Neutrophil-Derived Protein S100A8/A9 Alters the Platelet Proteome in Acute Myocardial Infarction and Is Associated With Changes in Platelet Reactivity
Abhishek JoshiLukas SchmidtSean A. BurnapRuifang LuMelissa V. ChanPaul C. ArmstrongFerheen BaigClemens GutmannPeter WilleitPeter SanterTemo BarwariKonstantinos TheofilatosStefan KiechlJohann WilleitTimothy D. WarnerAnthony MathurManuel Mayr
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Objective: Platelets are central to acute myocardial infarction (MI). How the platelet proteome is altered during MI is unknown. We sought to describe changes in the platelet proteome during MI and identify corresponding functional consequences. Approach and Results: Platelets from patients experiencing ST-segment–elevation MI (STEMI) before and 3 days after treatment (n=30) and matched patients with severe stable coronary artery disease before and 3 days after coronary artery bypass grafting (n=25) underwent quantitative proteomic analysis. Elevations in the proteins S100A8 and S100A9 were detected at the time of STEMI compared with stable coronary artery disease (S100A8: FC, 2.00; false discovery rate, 0.05; S100A9: FC, 2.28; false discovery rate, 0.005). During STEMI, only S100A8 mRNA and protein levels were correlated in platelets ( R =0.46, P =0.012). To determine whether de novo protein synthesis occurs, activated platelets were incubated with 13C-labeled amino acids for 24 hours and analyzed by mass spectrometry. No incorporation was confidently detected. Platelet S100A8 and S100A9 was strongly correlated with neutrophil abundance at the time of STEMI. When isolated platelets and neutrophils were coincubated under quiescent and activated conditions, release of S100A8 from neutrophils resulted in uptake of S100A8 by platelets. Neutrophils released S100A8/A9 as free heterodimer, rather than in vesicles or extracellular traps. In the community-based Bruneck study (n=338), plasma S100A8/A9 was inversely associated with platelet reactivity—an effect abrogated by aspirin. Conclusions: Leukocyte-to-platelet protein transfer may occur in a thromboinflammatory environment such as STEMI. Plasma S100A8/A9 was negatively associated with platelet reactivity. These findings highlight neutrophils as potential modifiers for thrombotic therapies in coronary artery disease.Keywords:
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Proteome
S100A8
The expression of calcium-binding protein S100A9 was investigated in 23 matched sets of colorectal carcinoma and normal colon mucosa using two-dimensional gel electrophoresis. We found that, from a group of 23 patients, the level of S100A9 protein, in comparison with matched normal colon mucosa, was significantly increased in malignant tissues of 16 patients (70%). Furthermore, an additional protein, identified by matrix-assisted laser desorption/ionization - mass spectrometry (MALDI-MS) as S100A8, exhibited an increased expression in the same specimens of malignant tissues as the S100A9 protein. The immunohistological analysis revealed the accumulation of S100A9 positive cells, macrophages and polymorphonuclear leukocytes along the invasive margin of colorectal carcinoma. The S100A8 protein was found to be produced in the same location. The possible participation of both proteins and, especially, its heterodimeric complex calprotectin in colorectal carcinoma regression could be taken into account.
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The expression of calcium-binding protein S100A9 was investigated in 23 matched sets of colorectal carcinoma and normal colon mucosa using two-dimensional gel electrophoresis. We found that, from a group of 23 patients, the level of S100A9 protein, in comparison with matched normal colon mucosa, was significantly increased in malignant tissues of 16 patients (70%). Furthermore, an additional protein, identified by matrix-assisted laser desorption/ionization - mass spectrometry (MALDI-MS) as S100A8, exhibited an increased expression in the same specimens of malignant tissues as the S100A9 protein. The immunohistological analysis revealed the accumulation of S100A9 positive cells, macrophages and polymorphonuclear leukocytes along the invasive margin of colorectal carcinoma. The S100A8 protein was found to be produced in the same location. The possible participation of both proteins and, especially, its heterodimeric complex calprotectin in colorectal carcinoma regression could be taken into account.
