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6 Mast Cells

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Table 6.1 Characteristics of two phenotypes of human mast cells

Phenotype MC Proteases Tryptase (+++) Tryptase (++)

Distribution Skin (++)

Relation to pathology Increased in brotic diseases Increased around the site of T cell

Response to non-immunological stimuli

Adapted from [1])

Kajiwara etal. [17]

Chymase (+) Carboxypeptidase A3 (++) Carboxypeptidase A3 (+) Cathepsin G (+)

Intestinal submucosa (+) Intestinal submucosa (++) Intestinal mucosa (−) Alveolar wall (++) Bronchial subepithelium (+) Bronchial subepithelium (+) Dispersed lung mast cells (−) Tonsils (++) Tonsils (++) Nasal mucosa (−)

Unchanged in allergic and parasitic diseases Unchanged in chronic immunodeciency diseases Substance P (+)

C5a (+)

PAF (−)

Chymase (−)

Skin (−)

Intestinal mucosa (++) Alveolar wall (−)

Dispersed lung mast cells (++)

Nasal mucosa (++)

aviation Increased in allergic and parasitic diseases Decreased in chronic immunodeciency diseases Substance P (−) C5a (−)

PAF (+)

lost chymase by the IL-13-activated epithelial cell-derived factor(s), respond to substance P or PAF.

6.3 Role ofMCs inAcute Allergic

Reactions

MCs express more than 105 high-afnity IgE receptor (FcεRI) per cell. When MCs that have been sensitized with some specic IgE antibody are challenged with the specic allergen, they are activated by cross-linking of FcεRI molecules. Thus, activated MCs evoke immediate-type reaction by releasing their granules in which histamine, neutral proteases, and heparin had been stored. Then, lipid mediators such as cysteinyl leukotriene (cys-LT) or prostaglandin D2 (PGD2) are synthesized on their membranes and are released into microenvironment within several minutes.

Released histamine and lipid mediators cause acute allergic symptoms such as nasal discharge, bronchospasms, and urticaria. Histamine plays an essential role in acute skin allergic reactions, whereas cys-LT plays a pivotal role in bronchoconstriction. MCs almost exclusively express PGD2 synthase compared to all other cell types. Although the role of PGD2 in immediate-type reaction is unclear, it serves as chemoattractant for eosinophils, basophils, and Th2 cells.

Human MCs also exclusively express tryptase, one of the neutral proteases, among all human cell types. Tryptase constitutes 10% of the MC by protein weight [1]. Proteoglycan (human MCs use “eosinophil” major basic protein instead of proteoglycan molecules) serves as a core protein in the crystalloid structure of the MC granules by binding to heparin and neutral proteases [18]. The MC tryptase acts as trypsin-like enzyme and thereby causes tissue remodeling such as abnormal proliferation of airway smooth muscles [19].

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H. Saito

6.4 Role ofMCs inAllergic Inammation

MCs secrete a variety of cytokines and chemokines several hours after allergen-induced degranulation via transcription of these genes. The representative cytokines/chemokines which are produced by activated human MCs are type 2 cytokines such as IL-5, IL-13, and GM-CSF and CC chemokines such as CCL1/I-309, CCL2/ monocyte chemoattractant protein-1, CCL3/ macrophage inammatory protein (MIP-)1α, and CCL4/MIP-1β. Activated human MCs also secrete a substantial amount of CXCL8/IL-8 [18, 20]. MCs can store and release some of cytokines such as tumor necrosis factor (TNF)-α during degranulation process. Regarding IL-4 production, the results are reproducible using mouse MCs. However, only a few groups succeeded to immunohistochemically demonstrate the presence of IL-4 on human MCs [21, 22]. In any case, at least in human, basophils are more potent producers of IL-4. Instead, IL-4 potently activates human MC function and maturation. Human MCs can produce a substantial amount of another type 2 cytokine, IL-13, in response to IgE-mediated stimuli, and the IL-13 production is markedly enhanced by preincubation with IL-4 [20]. However, these cytokines and chemokines are not unique to MCs and are produced by other cell types [23]. During antigen stimulation, more type 2 cytokines would be produced by proliferating T cells. Moreover, group 2 innate lymphoid cells (ILC2s) were recently found to produce higher levels of type 2 cytokines [24] and are currently considered to be the culprit for the innate phase of allergic inammation [25]. In a certain experimental setting invitro, however, human mast cells seem to produce IL-13, which plays an essential role in the pathogenesis of asthma or other allergic inammatory diseases, at the level comparable to that produced by human ILC2s. It would be useful if we could dissect the role of mast cells and ILC2s in the late

phase asthmatic responses accompanied by eosinophilic inammation in the same experimental setting (Fig.6.1).

