Cent. Eur. J. Biol. • 9(9) • 2014 • 869-873 DOI: 10.2478/s11535-014-0319-9

Central European Journal of Biology

The role of factor XIII-A in the development of inflammatory skin lesions

Mini-Review Marcin Włodarczyk1*, Aleksandra Sobolewska1, Aleksandra Lesiak2, Joanna Narbutt2

1Students’ Faculty at the Department of Dermatology and Venereology, Medical University of Lodz, 90-647 Lodz, Poland

2Department of Dermatology and Venereology, Medical University of Lodz, 90-647 Lodz, Poland

Received 30 January 2014; Accepted 20 March 2014

Abstract: Factor XIII (FXIII) is a unique clotting factor activated in the last stage of the cascade, with multiple other plasmatic and cellular functions, outside of the traditional homeostasis. Literature data show that FXIII is expressed in skin lesions in the course of various inflammatory skin disorders. Dermis contains a series of and dendritic cells, which express different phenotypes including FXIII. Increased levels of FXIII-positive cells are present in specific cutaneous inflammatory and fibrotic conditions. The aim of this review is to provide the relationship between FXIII and the development of the inflammatory skin lesions.

Keywords: Factor XIII • Macrophages • Dermal dendrocytes • Inflammation • Skin lesions • Psoriasis © Versita Sp. z o.o.

1. Introduction In addition to the functional haemostatic role in blood coagulation cascade, FXIII-A’s role is significant Plasma factor XIII (pFXIII) is a consisting of two to multiple extra- and intracellular functions. FXIII-A, catalytic A subunits (FXIII-A) exerting a as a potential active subunit is also present in the activity upon its activation, and two inhibitory B subunits cytoplasm of , , macrophages, (FXIII-B). FXIII-A is expressed primarily in cells of bone dendritic cells, chondrocytes, osteoblasts, and marrow origin, but it is not fully understood how FXIII-A osteocytes. It can be detected from the early stage of is released from the cellular compartments. FXIII-B monoblasts in the bone marrow via blood monocytes is a qlycoprotein synthesized and secreted by to the connective tissue macrophages [4-11]. as a result of excessive plasma levels of FXIII-A [1-3]. FXIII-A is considered as a positive marker FXIII-A is a blood coagulation proto-transglutaminase, of the cell line in which it acts as an intracellular which becomes activated in the last stage of the clotting transglutaminase with roles in various intracytoplasmatic cascade as a result of the concerted action of and intranuclear processes. The role of intracellular and Ca2+. The key haemostatic function of FXIII-A is FXIII-A in platelets, monocytes, macrophages, and other stabilization by cross-linking fibrin chains and covalently inflammatory cells is an open and widely discussed attaching to the main inhibitor of , α2-plasmin question. It was suggested that this factor is involved inhibitor (α2PI). FXIII-A activity considerably enhances in intracellular presentation, distribution, and other fibrin stiffness and rigidity and makes it more resistant possible activation of cells’ secretion [2,6]. against shear stress. The stabilization effect of the FXIII-A In healthy skin FXIII-A is confined to the dermis, has the predominant role in protecting newly formed with greater expression within the papillary dermis, fibrin from elimination by plasmin. The importance of at the dermo-epidermal junction, and in loose areolar these haemostatic mechanisms is underlined by severe connective tissue around the cutaneous appendages bleeding diathesis of FXIII-A deficient patients [4]. [12]. It is also used as a diagnostic marker in various