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High concentrations of the damage-associated molecular patterns S100A8 and S100A9 are found in skin and serum from patients suffering from psoriasis, an IL-17-related disease. Notably, although the expression of these proteins correlates with psoriatic disease severity, the exact function of S100A8 and S100A9 in psoriasis pathogenesis remains unclear. In this study, we investigated the role of S100A8 and S100A9 in psoriasis-associated skin hyperplasia and immune responses using
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Abstract S100A8 and S100A9 are small calcium-binding proteins that are highly expressed in neutrophil and monocyte cytosol and are found at high levels in the extracellular milieu during inflammatory conditions. Although reports have proposed a proinflammatory role for these proteins, their extracellular activity remains controversial. In this study, we report that S100A8, S100A9, and S100A8/A9 caused neutrophil chemotaxis at concentrations of 10−12–10−9 M. S100A8, S100A9, and S100A8/A9 stimulated shedding of L-selectin, up-regulated and activated Mac-1, and induced neutrophil adhesion to fibrinogen in vitro. Neutralization with Ab showed that this adhesion was mediated by Mac-1. Neutrophil adhesion was also associated with an increase in intracellular calcium levels. However, neutrophil activation by S100A8, S100A9, and S100A8/A9 did not induce actin polymerization. Finally, injection of S100A8, S100A9, or S100A8/A9 into a murine air pouch model led to rapid, transient accumulation of neutrophils confirming their activities in vivo. These studies 1) show that S100A8, S100A9, and S100A8/A9 are potent stimulators of neutrophils and 2) strongly suggest that these proteins are involved in neutrophil migration to inflammatory sites.
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S100A8 and S100A9 are important members of the S100 protein family. It was previously deemed that S100A8 and S100A9 participated in inflammatory reactions, were associated with innate immunity, and played key roles in regulating tumor cell generation, infiltration and transformation. However, recent studies have suggested that when the human body is under some special conditions, such as wound healing and ultraviolet irradiation, epithelial cells are induced to secrete both S100A8 and S100A9 proteins, which are also up-regulated in some dermatoses. With further insight into the relationship between S100A8, S100A9 and dermatoses, new strategies will be developed for the diagnosis and treatment of these entities.
Key words:
Skin diseases; S100 proteins; Calgranulin A; Calgranulin B; Wound healing
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背景 S100A8 和 S100A9 是在肿瘤生长，前进和 invasion.This 的重要功能学习的整个 S100 家庭显示试图决定二的表示，这家庭索引的建议的EF手 type.Previous 研究的二个Ca2+有约束力的地点的存在描绘的 S100 蛋白质家庭的二个成员， S100A8 和 S100A9 ，在肺癌症纸巾和正常的肺，有临床的 features.Methods A 的纸巾和它的关联与许多 cl 60 总计盒子 S100A9 P=0.022/0.026 )更高的表示被发现与腺癌，发炎和阶段 lesion.Conclusions S100A8 的临床的特征被相关的 .The ， S100A9 起来规定在肺腺癌和结束阶段肺癌症织物被发现，与他们在煽动性的肺的更高的表示，纸巾可以在癌症的前进上显示发炎的合作效果的关联。
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Calprotectin S100A8/A9, a heterodimer composed of S100A8 and S100A9, is the main component of cytoplasmic proteins in neutrophils. It plays multiple roles in the immuno-inflammatory reactions intracellularly and extracellularly. Recent studies find that S100A8/A9 is closely related with the initiation and progression of periodontal inflammatory diseases. S100A8/A9 is expected to be a new biomarker for diagnosing periodontal inflammatory diseases, monitoring inflammatory activities in patients with periodontitis, evaluating the outcome of periodontal treatments and predicting the susceptibility of individual patient to periodontitis. In this literature review, we summarize the clinical research progress on the relation between S100A8/A9 and periodontal inflammatory diseases.S100A8/A9蛋白是由S100A8与S100A9蛋白组成的异二聚体，属于钙结合蛋白S100家族，是中性粒细胞的主要胞质蛋白，在免疫炎症反应中发挥多种胞内、胞外的生物学功能。近年研究发现，S100A8/A9与牙周炎症性疾病的发生发展关系密切。S100A8/A9在诊断牙周炎症性疾病、监测牙周炎症活动性、评价牙周治疗效果以及预测牙周炎易感性等方面有望成为新的生物标志物。本文就S100A8/A9蛋白与牙周炎症性疾病关系的临床研究进展作一文献综述。.
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