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The mast cell as a pluripotent HDL-modifying effector in atherogenesis

from in vitro to in vivo significance

Lee-Rueckert, Miriam; Kovanen, Petri T.

doi: 10.1097/MOL.0000000000000224
ATHEROSCLEROSIS: CELL BIOLOGY AND LIPOPROTEINS: Edited by Andrew Newby and Mohamad Navab
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Purpose of review The purpose of this review is to summarize evidence about the effects that mast cell mediators can exert on the cholesterol efflux-inducing function of high density lipoproteins (HDL).

Recent findings Subendothelially located activated mast cells are present in inflamed tissue sites, in which macrophage foam cells are also present. Upon activation, mast cells degranulate and expel 2 major neutral proteases, chymase and tryptase, and the vasoactive compound histamine, all of which are bound to the heparin-proteoglycan matrix of the granules. In the extracellular fluid, the proteases remain heparin-bound and retain their activities, whereas histamine dissociates and diffuses away to reach the endothelium. The heparin-bound mast cell proteases avidly degrade lipid-poor HDL particles so preventing their ability to induce cholesterol efflux from macrophage foam cells. In contrast, histamine enhances the passage of circulating HDL through the vascular endothelium into interstitial fluids, so favoring HDL interaction with peripheral macrophage foam cells and accelerating initiation of macrophage-specific reverse cholesterol transport.

Summary Mast cells exert various modulatory effects on HDL function. In this novel tissue cholesterol-regulating function, the functional balance of histamine and proteases, and the relative quantities of HDL particles in the affected microenvironment ultimately dictate the outcome of the multiple mast cell effects on tissue cholesterol content.

Wihuri Research Institute, Helsinki, Finland

Correspondence to Petri T. Kovanen, MD, Wihuri Research Institute, Haartmaninkatu 8, Helsinki 00290, Finland. Tel: +358 9 6814131; fax: +358 9 637 476; e-mail: petri.kovanen@wri.fi

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INTRODUCTION

Two major components of the mast cells released during mast cell degranulation are capable of influencing the antiatherosclerotic role of high-density lipoproteins (HDL) as promoter of cholesterol efflux from macrophage foam cells. Here, we focus on the potential effects of mast cell-derived proteases and histamine on the quality and quantity of HDL particles entering interstitial fluids in which macrophage foam cells are present. We also attempt to clarify the role of mast cells under various physiological conditions and their major contributions to our understanding of two critical mast cell-dependent principles by which HDL may regulate tissue cholesterol homeostasis. First, a harmful effect caused by extracellular proteolysis of HDL leading to their functional inactivation, and, second, a compensatory beneficial effect caused by histamine, which leads to increased endothelial permeability to HDL at tissue sites in which cholesterol-loaded cells are located and more functional cholesterol acceptors are needed.

Box 1

Box 1

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MAST CELLS AND HIGH-DENSITY LIPOPROTEINS

During atherogenesis, low-density lipoproteins (LDL) enter atherosclerosis-susceptible sites of the arterial tree, are retained in the proteoglycan-rich intima, become modified and endocytosed by intimal macrophages, so leading to the formation of macrophage foam cells [1,2]. The human interstitial fluid contains the various species of HDL particles also found in the circulating blood capable of promoting efficient efflux of cholesterol from macrophages [3].