Although human MCs do not normally produce cytokines in response to other cytokines such as IL-4 without FcεRI cross-linking, it should be noted that IL-33, which are released during necrosis of epithelial-mesenchymal tissue, can stimulate MCs to release a variety of cytokines such as IL-13 [26]. Regarding other innate immune responses, mouse MCs are proven to play an essential role in protection against microbial infection via Toll-like receptors (TLRs) [27–29]. Human MCs can express functional TLR4 after preincubation with IFN-γ. These MCs can produce more TNF-a, CCL5, CXCL10, and CXCL11 compared to IgE dependently activated MCs [30].

Topical use of glucocorticoid (GC) is the rstline therapy for allergic diseases such as asthma and allergic rhinitis. Although GC does not block the degranulation of MCs, these drugs downregulate the gene expression of FcεRI in MCs and thereby downregulate IgE-mediated activation of MCs. More notably, glucocorticoid can inhibit gene expression of a variety of cytokines in MCs. Even in short time incubation, GC blocks the nuclear factor-κB (NF-κB)-dependent gene expression of cytokines, such as IL-13, CXCL8/ IL-8, and GM-CSF.On the other hand, GC does not inhibit nuclear factor-activated T (NFAT)dependent gene expression of cytokines, such as CCL1, CCL3, and CCL4.

Interestingly, an immunosuppressive agent, FK-506 inhibits NFAT-dependent-, but not NF-κB-dependent-, gene expression [31]. If GC and FK-506 are added simultaneously into the reaction buffer for MC activation, the expression of cytokines is almost completely blocked. Among cytokine or growth factor genes, only IgE-mediated amphiregulin gene upregulation is not blocked by preincubation with GC and FK-506. It would be difcult to surpass the effect of GC plus FK-506 even if we could develop a new anti-MC drug.

Mast Cell Degranulation

6 Mast Cells

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Mucus cell metaplasia

CCL13

Th2

IL-13

IL-5 IL-8

IL-4, IL-5, IL-13

Days/Months

Recruitment of Leukocytes

Chronic Eosinophilic Inflammation

Th2

Antigens, enzymes, viruses

IL-33, IL-25, TSLP

Antigen Challenge

10 min

ILC2

PGD

Airway Smooth Muscle Constriction

Cys-LTs

Early Response

6-24 hr

IL-5, IL-13

CCL17

Late Response

Microvessel

TNF

Fig. 6.1 Suggested roles of mast cell-derived and ILC2s-derived cytokines on the late phase allergic reactions. Mast cell-derived cytokines are shown in red, and ILC2s-derived cytokines are shown in blue

6.5 Conclusion

MCs trigger not only the immediate-type allergic reaction in an IgE-mediated manner but also the late-phase allergic response and chronic allergic inammation, thereby regulating the function of other immune cells. While histamine, tryptase, and PGD2 released in the immediate-type reaction are unique to MCs (or basophils), most cytokines and chemokines are produced by other cell types as well as MCs. It is necessary to determine the relative role of MCs in the allergic or innatetype inammation by understanding cytokines/ chemokines produced by other immune cell types and epithelial-mesenchymal tissues. The expression of these cytokines is almost completely blocked when GC and FK506 are added simultaneously into the reaction buffer for MC activation. It would be difcult to overwhelm this effect even if we could develop a new anti-MC drug.

References

1. Bradding P, Saito H.Biology of mast cells and their mediators. In: Adkinson F, Bochner BS, Burks AW, Holgate ST, Lemanske RF, O’Hehir R, editors. Middleton’s allergy: principles and practice, vol. 1. 8th ed. Philadelphia, PA: Elsevier Saunders; 2013. p.228–51.

2. Kitamura Y, Go S, Hatanaka K.Decrease of mast cells in W/Wv mice and their increase by bone marrow transplantation. Blood. 1978;52:447–52.

3. Kitamura Y, Go S.Decreased production of mast cells in S1/S1d anemic mice. Blood. 1979;53:492–7.

4. Kitamura Y, Shimada M, Hatanaka K, Miyano Y.Development of mast cells from grafted bone marrow cells in irradiated mice. Nature. 1977;268:442–3.

