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.
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 .
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 . 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  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 , 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 . 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. 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 . In particular, recent studies have indicated that HDL and apoA-I recovered from human atheroma are dysfunctional and are extensively oxidized by myeloperoxidase , a heme protein secreted by activated macrophages in the human atherosclerotic lesions . 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 . 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 . 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 .
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 . 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 . 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.
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 . 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 . 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 . 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 . 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 .
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. Indeed, HDL was degraded in the circulating plasma of an anaphylactic mouse, that is, under full systemic activation of mast cells . 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 . 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 , 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 . By applying the physical restraint stress model in mice, which is known to stimulate mast cell activation in the heart , brain , and also the skin through activation of cutaneous peripheral nerve fibers , 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 . 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 . 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 . 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  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 . 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].
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 . 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 , 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 . 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 . 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 . Importantly, the presence of a mixture of proteoglycans isolated from human aorta was found to increase the ability of tryptase to proteolyze HDL3. 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.
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 . 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 , 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.
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.
Wihuri Research Institute is maintained by the Jenny and Antti Wihuri Foundation.
Financial support and sponsorship
This work was partially supported by Veritas Foundation.
Conflicts of interest
There are no conflicts of interest.
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
1. Pentikainen MO, Oorni K, Ala-Korpela M, Kovanen PT. Modified LDL: trigger of atherosclerosis and inflammation in the arterial intima. J Internal Med 2000; 247:359–370.
2. Moore KJ, Sheedy FJ, Fisher EA. Macrophages in atherosclerosis: a dynamic balance. Nat Rev Immunol 2013; 13:709–721.
3. Smith EB. Transport, interactions and retention of plasma proteins in the intima: the barrier function of the internal elastic lamina. Eur Heart J 1990; 11 (Suppl E):72–81.
4. Lee-Rueckert M, Kovanen PT. Extracellular modification of HDL
and the evolving concept on the in-vivo proteolytic inactivation of prebeta-HDL
as cholesterol acceptors. Curr Opin Lipidol 2011; 22:394–402.
5. Riwanto M, Rohrer L, von Eckardstein A, Landmesser U. Dysfunctional HDL
: from structure-function-relationships to biomarkers. Handb Exp Pharmacol 2015; 224:337–366.
6. Rye KA, Barter PJ. Formation and metabolism of prebeta-migrating, lipid-poor apolipoprotein A-I. Arterioscler Thromb Vasc Biol 2004; 24:421–428.
7▪▪. Miller NE, Olszewski WL, Hattori H, et al. Lipoprotein remodeling generates lipid-poor apolipoprotein A-I particles in human interstitial fluid. Am J Physiol Endocrinol Metab 2013; 304:E321–E328.
This important article provides data on the dynamic changes in HDL subclasses in human plasma and peripheral lymph, this latter as a surrogate of interstitial fluid. It also provides a mechanistic insight into the origin of the high contents of preβ-HDL in lymph which was associated with the relative activities of the lipid transfer proteins in lymph.
8. Cavigiolio G, Geier EG, Shao B, et al. Exchange of apolipoprotein A-I between lipid-associated and lipid-free states: a potential target for oxidative generation of dysfunctional high density lipoproteins. J Biol Chem 2010; 285:18847–18857.
9. Nagao K, Hata M, Tanaka K, et al. The roles of C-terminal helices of human apolipoprotein A-I in formation of high-density lipoprotein particles. Biochim Biophys Acta 2014; 1841:80–87.
10. Navab M, Reddy ST, van Lenten BJ, Fogelman AM. HDL
and cardiovascular disease: atherogenic and atheroprotective mechanisms. Nat Rev Cardiol 2011; 8:222–232.
11. Huang Y, DiDonato JA, Levison BS, et al. An abundant dysfunctional apolipoprotein A1 in human atheroma. Nat Med 2014; 20:193–203.
12. Daugherty A, Dunn JL, Rateri DL, Heinecke JW. Myeloperoxidase, a catalyst for lipoprotein oxidation, is expressed in human atherosclerotic lesions. J Clin Invest 1994; 94:437–444.
13. Xu JM, Shi GP. Emerging role of mast cells
and macrophages in cardiovascular and metabolic diseases. Endocr Rev 2012; 33:71–108.
14. Theoharides TC, Alysandratos KD, Angelidou A, et al. Mast cells
and inflammation. Biochim Biophys Acta 2012; 1822:21–33.
15. Spinas E, Kritas SK, Saggini A, et al. Role of mast cells
in atherosclerosis: a classical inflammatory disease. Int J Immunopathol Pharmacol 2014; 27:517–521.