HDL particles are extremely heterogeneous in size and composition, and some HDL subpopulations are prone to undergo chemical and enzymatic modifications leading also to their functional inactivation [4,5]. Most of the functions of HDL in atherogenesis are attributed to apoA-I, the main HDL apolipoprotein. Small amounts of lipid-free apoA-I and lipid-poor apoA-I (nascent HDL particles) are considered to circulate in human blood, the former being originated by spontaneous detachment from the surface of HDL or by the continual action of lipid transfer proteins, namely CETP and PLTP [6]. Interestingly, Miller and coworkers have nicely demonstrated that, in contrast to the circulating blood, in which there was always initially a net conversion of small preβ-HDL to cholesteryl ester-rich α-HDL, in lymph, there was only net production of preβ-HDL from α-HDL [7▪▪]. As PLTP-specific activity was 3.5-fold greater in lymph than in plasma, they also claimed that PLTP is actively generating preβ-HDL in the extravascular compartments, that is, interstitial fluids and the lymph derived from them [7▪▪]. In contrast to the mature α-migrating HDL, both the lipid-free and the lipid-poor apoA-I fractions show preβ migration in agarose gel electrophoresis. The fast metabolic recycling of apoA-I between mature and nascent HDL [8] constitutes an experimental obstacle in identifying the specific form of apoA-I responsible for several properties observed in HDL isolated from plasma. Moreover, because of the high affinity for lipids of the carboxyl-terminal region of apoA-I [9], lipid-free apoA-I becomes immediately lipidated both in vitro and in vivo. Thus, in a system in which phospholipids and unesterified cholesterol are available for physical interaction with lipid-free apoA-I, it is extremely difficult to decide whether a studied function or its changes can be attributed to the apolipoprotein per se, to the rapidly generated poorly lipidated species of apoA-I, or to both.

Four distinct chemical modifications, namely enzymatic oxidation, lipolysis and proteolysis, and nonenzymatic glycosylation, can adversely affect HDL functionality [4]. The structural changes and accompanying functional alterations of HDL have been described in studies in vitro and, importantly, some of them have been reported to occur also in vivo[10]. Indeed, different cell types in the atherosclerotic arterial intima release enzymes into the intimal fluid, potentially capable of modifying the various components present in the lipid core or in the polar surface of the spherical α-HDL, and of the various forms of preβ-HDL particles [4]. In particular, recent studies have indicated that HDL and apoA-I recovered from human atheroma are dysfunctional and are extensively oxidized by myeloperoxidase [11], a heme protein secreted by activated macrophages in the human atherosclerotic lesions [12]. In addition to macrophages, mast cells are also inflammatory cells present in human atherosclerotic lesions and, when activated, they expel cytoplasmic granules that are filled with multiple preformed bioactive compounds [13]. Overall, mast cell effects in the body have been commonly judged as detrimental, particularly being their best known harmful effect triggering of chronic and acute (anaphylactic) allergic reactions [14]. Because mast cells generate several cytokines such as TNF-α, IL-6, and IFN-γ, and chemokines such as eotaxin and MCP-1 involved in monocyte recruitment and differentiation in the arterial wall, a role of mast cells in the inflammatory process during the early stages of atherogenesis has also been delineated [15].

In addition to the traditional IgE-mediated activation, as occurs in allergic reactions, mast cells can be activated by proinflammatory stimuli, including cytokines, complement factors, neuropeptides, various pathogens, oxidized LDL and immune complexes containing oxidized LDL and IgG, and even by hyperglycemia [16–18]. It was recently found that macrophages and mast cells are coactivated by oxidized LDL and can act synergistically by increasing monocyte-endothelium adhesion through the respective release of TNF-α and histamine, which led the authors to suggest that allergic patients under lipid-rich diets (resulting in hypercholesterolemia) may be at high risk for cardiovascular events because of high levels of LDL and histamine in atherosclerotic plaques harboring both macrophages and mast cells [19]. Mast cell degranulation results in a prompt release of histamine, proteoglycans (notably heparin proteoglycans), and various neutral proteases consisting of chymase and tryptase, and, depending on animal species, minor amounts of other proteases, such as cathepsin G, carboxypeptidase A, and granzyme B [20,21▪]. After degranulation, the various mediators expelled by the activated mast cells into the extracellular fluid have different fates. Whereas the soluble components of the granules, such as histamine and soluble proteoglycans, flow away, chymase and tryptase remain attached to the insoluble fraction of the granules, that is, the proteoglycans, forming functional composite super-structures, which we have designated granule remnants. Interestingly, the mast cell proteases released by activated mast cells have a variety of roles – both inflammatory and anti-inflammatory, protective and deleterious in allergy, tissue homeostasis, and innate immunity [22]. It also appears, as will be described in the following sections, that degranulation of mast cells can exert either detrimental or beneficial actions regarding the cholesterol efflux-inducing activity of HDL.

