Stifano Giuseppina, Affandi Alsya J, Mathes Allison L, Rice Lisa M, Nakerakanti Sashidhar, Nazari Banafsheh, Lee Jungeun, Christmann Romy B, Lafyatis Robert
Arthritis Res Ther. 2014 Jul 1;16(4):R136. doi: 10.1186/ar4598.
The crucial role of innate immunity in the pathogenesis of systemic sclerosis (SSc) is well established, and in the past few years the hypothesis that Toll-like receptor 4 (TLR4) activation induced by endogenous ligands is involved in fibrogenesis has been supported by several studies on skin, liver, and kidney fibrosis. These findings suggest that TLR4 activation can enhance transforming growth factor beta (TGF-β) signaling, providing a potential mechanism for TLR4/Myeloid differentiation factor 88 (MyD88)-dependent fibrosis.
The expression of TLR4, CD14 and MD2 genes was analyzed by real-time polymerase chain reaction from skin biopsies of 24 patients with diffuse cutaneous SSc. In order to investigate the effects of the chronic skin exposure to endotoxin (Lipopolysaccharide (LPS)) in vivo we examined the expression of inflammation, TGF-β signaling and cellular markers genes by nanostring. We also identified cellular subsets by immunohistochemistry and flow cytometry.
We found that TLR4 and its co-receptors, MD2 and CD14, are over-expressed in lesional skin from patients with diffuse cutaneous SSc, and correlate significantly with progressive or regressive skin disease as assessed by the Delta Modified Rodnan Skin Score. In vivo, a model of chronic dermal LPS exposure showed overexpression of proinflammatory chemokines, recruitment and activation of macrophages, and upregulation of TGF-β signature genes.
We delineated the role of MyD88 as necessary for the induction not only for the early phase of inflammation, but also for pro-fibrotic gene expression via activation of macrophages. Chronic LPS exposure might be a model of early stage of SSc when inflammation and macrophage activation are important pathological features of the disease, supporting a role for innate immune activation in SSc skin fibrosis.
先天性免疫在系统性硬化症（SSc）发病机制中的关键作用已得到充分证实，在过去几年中，内源性配体诱导的Toll样受体4（TLR4）激活参与纤维化形成的假说，已在多项关于皮肤、肝脏和肾脏纤维化的研究中得到支持。这些发现表明，TLR4激活可增强转化生长因子β（TGF-β）信号传导，为TLR4/髓样分化因子88（MyD88）依赖性纤维化提供了一种潜在机制。
通过实时聚合酶链反应分析了24例弥漫性皮肤型SSc患者皮肤活检样本中TLR4、CD14和MD2基因的表达。为了研究体内皮肤长期暴露于内毒素（脂多糖（LPS））的影响，我们通过纳米串技术检测了炎症、TGF-β信号传导和细胞标志物基因的表达。我们还通过免疫组织化学和流式细胞术鉴定了细胞亚群。
我们发现，TLR4及其共受体MD2和CD14在弥漫性皮肤型SSc患者的皮损中过度表达，并且与通过改良Rodnan皮肤评分评估的进行性或退行性皮肤疾病显著相关。在体内，慢性皮肤LPS暴露模型显示促炎趋化因子过度表达、巨噬细胞募集和激活以及TGF-β特征基因上调。
我们明确了MyD88的作用，它不仅是炎症早期诱导所必需的，而且通过激活巨噬细胞对促纤维化基因表达也是必需的。慢性LPS暴露可能是SSc早期的一种模型，此时炎症和巨噬细胞激活是该疾病的重要病理特征，支持先天性免疫激活在SSc皮肤纤维化中的作用。
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