* E-mail: [email protected] 869 FXIII-A in inflammatory skin lesions

dermatological diseases ranging from inflammatory C-reactive protein (CRP) in inflammatory process were lesions such as psoriasis, eczema, spongiotic considered. dermatoses, lichen planus, toxic epidermal necrolysis, The expression of FXIII-A specific mRNA in a number and uricaria, to malignancies such as dermatofibromas, of -derived macrophages including tumor Kaposi’s sarcomas, basal cell carcinomas and malignant macrophages, histocytes, dendritic reticulum cells, melanomas [4,10,12-19]. perivascular dendritic macrophages, and dermal dendrocytes was demonstrated, and their responsibility for the FXIII-A synthesis was strongly suggested 2. FXIII-A in inflammatory processes [6,8,12,15,22-25]. It was also observed that induction of monocytes differentiation into antigen presenting There is information about the relationship between dendritic cells resulted in highly elevated FXIII-A polymorphonuclear (PMN) leukocytes and the activation expression, and its crucial role by fibrin crosslinking of FXIII-A. The activated inflammatory PMN leukocytes in this transformation was suggested. The majority are the main source of human neutrophile elastase of macrophages in granulomas of sarcoidosis and (HNE), cathepisn G and metalloproteinases, which are tuberculosis are negative for FXIII-a, that fact indicates secreted upon their activation. This hypothesis was that the induction of the classical activation pathway by confirmed in studies demonstrating that HNE induced interferon γ (IFN- γ) or interleukin 6 (IL-6) down-regulated a cleavage of pFXIII or cellular dimeric form of XIII-A and FXIII-A mRNA and protein expression in cultured resulted in their catalytic effect activation. It was also macrophages. In the same study, it was suggested that suggested that HNE-activated FXIII-A was responsible up-regulation of the FXIII-A in macrophages indicates for cross-linking fibrin γ-, and α-chains. HNE-activated its activation on the alternative pathway induced by FXIII-A stabilize fibrin tissue deposits, the persistence the interleukin 4 (IL-4) and interleukin 13 (IL-13) [26]. of which is a hallmark of many acute and chronic IL-4 with granulocyte/-colony stimulating inflammatory diseases [6,20]. factor (GM-CSF) is also involved in the expression of The effect of active FXIII-A on leukocytes is an high levels of FXIII-A mRNA and induction of monocytes additional aspect of their interactions. It is suggested differentiation into antigen-presenting dendritic cells that activated FXIII-A improved the proliferation of present in tissue, like subsets of dermal dendrocytes in peripheral blood leukocytes, accelerated their migration, inflammatory response. FXIII-A as an indirect marker of and significantly reduced their apoptosis rate, leading the alternative macrophage activation pathway suggests to the development of the inflammatory infiltrate [6,20]. that FXIII-A-positive macrophages play an important The association of the enhanced cell proliferation and role in conditions where extracellular remodeling is the survival induced by FXIIIa with the down-regulation key feature. The current microarray technique analysis of thrombospondin-1 (TSP-1) and up-regulation of show that alternatively activated human macrophages c-Jun and early growth response protein 1(Egr-1) was FXIII-A-positive were involved in the regulation of observed [21]. expression leading to the most prominent differences Another interesting aspect of the indirect relationship in immunological protein activity [1,6]. Intracellular between FXIII-A and macrophages concerns the FXIII-A functions of FXIII-A in monocytes and macrophages related generation of monocyte chemotactic factor. in few studies were concerned, suggesting that In a recent study it was shown that a plasma protein FXIII-A has significant involvement in the inhibition with the features of ribosomal protein S19, is dimerized mechanism of phagocytosis activity. In another report by FXIIIa and converted into a monocyte-selective the intracellular role of FXIII-A in cell locomotion of chemoattractive factor [8,22]. Such monocyte specific dendritic cells was observed. As both phagocytosis chemotactic factors related to activated FXIII-A could be and cell migration involve in intracellular contractile involved in recruiting monocytes and in the development elements, the relationship between cytoplasmic FXIII-A of inflammatory infiltration. and cytoskeletal components seems feasible [1,6,20]. Fibrin derivatives are involved in inflammatory processes and the generation of a stable fibrin network is necessary for sufficient inflammation control. The 3. FXIII-A in inflammatory skin lesions density and stability of fibrin networks depend on FXIIIA. In the study conducted by Hopped et al. [23], FXIII-A Inflammatory skin dermatoses are a heterogeneous gene variants modulating inflammation by influencing group of entities which manifestation and progression fibrin crosslinking were identified. These haemostatic are driven by the interaction of multiple genetic as well gene variants as novel genetic determinants of as environmental factors. In recent studies the role of

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FXIII-A as a potential modulator factor in development eczema, spongiotic dermatoses, lichen planus, toxic of inflammatory process was indicated [1,4,6,9,12,15]. epidermal necrolysis, and uricaria was observed Generally, FXIII-A-positive cells in pathological skin [4,10,12-18,27-29]. Migration of FXIII-A-positive lesions can be divided into expression in inflammatory, inflammatory macrophages and dermal dendrocytes fibrosis, and in neoplastic pathology. Inflammatory in association with other inflammatory cells into the macrophages may release or express FXIII-A and epidermal compartment in chronic plaque psoriasis take a crucial role in the development and course was reported. It was postulated that FXIII-A dermal of inflammation processes in dermis (Figure 1). dendrocytes play a significant role in skin lymphocyte The important role assigned to FXIII-A in inflammation locomotion through tumor necrosis factor alpha (TNF-α) is related to the fact that several adhesive as the main proinflammatory cytokine, which suggests are transglutaminase substrates. The FXIII-A related a crucial role of factor in formation of the psoriasis skin may play an important role in formation of lesions. The FXIII-A-positive dermal dendrocytes may inflammatory infiltration, by modulation of cell adhesion proceed to development of psoriasis via TNF-α, which and migration. The role of FXIII-A in inflammatory skin stimulates keratinocyte to produce interleukin 8 (IL-8) lesions is important with wide-range interactions but still and to express ICAM. In acute and chronic graft-versus- remains not-fully understood. The reaction catalyzed host disease (GVHD), high dermal levels of FXIII-A by activated FXIII-A influence the structural integrity were observed [17]. Also observed was the migration and tensegrity of FXIII-A-positive dermal dendritic cell- of FXIII-A-positive cells from the papillary dermis rich tissues. Change in the FXIII-A-positive dermal into the epidermis in close proximity to lymphocytes, dendrocytes is characterized by intense cytoskeletal macrophages and other inflammatory cells in inflamed reorganization resulting in many cellular functions skin of atopic eczema or psoriasis [8,29]. and improvement of tensegrity. The intracellular The study conducted by Journdosson et al. [27] activity of FXIII-A may be responsible for proliferation, found that FXIII-A dermal dendrocytes in the elicitation differentiation, migration, survival and excessive phase of contact hypersensitivity constitute a major inflammatory cytokine secretion of dermal dendrocytes accessory cell population in the dermis. The role of [5,6,8,9,12,15]. FXIII-A in antigen presentation and its relationship to the The elevated dermal expression of FXIII-A in expression of antigen presenting molecules CD1 and the inflammatory skin diseases such as psoriasis, MHC II were suggested.