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PROTEOLYTIC ACTIVITY OF MAST CELL PROTEASES ON HIGH-DENSITY LIPOPROTEINS

Originally, we studied the effect of proteolysis by exocytosed granules, that is, granule remnants, isolated from rat peritoneal mast cells on the ultracentrifugally isolated HDL3 fraction derived from human plasma [23]. In such granules, the main protease present is the chymotrypsin-type enzyme chymase. The HDL3 fraction contained significant amounts of preβ-HDL, which most likely were generated during the ultralong ultracentrifugal running times required to obtain pure HDL preparations, leading to passive detachment of a labile pool of apoA-I located at the surface of the spherical α-HDL particles. Moreover, the preβ-migrating HDL component was possibly also derived from the PLTP activity present in the fractions [24]. We found that, in sharp contrast to α-HDL, the preβ-HDL particles were extremely susceptible to proteolysis, and treatment of HDL3 with the granule remnants was found to specifically deplete the apoA-I-containing preβ-HDL and other lipid-poor HDL particles that contain only apoA-IV or apoE [25]. As a consequence, the loss of the preβ-HDL fraction in HDL3 resulted in loss of the high-affinity component of cholesterol efflux from macrophage foam cells facilitated by the ATP-binding cassette transporter A1 (ABCA1), whereas the diffusional component of efflux promoted by α-HDL particles remained unchanged [26]. Identical results were found when HDL3 was treated with human skin-derived or recombinant human chymase, or with recombinant human tryptase, the second major mast cell protease. As shown in early studies, the compromised cholesterol efflux function of not only the chymase-treated HDL3 fraction, but also of unfractionated human plasma or of intimal fluid derived from human aortas, all were due to proteolytic depletion of cholesterol acceptors (i.e., the preβ-HDL) but not due to proteolytic impairment of the cholesterol efflux-mediating function of the ABCA1 transporters on macrophage foam cells [27].

As cholesterol efflux from macrophages initiates the specific component of RCT that originates in these cells and transfers cholesterol to the liver and, ultimately, to the gut, that is the macrophage-RCT (m-RCT), our data suggested that mast cell proteolysis of HDL could also decrease the overall efficiency of this critical antiatherosclerotic pathway in vivo[28]. Indeed, HDL was degraded in the circulating plasma of an anaphylactic mouse, that is, under full systemic activation of mast cells [29]. Demonstration of an inhibitory effect of activated mast cells on RCT in vivo was, however, challenging. Initially, we used a pharmacological model of local mast cell activation (in the peritoneal cavity of mice) and found that degranulation of mast cells in the peritoneal cavity triggered by intraperitoneal injection of compound 48/80 resulted in proteolytic degradation of also intraperitoneally administered human apoA-I, and, most importantly, compromised its function as inducer of m-RCT from intraperitoneally injected J774 macrophage foam cells [30]. Yet, when using this experimental approach without intraperitoneal injection of human apoA-I, triggering of mast cell degranulation failed to inhibit the basal rate of m-RCT promoted by the physiological HDL pool in the mouse, that is, when only endogenous plasma-derived HDL was present in the peritoneal cavity. It thus appeared that the acute but targeted proteolytic burden released by the activated peritoneal cells was not capable of degrading the mouse HDL particles in the peritoneal fluid, probably because only a single burst of granule exocytosis was triggered and the exocytosed mast cell granules are rapidly phagocytosed and degraded by the neighboring peritoneal macrophages [31], and so are no more capable of coping its continuous enrichment with new HDL particles constantly entering from the circulating HDL pool.

Recent evidence linking stress to acute coronary symptoms has indicated that activation of coronary mast cells by stress, through corticotropin releasing hormone and other neuropeptides, contributes to coronary inflammation and coronary artery disease [32]. By applying the physical restraint stress model in mice, which is known to stimulate mast cell activation in the heart [33], brain [34], and also the skin through activation of cutaneous peripheral nerve fibers [35], we wished to investigate the effect of mast cell activation on m-RCT in a physiological setting. Unexpectedly, we found that inducing acute stress resulted in a specific effect at the level of the intestine by repressing the expression in enterocytes of the critical cholesterol transporter protein Niemann Pick C1-like 1 [36]. This effect impaired intestinal reabsorption of macrophage-derived cholesterol and so accelerated the final steps of m-RCT, which involve reabsorption and fecal excretion of body cholesterol which has entered the gut lumen primarily through the hepato-biliary route [37]. In addition, the well known effect of stress shortening the large-intestinal transit time also reduced bile acid absorption in the stressed mice, and this way contributed to the increased efficiency of the m-RCT pathway [38]. Thus, it appeared that such a targeted effect of stress in the gut was able to abrogate any potential proteolytic inactivation of extravascularly located mouse HDL, which was expected to occur in the various tissue compartments in which mast cells would be expected to have been activated by stress.

