Like neutrophils, macrophages also contribute to lung injury through the production of a range of proinflammatory mediators, including chemokines, cytokines, proteases, ROIs, and RNIs. Several studies have implicated matrix metalloproteases (MMPs) in the destruction and/or remodeling of lung tissue in COPD. Alveolar macrophages from patients with COPD may be chronically activated, resulting in an increased release of MMP-9 (12). Exposure of macrophages to cigarette smoke increases the production of MMP-9 (12), but also of IL-8/CXCL8 (13). The central role of the macrophage-derived metalloprotease, MMP-12, and of monocyte-attracting chemokine, monocyte chemoattractant protein-1/CCL2 in experimental emphysema induced by prolonged smoke exposure in mice was demonstrated by Hautamaki and colleagues (14). Further studies provided evidence for a role of MMP-12 in COPD in humans by showing increased expression in bronchial biopsies, bronchoalveolar lavage fluid, and sputum (15, 16).

Macrophages and Host Defense against Infection in COPD In addition to their role in tissue injury, macrophages are also essential in host defense against respiratory infections. This is highly relevant to understanding the role of macrophages in COPD, because

respiratory infections markedly contribute to the progression of COPD and to exacerbations. Nontypeable Haemophilus influenza (NTHi), Moraxella catarrhalis, and Streptococcus pneumoniae are the most frequently encountered bacterial pathogens in COPD (17–19). These bacteria may contribute to inflammation and tissue destruction, thus linking these pathogens to COPD progression and exacerbations. However, these bacteria apparently persist in the lung of patients with COPD, despite the fact that macrophage and neutrophil numbers are increased. How do we explain this apparent paradox between increased macrophage numbers and respiratory infections in COPD? Various studies have demonstrated that the antimicrobial activity of alveolar macrophages from smokers with and without COPD is impaired. Vecchiarelli and colleagues (20) reported that both monocytes and alveolar macrophages from patients with COPD are less efficient in killing Candida albicans than cells from smoking control subjects. Other studies focused on NTHi, which is an opportunistic gram-negative bacterium causing respiratory infections and is associated with COPD exacerbations and progression. Berenson and colleagues (21) demonstrated impaired phagocytosis in alveolar macrophages from patients with COPD compared with smokers with a normal lung function using three different clinical isolates of NTHi. Mart´ı-Lliteras and colleagues (22) demonstrated that in vitro exposure of alveolar macrophages to cigarette smoke extract impaired NTHi phagocytosis, without an effect of cigarette smoke extract on macrophage or bacterial viability. Furthermore, they showed that phagocytosis of NTHi was lower in alveolar macrophages from smokers and patients with COPD when compared with neversmokers, whereas uptake of latex beads was similar among the three groups. This indicates that smoke may not cause a general impairment in phagocytic capacity. Others recently demonstrated an impaired expression of TLR3 on alveolar macrophages of smokers compared with nonsmokers, which was accompanied by a reduction in double-stranded RNA– induced CXCL10 production (23). No effects on other receptors for microbial nucleic acids were observed, and the effect was independent of COPD stage. Whereas this finding is important for S181

TRANSATLANTIC AIRWAY CONFERENCE understanding the effect of cigarette smoking on viral respiratory infections, it is also relevant for understanding bacterial infections, because TLR3 has been found to be involved in epithelial responses to NTHi (24). Interestingly, the impaired ability of macrophages in COPD to ingest microorganisms appears not to be restricted to the lung. Taylor and colleagues (25) showed that uptake of both live and heat-killed bacteria is impaired in COPD when studied using alveolar macrophages as well as monocyte-derived macrophages (MDM). No differences in receptor expression of TLR2, TLR4, CD163, CD36, and mannose receptor were observed between MDM from patients with COPD, smokers, and nonsmokers. Previous studies by Berenson and colleagues (21) did not detect a defect in phagocytosis by MDM, and it was suggested that this discrepancy may be explained by the fact that, in their study, Taylor and coworkers (25) used GM-CSF to generate MDM. This is of interest, because GM-CSF drives differentiation of monocytes toward M1 macrophages that are somewhat less phagocytic than M2 macrophages. It is possible that monocytes from patients with COPD are more prone to differentiate into M1 macrophages upon exposure to GM-CSF. Collectively, these studies show that bacterial phagocytosis by macrophages may be impaired in COPD, and that this effect can only partly be explained by a direct effect of cigarette smoke. Furthermore, the observation with MDM suggests that this is an inherent property of circulating monocytes, and raises the question of if and why this effect is only clinically manifest in the lung.