Figure 1. A hypothetic scheme for the involvement of FXIII-A pleiotropic role in inflammatory infiltration development.

871 FXIII-A in inflammatory skin lesions

Other studies showed that FXIII-A is considered in multiple effects in dermis by plasmatic signal factor, as a positive disease-nonspecific marker of skin clotting cascade, and extra- and intracellular acting on lesions with a possible common mechanism of dermal inflammatory cells. Factor XIII-A level may be used in dendrocytes, macrophages, lymphocytes and plasma diagnosis and could become the prognostic indicator of activity [14,19,30]. exacerbations and remissions in chronic inflammatory In conclusion, FXIII-A plays a significant, wide- skin diseases. Further studies on the FXIII-A range, but not-fully understood role in the development pathomechanism may facilitate diagnostic procedures of inflammatory skin disorders. Factor XIII-A participates and treatment.

References

[1] Muszbek L, Bereczky Z, Bagoly Z, Komaromi I, [11] Schaumburg-Lever G, Gehring B, Kaiserling E: Katona E: Factor XIII: a coagulation factor with Ultrastructural localization of factor XIIIa. J Cutan multiple plasmatic and cellular functions. Physiol Pathol 1994;21:129-134. Rev 2011;91:931-972. [12] Torocsik D, Bardos H, Hatalyak Z, Dezso B, [2] Adany R, Bardos H: Factor XIII subunit A as an Losonczy G, Paragh L, Peter Z, Balazs M, intracellular transglutaminase. Cell Mol Life Sci Remenyik E, Adany R: Detection of factor XIII-A 2003;60:1049-1060. is a valuable tool for distinguishing dendritic cells [3] Nakano Y, Al-Jallad HF, Mousa A, Kaartinen and tissue macrophages in granuloma annulare MT: Expression and localization of plasma and necrobiosis lipoidica. J Eur Acad Dermatol transglutaminase factor XIIIA in bone. J Histochem Venereol 2013. Cytochem 2007;55:675-685. [13] Altman DA, Nickoloff BJ, Fivenson DP: Differential [4] Cerio R, Griffiths CE, Cooper KD, Nickoloff BJ, expression of factor XIIIa and CD34 in cutaneous Headington JT: Characterization of factor XIIIa mesenchymal tumors. J Cutan Pathol 1993;20:154- positive dermal dendritic cells in normal and 158. inflamed skin. Br J Dermatol 1989;121:421-431. [14] Cerio R, Spaull J, Oliver GF, Jones WE: A study [5] Akagi A, Tajima S, Ishibashi A, Matsubara Y, of factor XIIIa and MAC 387 immunolabeling in Takehana M, Kobayashi S, Yamaguchi N: Type XVI normal and pathological skin. Am J Dermatopathol collagen is expressed in factor XIIIa+ monocyte- 1990;12:221-233. derived dermal dendrocytes and constitutes [15] Criado PR, Jardim Criado RF, Sotto MN, Pagliari a potential substrate for factor XIIIa. J Invest C, Takakura CH, Vasconcellos C: Dermal Dermatol 2002;118:267-274. dendrocytes FXIIIA+ phagocytizing extruded mast [6] Bagoly Z, Katona E, Muszbek L: Factor XIII and cell granules in drug-induced acute urticaria. J Eur inflammatory cells. Thromb Res 2012;129 Suppl Acad Dermatol Venereol 2013;27:e105-e112. 2:S77-S81. [16] Denton KJ, Cotton DW, Wright A, Hird P: Factor [7] Henriksson P, Becker S, Lynch G, McDonagh J: XIIIa in nodular malignant melanoma and Spitz Identification of intracellular factor XIII in human naevi. Br J Dermatol 1990;123:783-786. monocytes and macrophages. J Clin Invest [17] Hermanns-Le T, Paquet P, Pierard-Franchimont 1985;76:528-534. C, Arrese JE, Pierard GE: Regulatory function [8] Jayo A, Conde I, Lastres P, Jimenez-Yuste V, of factor-XIIIa-positive dendrocytes in incipient Gonzalez-Manchon C: Possible role for cellular toxic epidermal necrolysis and graft-versus-host FXIII in monocyte-derived dendritic cell motility. reaction. A hypothesis. Dermatology 1999;198:184- Eur J Cell Biol 2009;88:423-431. 186. [9] Quatresooz P, Paquet P, Hermanns-Le T, Pierard [18] Nickoloff BJ, Griffiths CE: Factor XIIIa-expressing GE: Molecular mapping of Factor XIIIa-enriched dermal dendrocytes in AIDS-associated cutaneous dendrocytes in the skin (Review). Int J Mol Med Kaposi’s sarcomas. Science 1989;243:1736-1737. 2008;22:403-409. [19] Zaba LC, Fuentes-Duculan J, Steinman RM, [10] Regezi JA, Daniels TE, Saeb F, Nickoloff BJ: Krueger JG, Lowes MA: Normal human dermis Increased submucosal factor XIIIa-positive contains distinct populations of CD11c+BDCA-1+ dendrocytes in oral lichen planus. J Oral Pathol dendritic cells and CD163+FXIIIA+ macrophages. Med 1994;23:114-118. J Clin Invest 2007;117:2517-2525.