5. Befus AD, Pearce FL, Gauldie J, Horsewood P, Bienenstock J. Mucosal mast cells. I. Isolation and functional characteristics of rat intestinal mast cells. J Immunol. 1982;128:2475.

6. Pearce FL, Befus AD, Gauldie J, Bienenstock J.Mucosal mast cells. II.Effects of anti-allergic compounds on histamine secretion by isolated intestinal mast cells. J Immunol. 1982;128:2481.

7. Ihle JN, Keller J, Oroszlan S, Henderson LE, Copeland TD, Fitch F, Prystowsky MB, Goldwasser E, Schrader

https://t.me/medicina_free

H. Saito

JW, Palaszynski E, Dy M, Lebel B.Biologic properties of homogeneous interleukin 3. I.Demonstration of WEHI-3 growth factor activity, mast cell growth factor activity, p cell-stimulating factor activity, colony-stimulating factor activity, and histamineproducing cell-stimulating factor activity. J Immunol. 1983;131:282–7.

8. Saito H, Hatake K, Dvorak AM, Leiferman KM, Donnenberg AD, Arai N, Ishizaka K, Ishizaka T. Selective differentiation and proliferation of hematopoietic cells induced by recombinant human interleukins. Proc Natl Acad Sci U S A. 1988;85:2288–92.

9. Miyajima A. Molecular structure of the IL-3, GM-CSF and IL-5 receptors. Int J Cell Cloning. 1992;10:126–34.

10. Irani AMA, Schecter NM, Craig SS, DeBlois G, Schwartz LB. Two types of human mast cells that have distinct neutral protease compositions. Proc Natl Acad Sci U S A. 1986;83:4464–9.

11. Enerback L, Pipkorn U, Olofsson A. Intraepithelial migration of mucosal mast cells in hay fever. Int Arch Allergy Appl Immunol. 1986;80:44.

12. Pawankar R, Ra C.Heterogeneity of mast cells and T cells in the nasal mucosa. J Allergy Clin Immunol. 1996;98:249.

13. Dougherty RH, Sidhu SS, Raman K, Solon M, Solberg OD, Caughey GH, Woodruff PG, Fahy JV. Accumulation of intraepithelial mast cells with a unique protease phenotype in TH2-high asthma. J Allergy Clin Immunol. 2010;125:1046–53.

14. Corren J, Lemanske RF, Hanania NA, Korenblat PE, Parsey MV, Arron JR, Harris JM, Scheerens H, Wu LC, Su Z, Mosesova S, Eisner MD, Bohen SP, Matthews JG.Lebrikizumab treatment in adults with asthma. N Engl J Med. 2011;365:1088–98.

15. Kashiwakura J, Yokoi H, Saito H, Okayama Y. T cell proliferation by direct cross-talk between OX40 ligand on human mast cells and OX40 on human T cells: comparison of gene expression proles between human tonsillar and lung-cultured mast cells. J Immunol. 2004;173:5247–57.

16. Takabayashi T, Kato A, Peters AT, Suh LA, Carter R, Norton J, Grammer LC, Tan BK, Chandra RK, Conley DB, Kern RC, Fujieda S, Schleimer RP. Glandular mast cells with distinct phenotype are highly elevated in chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol. 2012;130:410–20.e5.

17. Kajiwara N, Sasaki T, Bradding P, Cruse G, Sagara H, Ohmori K, Saito H, Ra C, Okayama Y.Activation of human mast cells through the platelet-activating factor receptor. J Allergy Clin Immunol. 2010;125:1137–45.

18. Nakajima T, Inagaki N, Tanaka H, Tanaka A, Yoshikawa M, Tamari M, Hasegawa K, Matsumoto K, Tachimoto H, Ebisawa M, Tsujimoto G, Matsuda H, Nagai H, Saito H.Marked increase in CC chemokine

gene expression in both human and mouse mast cell transcriptomes following Fcε receptor I cross-linking: an interspecies comparison. Blood. 2002;100:3861–8.

19. Brightling CE, Bradding P, Symon FA, Holgate ST, Wardlaw AJ, Pavord ID. Mast-cell inltration of airway smooth muscle in asthma. N Engl J Med. 2002;346:1699–705.