The major cleavage sites on human apoA-I by human chymase have been characterized in vitro to be Phe229 and Tyr192, and a minor cleavage site has been also found at Phe225[39▪▪]. Although the extremely rapid clearance of the proteolytic fragments of apoA-I [40] may constitute a technical limitation for their detection in circulation, traces of proteolytic fragments of apoA-I have been detected with the use of sensitive analytical tools. Notably, by aid of the antibody 16–4 mAb generated against the human chymase-digested apoA-I, the chymase-specific fragment truncated at Phe225 was recently detected in normal human serum [41]. ApoA-I fragments have been also found in plasma from patients with chronic inflammatory conditions that may have involved activation of mast cells [42,43].

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GRANULE PROTEOGLYCANS STABILIZE THE PROTEOLYTIC ACTIVITY OF MAST CELLS

As introduced above, the key morphological feature of mast cells is their large content of secretory granules, filled with proteases and other secretory compounds in a network of highly negatively charged heparin proteoglycans or chondroitin sulfate proteoglycans of the serglycin type [44]. The granule proteoglycans form the insoluble structure of the granules which is critical for the storage of proteases and histamine in the granules [21▪]. Importantly, the mast cell proteoglycans also have a functional role in regulating the enzymatic activities of mast cell proteases [44], and such mast cell proteoglycan-dependent ‘gain-in-function’ of mast cell protease activity is reflected in different ways. Thus, chymase activity is stabilized by heparin and, moreover, attachment of the protease to the proteoglycan mesh of the granule remnants protects the enzyme from the inhibitory effect of α1-antitrypsin and other serpins [45]. This effect, when observed in vitro by using commercial protease inhibitors, was also found in the presence of human aortic intimal fluid, which contains a variety of physiological protease inhibitors [46]. Another example of a heparin-stabilized neutral protease is the mast cell tryptase, which is enzymatically active mainly as a heparin-stabilized tetramer, and is resistant to all known endogenous proteinase inhibitors [47]. Importantly, the presence of a mixture of proteoglycans isolated from human aorta was found to increase the ability of tryptase to proteolyze HDL3[48]. Thus, we can envision that in the vicinity of an activated mast cell in the arterial intima, both the mast cell-derived proteoglycans and the intimal matrix proteoglycans may create a microenvironment in which the inhibitor-resistant tryptase may act on apoA-I for prolonged times.

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MAST CELL-DERIVED VASOACTIVE COMPOUNDS INCREASE THE ENDOTHELIAL PERMEABILITY TOWARD CIRCULATING HIGH-DENSITY LIPOPROTEINS