Efferocytosis in COPD: Role of Macrophages Whereas phagocytosis of micro-organisms is an important function in COPD, it is now recognized that uptake and removal of apoptotic cells is another important function of macrophages that is essential to prevent excessive inflammation. This process of cell corpse removal (efferocytosis) has been especially well studied for removal of neutrophils (8). During inflammation, neutrophils will infiltrate tissue in large numbers, and these short-lived cells will mostly die by apoptosis. However, unless these cells are removed, they may undergo secondary necrosis, and thereby release S182

numerous toxic compounds that may cause tissue injury. In view of the role of neutrophils in a variety of chronic lung diseases, including COPD, it is evident that this mechanism of removal of neutrophils is important in preventing disease progression. The activation state of macrophages is an important determinant of their capacity to ingest these apoptotic cells, and alternatively activated macrophages are better at efferocytosis than classically activated macrophages. Various studies have now investigated the capacity of macrophages in COPD to ingest apoptotic cells, and have shown that this activity of macrophages is decreased in COPD. First, it was shown that macrophages that interact with extracellular matrix proteins that have been modified by cigarette smoke exposure increase their adhesion, and decrease their capacity to ingest apoptotic neutrophils (26). This may, thus, not only increase macrophage retention in the lungs that are exposed to smoke, but also amplify inflammation through decreased clearance of apoptotic neutrophils. Hodge and colleagues (27) showed that alveolar macrophages from patients with COPD have a decreased capacity to ingest apoptotic epithelial cells compared with nonsmokers, and that this effect is largely explained by active smoking (28). These differences in phagocytosis of apoptotic cells and microorganisms are not simply explained by differences in receptor expression. Pons and colleagues (29) did not observe differences in expression of a variety of receptors involved in phagocytosis (CD44, CD36, CD51, CD61, CD14, and CR3), but did show lower expression of human leukocyte antigen class II and CD80 (both associated with antigen presentation) in alveolar macrophages from patients with COPD compared with smokers and nonsmokers. No differences in peripheral blood monocytes were observed.

Several drugs used in COPD or with a potential benefit for patients with COPD have been shown to modulate macrophage phagocytic function, and a selection of these is discussed in this section. d

d

d

d

Restoration of Macrophage Phagocytosis and Efferocytosis To improve macrophage function in COPD, a treatment that inhibits proinflammatory activities of macrophages and restores the ability of macrophages to ingest and kill pathogens and remove apoptotic cells through efferocytosis, would be optimal.

d

Glucocorticoids. Glucocorticoids are known to modulate a range of macrophage functions, but are less effective in controlling inflammation in COPD than in other inflammatory lung disorders. This apparent steroid resistance is also found in macrophages, and is associated with a decreased expression and activity of histone deacetylase 2, which is an important transcriptional regulator of inflammation that is recruited by glucocorticoids (30). Macrolides. Members of the macrolide class of antibiotics, including azithromycin and erythromycin, have both antibacterial activity, as well as antiinflammatory and immune modulating effects. Treatment of patients with COPD who had an increased risk of exacerbations with azithromycin was shown to reduce the number of exacerbations and improve quality of life (31). Interestingly, azithromycin treatment of patients also improved ex vivo macrophage function in COPD, as shown by increased efferocytosis and phagocytosis of bacteria by alveolar macrophages (32). Statins. Efferocytosis by COPD macrophages was also enhanced by in vitro treatment with statins (33), which is interesting in view of the reported beneficial effects of these cholesterol-lowering anti-inflammatory drugs in COPD. Sulforaphane. Harvey and colleagues (34) used sulforaphane to activate the transcription factor, nuclear erythroidrelated factor 2, a key regulator of cytoprotective protective proteins, including antioxidants, in alveolar macrophages from patients with COPD and cigarette smoke–exposed mice. Sulforaphane increased bacterial recognition and uptake by alveolar macrophages from patients with COPD, and reduced inflammation in smokeexposed mice. Vitamin D. Vitamin D improves macrophage function by its ability to reduce inflammation and increase expression of antimicrobial peptides in, for example, macrophages (35), which

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TRANSATLANTIC AIRWAY CONFERENCE may help explain the reported beneficial effects of vitamin D treatment in patients with COPD with a vitamin D deficiency (36). Collectively, these studies show that the phagocytic and antimicrobial capacity of macrophages in COPD can be restored by a variety of treatments. The extent to which this explains the clinical benefits of these treatments in COPD requires further study.