872 M. Włodarczyk et al.

[20] Bagoly Z, Fazakas F, Komaromi I, Haramura G, gene expression in alternatively activated human Toth E, Muszbek L: Cleavage of factor XIII by macrophages. Thromb Haemost 2010;104:709- human neutrophil elastase results in a novel active 717. truncated form of factor XIII A subunit. Thromb [26] Navarrete M, Garcia J, Dutzan N, Henriquez L, Haemost 2008;99:668-674. Puente J, Carvajal P, Hernandez M, Gamonal [21] Dardik R, Krapp T, Rosenthal E, Loscalzo J, Inbal J: IFN-gamma, IL-6, IL-4, and FXIII-A as A: Effect of FXIII on monocyte and fibroblast Indirect Markers of the Classical and Alternative function. Cell Physiol Biochem 2007;19:113-120. Macrophage Activation Pathways in Chronic [22] Cordell PA, Kile BT, Standeven KF, Josefsson EC, Periodontitis. J Periodontol 2013. Pease RJ, Grant PJ: Association of coagulation [27] Jorundsson E, Press CM, Landsverk T: Factor factor XIII-A with Golgi within monocyte- XIIIa positive dendritic cells are a major accessory macrophages: implications for subcellular trafficking cell population in the elicitation phase of DNCB- and secretion. Blood 2010;115:2674-2681. induced contact hypersensitivity. Vet Immunol [23] Hoppe B, Haupl T, Skapenko A, Ziemer S, Tauber Immunopathol 1999;71:99-113. R, Salama A, Schulze-Koops H, Burmester GR, [28] Talme T, Schultzberg M, Sundqvist KG, Marcusson Dorner T: and factor XIII A-subunit JA: Somatostatin- and factor XIIIa-immunoreactive genotypes interactively influence C-reactive cells in psoriasis during clobetasol propionate protein levels during inflammation. Ann Rheum Dis and calciprotriol treatment. Acta Derm Venereol 2012;71:1163-1169. 1999;79:44-48. [24] Semba U, Chen J, Ota Y, Jia N, Arima H, Nishiura [29] Okamoto M, Yamamoto T, Matsubara S, Kukita H, Yamamoto T: A plasma protein indistinguishable I, Takeya M, Miyauchi Y, Kambara T: Factor from ribosomal protein S19: conversion to a XIII-dependent generation of 5th complement monocyte chemotactic factor by a factor XIIIa- component(C5)-derived monocyte chemotactic catalyzed reaction on activated membrane factor coinciding with plasma clotting. Biochim phosphatidylserine in association with blood Biophys Acta 1992;1138:53-61. coagulation. Am J Pathol 2010;176:1542-1551. [30] Torocsik D, Bardos H, Nagy L, Adany R: [25] Torocsik D, Szeles L, Paragh G, Jr., Rakosy Z, Identification of factor XIII-A as a marker of Bardos H, Nagy L, Balazs M, Inbal A, Adany alternative macrophage activation. Cell Mol Life R: Factor XIII-A is involved in the regulation of Sci 2005;62:2132-2139.

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