In cells that reside in peripheral tissues, the RCT is initiated by the cholesterol efflux-inducing abilities of circulating HDL particles that have entered the interstitial fluid. A given concentration of lipoprotein particles in the interstitial fluid depends on the balance determined by the ratio of particles entering through the capillaries and those removed through the lymphatic vasculature [7▪▪,49]. Notably, it has been recently found that the lymphatic vasculature, by facilitating removal of HDL from interstitial fluids, stimulates cholesterol clearance from the skin and the arterial wall and, accordingly, enables RCT from these sites [50,51]. We hypothesized that, in a complementary fashion, an increase in the transendothelial passage of circulating HDL into tissue sites in which foam cells are present, such as the subcutaneous layer of skin, would locally enhance the interstitial pool of HDL and so promote m-RCT. The best candidate to test such hypothesis was the potent vasoactive mediator histamine, which is acutely released into the immediate vicinity of endothelial cells by activated subendothelial mast cells. Thus, we evaluated in mice the effect of histamine released from activated subcutaneous mast cells on the microvascular permeability in the skin, and on the rate of RCT from J774 macrophage foam cells injected into the same skin site in which the mast cells were stimulated [52▪]. When we triggered the subcutaneous mast cells to degranulate and release histamine or, alternatively, injected exogenous histamine subcutaneously, the transfer of circulating HDL into the extravascular space of the treated skin areas was increased, and the rate of m-RCT from skin to feces was accelerated. The second mast cell-derived vasoactive mediator, serotonin, fully reproduced this effect in vivo. These findings revealed that an increased passage of HDL to the interstitial fluid of the skin is capable of locally accelerating m-RCT from cholesterol-loaded cells, and they also suggested a novel role of vasoactive compounds released by activated mast cells in regulating the cholesterol content of peripheral tissues. Yet, the effect of the acutely released histamine was only transient; thus, sustained release of histamine would be necessary for a sustained m-RCT-enhancing effect. The recent notion about the role of mast cells as active modulators of chronic inflammation well suits the idea of mast cell histamine being constantly released in diseases such as atherosclerosis, a chronic inflammatory disease [53]. Inasmuch as an activated and degranulating mast cell coreleases the entire cargo of a granule, among them histamine, heparin, and the proteases, the net effect of a degranulating mast cell on apoA-I-dependent antiatherogenic functions, beneficial or harmful, is difficult to comprehend at present.

Based on the above notions, the following speculative ideas can be cautiously presented. When considering the proteolytic inactivation of HDL by mast cell proteases, it is likely that the actual impact of mast cell activation on HDL functionality in vivo will depend on the balance between the proteolytic and vasoactive effects, which may vary when tested in different experimental settings (Fig. 1). We can actually infer that an acute endogenous release of a mixture of vasoactive compounds, by increasing the influx of HDL to the skin, may be capable of overriding the inhibitory effect of the coreleased proteases on the expanded interstitial pool of HDL, which by being plasma-derived will most likely enrich the interstitial fluid with the more protease-resistant α-HDL particles. In this context, the recently emerged notion of a continuous and significant net generation of preβ-HDL from α-HDL in human extracellular fluids is of particular interest [7▪▪]. Again, like under our experimental settings in the peritoneal cavity or skin of mice and rats, it is likely that the transient and highly local proteolytic extravascular effect of the granule-bound proteases is challenged by their rapid phagocytosis by neighboring skin cells, such as fibroblasts, endothelial cells, and macrophages [54,55]. This effect could have particularly affected the proteolytic action of the granules on m-RCT at the studied body sites that were artificially enriched with the J774 macrophages [30,52▪]. Because mast cells have the capability to selectively secrete mediators without degranulation under conditions of nonallergic activation [14], such experimental models would be of interest to study the differential effects on m-RCT of histamine and the granule-bound proteases. For such studies, specific inhibitors of the various mast cell-derived bioactive compounds will be required. If successful, the studies may even pave the way for selective targeting of mast cells effector functions in HDL metabolism, and beyond, with an ultimate goal of translating such knowledge into novel therapeutic approaches.

FIGURE 1

FIGURE 1

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CONCLUSION

In summary, considering the evidence accumulated about the opposite effects of the mast cell-derived proteases and histamine on HDL cholesterol efflux-inducing ability, evaluation of the ultimate role of activated mast cells on HDL function in vivo is challenging. Moreover, the release of mast cell mediators with distinct roles during degranulation can result in different responses depending on whether they will act in concert or not. Finally, the degree and duration of mast cell activation is of critical importance. Experimental evidence has demonstrated that mast cells, in addition to the traditional acute anaphylactic explosive degranulation, can undergo a low-grade prolonged activation with continued release of histamine and occasional release of granules in inflamed tissues. An atherosclerotic tissue site displaying low-degree of inflammation and many macrophage foam cells is exactly the kind of environment in which such mast cell scenario could exist.

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Acknowledgements

Wihuri Research Institute is maintained by the Jenny and Antti Wihuri Foundation.

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Financial support and sponsorship

This work was partially supported by Veritas Foundation.

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Conflicts of interest

There are no conflicts of interest.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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Keywords:

chymase; HDL; histamine; mast cell proteoglycans; mast cells

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