20. Bischoff SC.Role of mast cells in allergic and nonallergic immune responses: comparison of human and murine data. Nat Rev Immunol. 2007;7:93–104.

21. Bradding P, Feather IH, Howarth PH, Mueller R, Roberts JA, Britten K, Bews JP, Hunt TC, Okayama Y, Heusser CH, Bullock GR, Church MK, Holgate ST. Interleukin 4 is localized to and released by human mast cells. J Exp Med. 1992;176:1381–6.

22. Pawankar R, Okuda M, Yssel H, Okumura K, Ra C. Nasal mast cells in perennial allergic rhinitics exhibit increased expression of the fc epsilonRI, CD40L, IL-4, and IL-13, and can induce IgE synthesis in B cells. J Clin Invest. 1997;99:1492–9.

23. Mukai K, Mindy T, Saito H, Galli S. Mast cells as sources of cytokines, chemokines and growth factors. Immunol Rev. 2018;282:121–50.

24. Moro K, Yamada T, Tanabe M, Takeuchi T, Ikawa T, Kawamoto H, etal. Innate production of T(H)2 cytokines by adipose tissue-associated c-kit(+)Sca-1(+) lymphoid cells. Nature. 2010;463:540–4.

25. Morita H, Moro K, Koyasu S.Innate lymphoid cells in allergic and nonallergic inammation. J Allergy Clin Immunol. 2016;138:1253–64.

26. Iikura M, Suto H, Kajiwara N, Oboki K, Ohno T, Okayama Y, Saito H, Galli SJ, Nakae S. IL-33 can promote survival, adhesion and cytokine production in human mast cells. Lab Investig. 2007;87:971–8.

27. Krämer S, Sellge G, Lorentz A, Krueger D, Schemann M, Feilhauer K, Gunzer F, Bischoff SC.Selective activation of human intestinal mast cells by Escherichia coli hemolysin. J Immunol. 2008;181:1438–45.

28. Nakajima S, Krishnan B, Ota H, Segura AM, Hattori T, Graham DY, Genta RM.Mast cell involvement in gastritis with or without helicobacter pylori infection. Gastroenterology. 1997;113:746–54.

29. Supajatura V, Ushio H, Nakao A, Akira S, Okumura K, Ra C, Ogawa H.Differential responses of mast cell toll-like receptors 2 and 4in allergy and innate immunity. J Clin Invest. 2002;109:1351–9.

30. Okumura S, Kashiwakura J, Tomita H, Matsumoto K, Nakajima T, Saito H, Okayama Y. Identication of specic gene expression prole in human mast cells via toll-like receptor 4 and FcεRI. Blood. 2003;102:2547–54.

31. Kato A, Chustz RT, Ogasawara T, Kulka M, Saito H, Schleimer RP, Matsumoto K. Dexamethasone and FK506 inhibit expression of distinct subsets of chemokines in human mast cells. J Immunol. 2009;182:7233–43.

Macrophage andMast Cell

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HideyukiKawauchi

Core Message

• There are various immunocompetent cells including the so-called macrophages in human nasal mucosa. Those cells are essential for a defense system against various invading pathogens such as bacteria and viruses. Those cells are also key players in the pathogenesis of rhinosinusitis and allergic rhinitis at the epithelial linings of nasal cavity and paranasal sinuses. Among them, macrophages are well known to have immunologically an important role as scavenger cells and antigen-presenting cells (APCs), in order to mount innate and acquired immunity in the upper and lower respiratory tract.

7.1 Part I: General Concept

ofMacrophage

7.1.1 Origin andClassication

ofMacrophages

Macrophage lineage cells are produced from pluripotent progenitor cells in the bone marrow [1]. These cells require a combined stimulus from colony-stimulating factor-1 (CSF-1) and factors

H. Kawauchi (*) Department of Microbiology, Faculty of Medicine, Shimane University, Izumo, Japan e-mail: Kawauchi@med.shimane-u.ac.jp

including interleukin-1 (IL-1), IL-3, GM-CSF, and interferon-gamma so far to differentiate to mature functional macrophages distributed to peripheral tissues through the blood vessel and lymphatic circulation. The denition and nomenclature of tissue-resident macrophage or recruiting inammatory macrophage are taken into account with evidence that the monocyte subpopulations may possess different propensities to give rise to particular resident populations, particularly in the mucosal surface such as the respiratory and digestive tract. It is clearly demonstrated that blood monocytes are heterogeneous in terms of their expression of key molecules, chemokine receptors, and cell adhesion molecules [2]. But it is yet to remain to categorize the monocyte subsets and how to further divide them in terms of their effector functions with distinct stimuli and locations.