16. Bot I, Biessen EA. Mast cells
in atherosclerosis. Thromb Haemost 2011; 106:820–826.
17. Lappalainen J, Lindstedt KA, Oksjoki R, Kovanen PT. OxLDL-IgG immune complexes induce expression and secretion of proatherogenic cytokines by cultured human mast cells
. Atherosclerosis 2011; 214:357–363.
18. Nagai K, Fukushima T, Oike H, Kobori M. High glucose increases the expression of proinflammatory cytokines and secretion of TNFalpha and beta-hexosaminidase in human mast cells
. Eur J Pharmacol 2012; 687:39–45.
19. Chen C, Khismatullin DB. Oxidized low-density lipoprotein contributes to atherogenesis via co-activation of macrophages and mast cells
. PLoS One 2015; 10:e0123088.
20. Maaninka K, Lappalainen J, Kovanen PT. Human mast cells
arise from a common circulating progenitor. J Allergy Clin Immunol 2013; 132:463–469.
21▪. Wernersson S, Pejler G. Mast cell secretory granules: armed for battle. Nat Rev Immunol 2014; 14:478–494.
This review examines the various pathways of mast cell degranulation and the protective and detrimental effects of mast cell granule components under various inflammatory conditions.
22. Caughey GH. Mast cell proteases as protective and inflammatory mediators. Adv Exp Med Biol 2011; 716:212–234.
23. Lee M, Lindstedt L, Kovanen PT. Mast cell-mediated inhibition of reverse cholesterol transport. Arterioscler Thromb 1992; 12:1329–1335.
24. Vikstedt R, Metso J, Hakala J, et al. Cholesterol efflux from macrophage foam cells is enhanced by active phospholipid transfer protein through generation of two types of acceptor particles. Biochemistry 2007; 46:11979–11986.
25. Lee M, von Eckardstein A, Lindstedt L, et al. Depletion of preá 1 LpA1 and LpA4 particles by mast cell chymase
reduces cholesterol efflux from macrophage foam cells induced by plasma. Arterioscler Thromb Vasc Biol 1999; 19:1066–1074.
26. Favari E, Lee M, Calabresi L, et al. Depletion of prebeta-HDL
by human chymase
impairs ATP-binding cassette transporter A1- but not SR-B1-mediated lipid efflux to HDL
. J Biol Chem 2004; 279:9930–9936.
27. Lee-Rueckert M, Kovanen PT. Mast cell proteases: physiological tools to study functional significance of high density lipoproteins in the initiation of reverse cholesterol transport. Atherosclerosis 2006; 189:8–18.
28. Cuchel M, Rader DJ. Macrophage reverse cholesterol transport: key to the regression of atherosclerosis? Circulation 2006; 113:2548–2555.
29. Judstrom I, Jukkola H, Metso J, et al. Mast cell-dependent proteolytic modification of HDL
particles during anaphylactic shock in the mouse reduces their ability to induce cholesterol efflux from macrophage foam cells ex vivo. Atherosclerosis 2010; 208:148–154.
30. Lee-Rueckert M, Silvennoinen R, Rotllan N, et al. Mast cell activation in vivo impairs the macrophage reverse cholesterol transport pathway in the mouse. Arterioscler Thromb Vasc Biol 2011; 31:520–527.
31. Kokkonen JO. Stimulation of rat peritoneal mast cells
enhances uptake of low density lipoproteins by rat peritoneal macrophages in vivo. Atherosclerosis 1989; 79:213–223.
32. Alevizos M, Karagkouni A, Panagiotidou S, et al. Stress triggers coronary mast cells
leading to cardiac events. Ann Allergy Asthma Immunol 2014; 112:309–316.
33. Huang M, Pang X, Letourneau R, et al. Acute stress induces cardiac mast cell activation and histamine
release, effects that are increased in Apolipoprotein E knockout mice. Cardiovasc Res 2002; 55:150–160.
34. Esposito P, Gheorghe D, Kandere K, et al. Acute stress increases permeability of the blood-brain-barrier through activation of brain mast cells
. Brain Res 2001; 888:117–127.
35. Liu N, Wang LH, Guo LL, et al. Chronic restraint stress inhibits hair growth via substance P mediated by reactive oxygen species in mice. PLoS One 2013; 8:e61574.
36. Silvennoinen R, Escola-Gil JC, Julve J, et al. Acute psychological stress accelerates reverse cholesterol transport via corticosterone-dependent inhibition of intestinal cholesterol absorption. Circ Res 2012; 111:1459–1469.
37. Lee-Rueckert M, Blanco-Vaca F, Kovanen PT, Escola-Gil JC. The role of the gut in reverse cholesterol transport - Focus on the enterocyte. Prog Lipid Res 2013; 52:317–328.