Macrophage Polarization in COPD Based on the association of macrophages with inflammation and tissue destruction in COPD, one would expect that macrophages in COPD are polarized toward the proinflammatory M1 phenotype in COPD. Indeed, because anti-inflammatory M2 macrophages have a higher capacity for phagocytosis than M1 macrophages, the observed decreased phagocytosis in COPD is in line with a shift toward a proinflammatory M1 phenotype. In line with these findings, proinflammatory macrophages (characterized by high human leukocyte antigen class II expression and production of TNF-a) were reported to predominate in induced sputum from patients with COPD (37). We have used the M2 marker, CD163, to analyze alveolar macrophages in COPD, and obtained evidence to suggest that smoking cessation in COPD is associated with a change toward an anti-inflammatory M2 phenotype (38). In addition, the observation that resolvin D1 inhibits cigarette smoke–induced inflammation in mice, while increasing M2 macrophages and neutrophil efferocytosis (39), is in line with an effect of smoke on macrophage polarization toward an M1 phenotype. In contrast to these findings, one of the studies that has investigated alveolar macrophage gene expression in COPD in most detail to date concluded that expression of genes related to M1 polarization is decreased in macrophages from smokers, and revealed an unusual M2 polarization program (i.e., a mixture of different M2-related phenotypes) in these cells (40). This conclusion was based on transcriptional profiling of alveolar macrophages obtained by bronchoalveolar lavage of healthy nonsmokers and smokers with or without COPD. This pattern of alveolar Hiemstra: Macrophage Function in COPD

Figure 1. Macrophage polarization: an intermediate phenotype in chronic obstructive pulmonary disease (COPD)? Activated macrophages are classified into proinflammatory M1 macrophages and anti-inflammatory M2/M2-like macrophages. In COPD, macrophages have been suggested to adopt an intermediate phenotype. MMP = matrix metalloprotease; ROS = reactive oxygen species.

macrophage polarization was more advanced in macrophages from smokers with COPD. These and other studies on macrophage polarization in patients with COPD, as well as murine COPD models, have provided partly conflicting results that would suggest that the concept of development of M1 and M2/M2-like macrophages may be an oversimplification (Figure 1; see also reviews by Lee [41] and Boorsma and colleagues [42]). Several issues may have contributed to this notion. First, there are major differences between mice and men

in macrophage polarization. Second, most studies do not take into account the large plasticity of the macrophage phenotype. The outcome of a certain trigger on macrophage polarization may be determined, for instance, by the state of polarization of the macrophage that responds to that trigger, as well as by the presence of other triggers in the microenvironment. Finally, COPD is a highly heterogeneous disease, and different macrophage phenotypes may predominate in different COPD phenotypes.

Figure 2. Macrophage function in chronic obstructive pulmonary disease (COPD). Exposure to cigarette smoke or other irritants causes recruitment and activation of macrophages, either directly or through activation of epithelial cells. These macrophages cause tissue injury by release of reactive oxygen intermediates (ROIs), nitrogen intermediates (RNIs), and proteases, or by increasing inflammation. Inflammation is further enhanced due to the decreased capacity of macrophages in COPD to clear pathogens and apoptotic cells.

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TRANSATLANTIC AIRWAY CONFERENCE Conclusions A large number of studies have now documented that macrophages in patients with COPD are not only increased in numbers, but also differ in function when compared with healthy subjects or smokers with normal lung function. Increased expression of proinflammatory mediators and effector molecules is a characteristic of COPD, which is accompanied by decreased phagocytosis of respiratory pathogens and apoptotic cells. These mechanisms may contribute to inflammation and tissue injury, as observed in COPD (Figure 2). Interestingly,

pharmaceutical interventions have been shown to reverse these characteristics, and hold promise for future macrophage-targeted therapy of COPD. The conventional concept of polarization of macrophages into pro- and anti-inflammatory phenotypes may oversimplify macrophage heterogeneity in COPD, and more studies with better M1 and M2 markers are needed. This is complicated by the fact that not all markers for these macrophage phenotypes that are derived from mouse studies may be useful in human studies. Furthermore, information on macrophage phenotypes and markers that is derived from in vitro studies should be

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Altered macrophage function in chronic obstructive pulmonary disease.

The observation that macrophages are increased in chronic obstructive pulmonary disease (COPD) and are associated with COPD severity has led to a larg...
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