7.1.2 Heterogeneity andMarkers

Tissue macrophages have many characteristics, including extensive lysosomes and stellate morphology and location, and they are heterogeneous in terms of function and surface marker expression, although we already know their phagocytic and antigen-presenting cell (APC) function. For example, CD11c in humans is a

https://doi.org/10.1007/978-3-031-12386-3_7

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Fig. 7.1 The mechanisms of host defense system from innate to adaptive immunity. PMN polymorphonuclear cells, CTL cytotoxic lymphocytes, Mo macrophages, DC dendritic cells

H. Kawauchi

marker for the mononuclear phagocyte system and was later shown to be an active complement receptor 4 (CR4) that is induced during macrophage maturation, although CD11c is clearly not linked to APC function. More importantly, various cell surface molecules in response to Toll-like receptor (TLR) signaling are functionally of particular interest because they determine the ability of macrophage lineage cells to interact with pathogens, and with other cell types, to generate appropriate innate and acquired immune responses (Fig. 7.1). But, there are no markers that are expressed specically and ubiquitously on all macrophage lineage cells except CSF-1 receptor. Co-stimulatory molecules (CD80, CD86, CD40) are considered to be essential for antigen uptake and antigen presentation from macrophages to T and B cells. And chemokine receptors and integrin family on macrophages may determine the recruitment and locations in tissues. However, for many reasons, surface marker expression cannot be taken as the sole indication of lineage, function, or destiny among macrophages [3].

7.1.3 Recruitment ofMacrophages into Peripheral Mucosal Inammatory Sites

Macrophages are recruited into peripheral mucosal inammatory sites with a wide range of different stimuli. If microbial infection takes place, neutrophil inltration precedes and releases toxic agents designed to kill extracellular pathogens, and then macrophages come and evacuate degraded pathogens and apoptotic neutrophils. The tissue-entering process of these cells is called chemotaxis. Chemokines are essential for the recruitment of inammatory cells into the peripheral mucosal inammatory sites [4]. Chemokines are subdivided based on the core cysteine motifs that form disulde bonds to fold the molecule. CC chemokines have two adjacent cysteines, while in CXC chemokines, there is an intervening amino acid. Chemokine receptors are classied in accordance with CCR, CXCR, and CX3CR families. The expression of specic chemokine receptors on different populations of macrophages and dendritic cells provides differ-

7 Macrophage andMast Cell

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Fig. 7.2 (a) Pattern recognition receptors on macrophages. (b) Cytokines and chemokines produced by macrophage via Toll-like receptors

ent kinds of effector mechanisms for their differential recruitment in response to different signals and, consequently, might modify inammatory reactions in mucosal sites such as the respiratory or digestive tract.

7.1.4 Phagocytosis

trations of charge that are unique to pathogens (socalled pathogen- associated molecular patterns) (Fig.7.2a, b). Particles may also be recognized indi- rectly if they are coated with opsonins such as specic antibodies or complement components.

7.1.5 Antigen Presentation by Macrophages andDendritic

Phagocytosis is a front-line defense against pathogen attack, so almost by denition, a pathogen is an infectious agent that avoids being killed by phagocytosis. Phagocytosis is a process that requires a mechanism for self–nonself discrimination [5]. Macrophages possess numerous receptors that allow the direct recognition of particles based on novel sugars, lipids, protein sequences, and concen-

It is generally accepted that antigens derived from extracellular sources must be taken up, processed by macrophages (phagocytic antigenpresenting cells) and dendritic cells (nonphagocytic or much less-phagocytic antigenpresenting cells), and afterward presented to T

Cells

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Fig. 7.3 Schematic function of dendritic cells

H. Kawauchi

lymphocytes (Fig. 7.3). The process of uptake, processing, and presentation is now well understood [6, 7]. However, recognition of the antigen major histocompatibility complex (MHC)-II by the T cell receptor is not sufcient to trigger T cell activation. Moreover, T cell activation needs second co-stimulatory signals from the APC in the form of specic cytokines and coreceptors.

