Altered monocyte and fibrocyte phenotype and function in scleroderma interstitial lung disease: reversal by caveolin-1 scaffolding domain peptide.
Altered monocyte and fibrocyte phenotype and function in scleroderma interstitial lung disease: reversal by caveolin-1 scaffolding domain peptide.
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DOI：
10.1186/1755-1536-4-15
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发表时间：
2011-07-01
期刊：
影响因子：
--
通讯作者：
Hoffman S
中科院分区：
文献类型：
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作者：
Tourkina E;Bonner M;Oates J;Hofbauer A;Richard M;Znoyko S;Visconti RP;Zhang J;Hatfield CM;Silver RM;Hoffman S
间质性肺疾病（ILD）是硬皮病（系统性硬化症，或SSc）发病和死亡的主要原因。纤维细胞是一种单核细胞来源的细胞群，与纤维化疾病的发病机制有关。鉴于最近认识到caveolin-1在调节SSc单核细胞功能和信号传导中的重要性，在本研究中，我们在人类患者和动物模型中研究了caveolin-1在纤维化肺疾病中单核细胞和纤维细胞的迁移和/或运输以及表型中的作用。这些研究填补了我们对单核细胞和纤维细胞如何促进SSc-ILD病理的理解空白。我们发现C-X-C趋化因子受体4型阳性(CXCR4+)/ i型胶原阳性（ColI+）、CD34+/ColI+和CD45+/ColI+细胞存在于SSc-ILD肺中，但不存在于对照肺中，其中CXCR4+细胞最为普遍。在SSc-ILD肺组织中，CXCR4及其配体基质细胞衍生因子1 （CXCL12）的表达也高度上调。SSc单核细胞缺乏caveolin-1，因此过度表达CXCR4，与对照单核细胞相比，向CXCL12的迁移增加了近7倍。通过给药小窝蛋白支架结构域（CSD）肽来恢复小窝蛋白-1功能可以逆转这种过度迁移。同样，转化生长因子β处理的正常单核细胞失去小泡蛋白-1，过度表达CXCR4，单核细胞迁移增加15倍，这是CSD肽敏感的。SSc单核细胞表现出与正常单核细胞不同的表型，表达高水平的ColI、CD14和CD34。由于大肠杆菌+/CD14+细胞在SSc血液中普遍存在，我们在肺组织中寻找这些细胞，并证实它们存在于SSc- ild肺中，而不存在于正常肺中。最后，在博来霉素肺纤维化模型中，我们发现CSD肽减少了肺中纤维细胞的积累。我们的研究结果表明，SSc单核细胞中低caveolin-1通过影响细胞迁移和表型来促进ILD的发生，SSc-ILD中纤维细胞的过度积累可能是由于其单核细胞前体表型和迁移活性的改变。
Interstitial lung disease (ILD) is a major cause of morbidity and mortality in scleroderma (systemic sclerosis, or SSc). Fibrocytes are a monocyte-derived cell population implicated in the pathogenesis of fibrosing disorders. Given the recently recognized importance of caveolin-1 in regulating function and signaling in SSc monocytes, in the present study we examined the role of caveolin-1 in the migration and/or trafficking and phenotype of monocytes and fibrocytes in fibrotic lung disease in human patients and an animal model. These studies fill a gap in our understanding of how monocytes and fibrocytes contribute to SSc-ILD pathology. We found that C-X-C chemokine receptor type 4-positive (CXCR4+)/collagen I-positive (ColI+), CD34+/ColI+ and CD45+/ColI+ cells are present in SSc-ILD lungs, but not in control lungs, with CXCR4+ cells being most prevalent. Expression of CXCR4 and its ligand, stromal cell-derived factor 1 (CXCL12), are also highly upregulated in SSc-ILD lung tissue. SSc monocytes, which lack caveolin-1 and therefore overexpress CXCR4, exhibit almost sevenfold increased migration toward CXCL12 compared to control monocytes. Restoration of caveolin-1 function by administering the caveolin scaffolding domain (CSD) peptide reverses this hypermigration. Similarly, transforming growth factor β-treated normal monocytes lose caveolin-1, overexpress CXCR4 and exhibit 15-fold increased monocyte migration that is CSD peptide-sensitive. SSc monocytes exhibit a different phenotype than normal monocytes, expressing high levels of ColI, CD14 and CD34. Because ColI+/CD14+ cells are prevalent in SSc blood, we looked for such cells in lung tissue and confirmed their presence in SSc-ILD lungs but not in normal lungs. Finally, in the bleomycin model of lung fibrosis, we show that CSD peptide diminishes fibrocyte accumulation in the lungs. Our results suggest that low caveolin-1 in SSc monocytes contributes to ILD via effects on cell migration and phenotype and that the hyperaccumulation of fibrocytes in SSc-ILD may result from the altered phenotype and migratory activity of their monocyte precursors.