38. Silvennoinen R, Quesada H, Kareinen I, et al. Chronic intermittent psychological stress promotes macrophage reverse cholesterol transport by impairing bile acid absorption in mice. Physiol Rep 2015; 3:e12402.
39▪▪. Usami Y, Kobayashi Y, Kameda T, et al. Identification of sites in apolipoprotein A-I susceptible to chymase
and carboxypeptidase A digestion. Biosci Rep 2013; 33:49–56.
With the use of specific monoclonal antibody for a chymase-derived proteolytic product of apoA-I, that is, Phe225 carboxyl-terminally truncated form, this work identified for the first time small amounts of this polypeptide in normal human serum.
40. Schmidt HHJ, Remaley JA, Stonic JA, et al. Carboxyl-terminal domain truncation alters apolipoprotein A-I in vivo catabolism. J Biol Chem 1995; 270:5469–5475.
41. Usami Y, Matsuda K, Sugano M, et al. Detection of chymase
-digested C-terminally truncated apolipoprotein A-I in normal human serum. J Immunol Methods 2011; 369:51–58.
42. Eberini I, Gianazza E, Breghi L, et al. Apolipoprotein A-I breakdown is induced by thrombolysis in coronary patients. Ann Med 2007; 39:306–311.
43. Ndao M, Spithill TW, Caffrey R, et al. Identification of novel diagnostic serum biomarkers for Chagas’ disease in asymptomatic subjects by mass spectrometric profiling. J Clin Microbiol 2010; 48:1139–1149.
44. Ronnberg E, Melo FR, Pejler G. Mast cell proteoglycans
. J Histochem Cytochem 2012; 60:950–962.
45. Lindstedt L, Lee M, Kovanen PT. Chymase
bound to heparin is resistant to its natural inhibitors and capable of proteolyzing high density lipoproteins in aortic intimal fluid. Atherosclerosis 2001; 155:87–97.
46. Lindstedt L, Lee M, Castro GR, et al. Chymase
in exocytosed rat mast cell granules effectively proteolyzes apolipoprotein AI-containing lipoproteins, so reducing the cholesterol efflux-inducing ability of serum and aortic intimal fluid. J Clin Invest 1996; 97:2174–2182.
47. Pereira PJ, Bergner A, Macedo-Ribeiro S, et al. Human beta-tryptase is a ring-like tetramer with active sites facing a central pore. Nature 1998; 392:306–311.
48. Lee M, Sommerhoff CP, von Eckardstein A, et al. Mast cell tryptase degrades HDL
and blocks its function as an acceptor of cellular cholesterol. Arterioscler Thromb Vasc Biol 2002; 22:2086–2091.
49. Miller NE, Michel CC, Nanjee MN, et al. Secretion of adipokines by human adipose tissue in vivo: partitioning between capillary and lymphatic transport. Am J Physiol Endocrinol Metab 2011; 301:E659–E667.
50. Lim HY, Thiam CH, Yeo KP, et al. Lymphatic vessels are essential for the removal of cholesterol from peripheral tissues by SR-BI-mediated transport of HDL
. Cell Metab 2013; 17:671–684.
51. Martel C, Li W, Fulp B, et al. Lymphatic vasculature mediates macrophage reverse cholesterol transport in mice. J Clin Invest 2013; 123:1571–1579.
52▪. Kareinen I, Cedo L, Silvennoinen R, et al. Enhanced vascular permeability facilitates entry of plasma HDL
and promotes macrophage-reverse cholesterol transport from skin in mice. J Lipid Res 2014; 56:241–253.
In this article, it is shown for the first time that mere disruption of the endothelial barrier by mast cell-derived histamine and serotonin enhanced the passage of circulating HDL into the interstitial fluid and increased the rate of macrophage-specific reverse cholesterol transport from peripheral tissues, such as the skin.
53. Metz M, Grimbaldeston MA, Nakae S, et al. Mast cells
in the promotion and limitation of chronic inflammation. Immunol Rev 2007; 217:304–328.
54. Kaartinen M, Penttila A, Kovanen PT. Extracellular mast cell granules carry apolipoprotein B-100- containing lipoproteins into phagocytes in human arterial intima. Functional coupling of exocytosis and phagocytosis in neighboring cells. Arterioscler Thromb Vas Biol 1995; 15:2047–2054.
55. Kokkonen JO, Kovanen PT. Stimulation of mast cells
leads to cholesterol accumulation in macrophages in vitro by a mast cell granule-mediated uptake of low density lipoprotein. Proc Natl Acad Sci USA 1987; 84:2287–2291.