7.1.6 Macrophage Activation

Activated macrophages are strongly positive for class II-MHC molecules and adapted to kill microorganisms and tumor cells and present antigen to T lymphocytes. The classical macrophage activating factor, produced by stimulated Th1 lymphocytes and NK cells, is interferon-gamma [8]. Classical macrophage activation, involving a synergistic interaction between interferongamma and a pathogen molecule such as lipopolysaccharide (LPS), is just one of the numerous interactions that occur between distinct stimuli. We know that LPS acts on macrophages to initiate a cascade of inammatory processes that are essential for innate immunity in the upper respi-

ratory tract such as middle and inner ear as well [9, 10]. T cell products are, of course, only part of the story of macrophage activation. Macrophages respond directly to pathogen-associated molecular patterns (PAMPs). They recognize them through the plasma membrane and cytoplasmic receptors such as the Toll-like receptors and intracellular receptors of the NOD-like receptor (NLR) family [11].

7.1.7 Role ofMacrophages inInduction ofImmune Tolerance

Immunological tolerance is described as no ability of acquired immunity to respond to specic antigens. Central tolerance induction occurs in the thymus for T cells and the bone marrow for B cells. The main mechanism for central tolerance in T cells is the induction of T cell death. Dendritic cells (DCs) are found in abundance in the thymus, where newly produced T cells are educated to become functional CD4+ T or CD8+ T cells and undergo selection to eliminate clones against self. Low-afnity reactive T cells are pos-

7 Macrophage andMast Cell

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itively selected and allowed to survive and reach the periphery. The mechanism of peripheral tolerance is a little different from the central one but includes T cell death, anergy, and active suppression by regulatory T cells (Tregs). In this mechanism, DCs could contribute by inducing apoptosis in T cells and by producing IL-10 that induces Tregs [12].

7.2 Part II: Distribution ofMacrophages inMurine andHuman Nasal Mucosa

There are so many reports as regards the actual distribution of macrophages and dendritic cells in murine and human nasal mucosa, by employing immunohistochemistry with various specic antibodies to those cells. Ichimiya and Kawauchi reported in their article that in nasal mucosa of conventional (CV) mice, Mac-1 positive macrophages, mast cells, and all cell types of lymphocyte subsets were present [13]. But, in the nasal mucosa of specic pathogen-free mice, all cell types were fewer in number than those of CV mice. And they concluded that macrophages and lymphocytes are mobilized to nasal mucosa, responding to continuous antigenic stimuli, and play an important role in the local defense mechanism of the upper respiratory tract. The analysis of macrophages in human nasal mucosa is abundant, and all published articles demonstrated the signicant contribution of macrophages to provoke immune responses and control inammation in nasal mucosa. Albegger investigated to nd out macrophages and lymphocytes in the cluster formation of human nasal polyps, employing light and electron microscopy [14]. And his data indicated that cell clusters consisted mainly of macrophages and lymphoid cells. In their study, within the clusters, the cells showed intimate physical contacts being performed by microvilli with varying lengths, suggesting cellto- cell interaction. These cell clusters may remind us of morphologically those found invitro and in vivo in the course of immune responses. Jahnsen etal. in their histological study of human nasal mucosa demonstrated the dense network of

human leukocyte antigen-DR+ cells with dendritic morphology not only in the epithelium but also in the lamina propria [15]. In addition, they also reported that, in both compartments, these cells could be divided into two main populations based on their phenotypic characteristics: the majority expressed a macrophage-like phenotype (CD11b+CD14+CD64+CD68+RFD7+), whereas the smaller population was predominantly constituted by CD1c+CD11c+ immature DCs. Krysko and Bachert aimed to determine macrophage phenotypes in nasal mucosa of chronic rhinosinusitis with nasal polyp (CRSwNP) and chronic rhinosinusitis without polyp (CRSsNP) and to examine phagocytosis of Staphylococcus aureus (S. aureus) in these pathologies [16]. They reported that more M2 macrophages were present in CRSwNP than in CRSsNP.This also was positively correlated with increased levels of IL-5, ECP, and locally produced IgE and decreased levels of IL-6, IL-1β, and IFN-γ. In their study, phagocytosis of S. aureus by human tissue-derived macrophages was reduced in CRSwNP as compared to macrophages from the control inferior turbinates. Furthermore, they concluded that decreased phagocytosis of S. aureus and an M2 activation phenotype in CRSwNP could potentially contribute to the persistence of chronic inammation in CRSwNP.

