Platelet-derived microparticles and soluble P-selectin as platelet activation markers in patients with atopic dermatitis☆
Introduction
It is increasingly widely understood that platelets have roles in inflammatory and immune processes, in addition to their function in hemostasis and thrombosis[1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15]. On activation by thrombin, collagen, adenosine diphosphate, chemokines and high shear stress, platelets rapidly release soluble immune mediators stored in α or dense granules, including chemokines, cytokines, and antibacterial proteins that induce and maintain inflammatory reactions [1], [2]. Platelets also migrate extravascularly and accumulate in inflammatory lesions concomitantly with leukocytes in response to a stimulation such as antigen exposure [3], [4], and have been associated with pathomechanisms of inflammatory disorders such as asthma[3], [4], [5], [6], [7], [8], [9], [10], [11], arthritis [12], [13] and inflammatory bowel disease [14], [15], [16].
Atopic dermatitis (AD) is a recurrent pruritic eczematous skin disease that is characterized by high serum IgE levels, increased levels of T helper 2-type cytokines such as interleukin (IL)-4, IL-5 and IL-13, positive immediate hypersensitivity to food or environmental allergens, and peripheral blood eosinophilia [17], [18]. In patients with AD, scratching due to severe itch often results in excoriation and subsequent platelet aggregation at the inflamed skin lesion, implying that blood platelets may be activated compared with those in normal individuals. We and others have shown that plasma levels of β-thromboglobulin and platelet factor 4, which are widely known as platelet activation markers, are significantly increased in patients with AD [19], [20], suggesting that platelets may be important in the pathomechanism of AD.
During platelet activation, microparticles are formed from the surface membrane of platelets by an exocytotic budding process [21]. These platelet-derived microparticles (PDMPs) range in size from 0.02 to 0.1 μm and have both pro- and anticoagulant activities[22]. PDMPs have been detected in blood from patients with activated coagulation and fibrinolysis [23] and autoimmune thrombocytopenia [24], [25], and also after cardiopulmonary bypass [26]. The adhesion molecule P-selectin is also expressed on activated platelets. This molecule is stored in the α-granules of platelets and in Weibel-Palade bodies of endothelial cells. Upon cell activation, P-selectin is expressed on the cell surface and secreted into plasma [27], [28]. Soluble P-selectin (sP-selectin) in plasma has been reported to originate from platelets [29]. Increased levels of sP-selectin are found in diseases such as thrombotic thrombocytopenic purpura [30], eclampsia [31], thromboembolic diseases [32], and diabetes [33]. Based on these findings, PDMPs and sP-selectin are regarded as platelet activation markers, but the plasma levels of these markers have not been determined in patients with AD.
In the current study, we evaluated platelet activity based on the plasma levels of PDMPs and sP-selectin in AD patients, non-atopic urticaria patients and healthy controls, and then investigated the relationship between the platelet activation markers and clinical parameters in AD. We also examined changes in the marker levels in association with improvement of eruption in AD.
Section snippets
Subjects
Forty-six adult patients (21 men, 25 women; median age: 28 years old; range: 17–52 years old) with AD were enrolled in the study. Diagnosis of AD was based on the criteria of Hanifin and Rajka [34] and clinical severity was determined using the scoring AD (SCORAD) index [35] (median score: 47.2; range: 24.5–59.8). The peripheral eosinophil count (median: 780; range: 300–1600/μl; reference range: 50–590/μl), serum IgE (median: 4150; range: 839–81200 IU/ml; reference range: 0–380 IU/ml), and
Plasma levels of PDMPs and sP-selectin in AD patients and non-atopic individuals
The plasma levels of PDMPs were significantly higher in AD patients (42.3 ± 6.2 U/ml) compared with those in non-atopic urticaria patients (20.7 ± 4.4 U/ml, P < 0.01) or control subjects (18.2 ± 2.5 U/ml, P < 0.01), and a similar significant elevation of plasma sP-selectin levels was found in AD patients (148.7 ± 10.1 U/ml) compared to urticaria patients (101.8 ± 9.5 U/ml, P < 0.01) and controls (98.7 ± 8.0 ng/ml, P < 0.01) (Fig. 1A). These data suggest that circulating platelets are activated in patients with AD
Discussion
The results of the study show for the first time that plasma levels of PDMPs and sP-selectin are both significantly elevated in AD patients compared with urticaria patients and healthy controls, suggesting that circulating platelets are activated in AD patients. The SCORAD index was significantly associated with the plasma levels of PDMPs and sP-selectin, and the elevated levels were significantly reduced after clinical improvement of skin lesions. We have also observed elevation of plasma
Acknowledgments
This study was supported by a grant from the Ministry of Education, Science, Sports, and Culture (to R.T.M. and N.K.), a grant for Basic Dermatological Research from Shiseido Co. Ltd. (to R.T.M.), and a grant from the Cosmetology Research Foundation (to N.K.).
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2019, Journal of Allergy and Clinical ImmunologyA novel mechanism for improvement of dry skin by dietary milk phospholipids: Effect on epidermal covalently bound ceramides and skin inflammation in hairless mice
2015, Journal of Dermatological ScienceCitation Excerpt :Skin injury, caused by environmental allergens, scratching, or microbial toxins, activates keratinocytes to release proinflammatory cytokines and chemokines that induce the expression of adhesion molecules on the vascular endothelium and facilitate the extravasation of inflammatory cells into the skin [13]. Serum levels of thymus and activation-regulated chemokine (TARC) [14], thymic stromal lymphopoietin (TSLP) [15], and soluble P-selectin (sP-selectin) [16] appear to be significantly higher in patients with AD than in people without this type of skin condition. Thus, serum markers of chemokines and platelet activator appear to be useful for assessing the severity of dry skin conditions.
Important roles of platelets as immune cells in the skin
2015, Journal of Dermatological ScienceCitation Excerpt :In individuals with AD, scratching due to pruritus often results in bleeding and excoriation at the inflamed skin lesion, implying that blood platelets may be activated compared with those in healthy individuals. The levels of platelet-derived chemokines such as PF-4 (CXCL4) and β-TG (CXCL7), PDMPs and soluble P-selectin in blood, that are known as platelet activation indicators, are greatly elevated in patients with AD [32,33]. In addition, plasma levels of serotonin are also elevated in patients with AD [28].
Links between allergy and cardiovascular or hemostatic system
2014, International Journal of CardiologyCitation Excerpt :A number of potent mediators of vasodilatation and enhanced vascular permeability are secreted by blood platelets, which together with platelet-released substances chemoattracting the immune cells promote the development of allergic inflammation [119–121]. Increased platelet activation has been observed in AD [120–122] with elevated plasma levels of platelet activation blood markers in AD patients reported by several independent groups [123–128]. Kasperska-Zając et al. [123] observed increased plasma β-thromboglobulin (β-TG) and platelet factor-4 (PF4) levels in AD patients when compared to healthy controls.
Protein kinase C-theta in platelet activation
2011, FEBS LettersCitation Excerpt :The plasma membrane expressed CD62P serves as an adhesion receptor that can interact with P-selectin glycoprotein ligand-1 (PSGL-1) on the surface of leukocytes, thereby promoting platelet-leukocyte adhesion, leukocyte activation and adhesion to endothelial cells, and trans-migration to sites of inflammation [88,89]. Expression of CD62P on the outer surface of platelets directly correlates with platelet degranulation and secretion, and therefore serves as a marker of platelet activation [90–92]. A positive regulatory role for PKCθ in PAR-linked signaling pathways was demonstrated by Nagy et al. [68] in human and mouse platelets.
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Platelet activation markers in patients with atopic dermatitis