Regulatory T Cells Reduce Acute Lung Injury Fibroproliferation by Decreasing Fibrocyte Recruitment
Regulatory T Cells Reduce Acute Lung Injury Fibroproliferation by Decreasing Fibrocyte Recruitment
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DOI：
10.1165/rcmb.2012-0198oc
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发表时间：
2013-01-01
影响因子：
6.4
通讯作者：
King, Landon S.
中科院分区：
文献类型：
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作者：
Garibaldi, Brian T.;D'Alessio, Franco R.;King, Landon S.
急性肺损伤（ALI）导致显着的发病率和死亡率。 ALI 中的纤维增殖会导致更糟糕的结果，但控制纤维增殖的机制仍知之甚少。调节性 T 细胞 (Treg) 对于肺损伤的缓解非常重要。它们在纤维增殖中的作用尚不清楚。我们试图利用小鼠肺损伤模型来确定 Tregs 在 ALI 纤维增殖中的作用。野生型（WT）和淋巴细胞缺陷型Rag-1（-/-）小鼠接受气管内LPS。通过组织学和肺胶原蛋白的测量来表征纤维增殖。通过流式细胞术测量肺纤维细胞。为了剖析Tregs在纤维增殖中的作用，Rag-1（-/-）小鼠在LPS损伤时接受CD4（+）CD25（+）（Tregs）或CD4（+）CD25（+）T细胞（非Tregs）。为了确定趋化因子（C-X-C 基序）配体 12 (CXCL12)-CXCR4 通路在 ALI 纤维增殖中的作用，用 CXCR4 拮抗剂 AMD3100 治疗 Rag-1(-/-) 小鼠以阻止纤维细胞募集。 WT 和 Rag-1(-/-) 小鼠在 LPS 后第 3 天表现出明显的胶原蛋白沉积。 WT 小鼠表现出胶原蛋白清除，但 Rag-1(-/-) 小鼠出现持续性纤维化。这种纤维化是由 CXCL12（或基质细胞衍生因子 1 [SDF-1]）的持续上皮表达介导的，导致纤维细胞募集增加。 Tregs 的过继转移通过降低 CXCL12 表达和随后的纤维细胞募集来解决纤维增殖问题。用 AMD3100 阻断 CXCL12-CXCR4 轴也减少了肺纤维细胞和纤维增殖。这些结果表明，Treg 通过减少沿着 CXCL12-CXCR4 轴的纤维细胞募集，在解决 ALI 纤维增殖中发挥核心作用。对 Tregs 在 ALI 纤维增殖中的作用的剖析可能为 ALI 患者新治疗工具的设计提供信息。
Acute lung injury (ALI) causes significant morbidity and mortality. Fibroproliferation in ALI results in worse outcomes, but the mechanisms governing fibroproliferation remain poorly understood. Regulatory T cells (Tregs) are important in lung injury resolution. Their role in fibroproliferation is unknown. We sought to identify the role of Tregs in ALI fibroproliferation, using a murine model of lung injury. Wild-type (WT) and lymphocyte-deficient Rag-1(-/-) mice received intratracheal LPS. Fibroproliferationwas characterizedby histology and the measurement of lung collagen. Lung fibrocytes were measured by flow cytometry. To dissect the role of Tregs in fibroproliferation, Rag-1(-/-) mice received CD4(+) CD25(+) (Tregs) or CD4(+) CD25(+) Tcells (non-Tregs) at the time of LPS injury. To define the role of the chemokine (C-X-C motif) ligand 12 (CXCL12)-CXCR4 pathway in ALI fibroproliferation, Rag-1(-/-) mice were treated with the CXCR4 antagonist AMD3100 to block fibrocyte recruitment. WT and Rag-1(-/-) mice demonstrated significant collagen deposition on Day 3 after LPS. WT mice exhibited the clearance of collagen, but Rag-1(-/-) mice developed persistent fibrosis. This fibrosis was mediated by the sustained epithelial expression of CXCL12 (or stromal cell-derived factor 1 [SDF-1]) that led to increased fibrocyte recruitment. The adoptive transfer of Tregs resolved fibroproliferation by decreasing CXCL12 expression and subsequent fibrocyte recruitment. Blockade of the CXCL12-CXCR4 axis with AMD3100 also decreased lung fibrocytes and fibroproliferation. These results indicate a central role for Tregs in the resolution of ALI fibroproliferation by reducing fibrocyte recruitment along the CXCL12-CXCR4 axis. A dissection of the role of Tregs in ALI fibroproliferation may inform the design of new therapeutic tools for patients with ALI.