7.3 Part III: Modication ofMacrophages andDendritic Cells andIts Clinical Impact onInammatory Disorders Such asAllergic Rhinitis

In this part, we would like to introduce a couple of our experimental data in mice as regards how macrophages or dendritic cells are modifying the sinonasal inammation such as allergic rhinitis and rhinosinusitis. Mature DCs are established as unrivaled APCs in the initiation of immune responses, whereas steady-state DCs are demonstrated to induce peripheral T cell tolerance and consequently attenuate autoimmune-mediated inammation in animal experiments [17, 18].

350

wild type TLR2ko

IL–12(pg/ml)

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H. Kawauchi

In our series of animal experiments, macrophage activation with OK-432 and its effect on allergic rhinitis [19] and regulatory role of lymphoid chemokines CCL19 and CCL21 in the control of allergic rhinitis [20, 21] are introduced as examples, in order, to explain how macrophages or DCs modify the sinonasal inammation such as allergic rhinitis and rhinosinusitis.

7.3.1 Endogenous IL-12 Induction

fromMacrophages by OK-432 andIts Eect ontheMurine Allergic Rhinitis Model

OK-432, preparation of a low-virulence strain (Su) of Streptococcus pyogenes (Group A) killed by a penicillin and lyophilized, is a stiff inducer of Th1 cytokines and brings out anticancer effect in cancer-bearing mice. OK-432 has been reported to consist of many bacterial compo-

nents, such as peptidoglycan and M-protein. Recently, Toll-like receptor (TLR) family proteins are reported to play a role of recognition of bacterial components and induce interleukin-12 (IL-12) from macrophages. So, we have examined the role of TLR2 for the recognition of OK-432 by macrophages and the effects of OK-432 on allergic rhinitis model. As results, interestingly, IL-12 production by macrophages derived from TLR2 knockout mice was markedly reduced in comparison with that of macrophages derived from wild type of mice (Fig. 7.4). Besides, no regulatory effect of OK-432 was observed on allergic rhinitis model in TLR2 knockout mice, although nasal symptom of wild type of mice was attenuated upon nasal antigen challenge after systemic sensitization with OK-432 pretreatment (Figs.7.5 and 7.6). These ndings strongly suggest that OK-432 pretreatment provokes macrophage activation to induce IL-12 via TLR2 signaling pathway and conse-

300 250

200 150 100

None

LipidA Lipoprotein 0.1

250

200

150

100

IL–12(pg/ml)

None

Fig. 7.4 IL-12 production from macrophages with OK-432 stimulation in C3H/HeN, C3H/HeJ, and TLR2 knockout mice

∗∗

Ok–432 (µg/ml)

C3H/HeN

∗

LipidA Lipoprotein 0.1

Ok–432 (µg/ml) Ok–432 (µg/ml)

∗

None

10 10

LipidA Lipoprotein 0.1

C3H/HeJ (TLR4–deficientmutant)

∗

None

LipidA Lipoprotein 0.1

∗

Ok–432 (µg/ml)

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Соседние файлы в папке Библиотека им академика М.И. Перельмана

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30.08.202645 Мб0Книга_4465_Библиотеки_им_академика_М_И_Перельмана.pdf
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30.08.202644 Мб0Книга_4466_Библиотеки_им_академика_М_И_Перельмана.pdf
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30.08.202643 Мб0Книга_4470_Библиотеки_им_академика_М_И_Перельмана.pdf
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30.08.202643 Мб0Книга_4471_Библиотеки_им_академика_М_И_Перельмана.pdf
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30.08.202642 Мб0Книга_4472_Библиотеки_им_академика_М_И_Перельмана.pdf
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30.08.202642 Мб0Книга_4473_Библиотеки_им_академика_М_И_Перельмана.pdf
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30.08.202641 Мб0Книга_4475_Библиотеки_им_академика_М_И_Перельмана.pdf
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30.08.202641 Мб0Книга_4476_Библиотеки_им_академика_М_И_Перельмана.pdf
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31.08.202641 Мб0Книга_4478_Библиотеки_им_академика_М_И_Перельмана.pdf
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31.08.202641 Мб0Книга_4479_Библиотеки_им_академика_М_И_Перельмана.pdf
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31.08.202641 Мб0Книга_4480_Библиотеки_им_академика_М_И_Перельмана.pdf