Toll-like receptor deficiency worsens inflammation and lymphedema after lymphatic injury.

Toll-like receptor deficiency worsens inflammation and lymphedema after lymphatic injury.
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DOI：
10.1152/ajpcell.00284.2011
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发表时间：
2012-02
期刊：
American journal of physiology. Cell physiology
影响因子：
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通讯作者：
Jamie C. Zampell;Sonia Elhadad;Tomer Avraham;E. Weitman;Seth Z. Aschen;Alan Yan;B. Mehrara
Jamie C. Zampell;Sonia Elhadad;Tomer Avraham;E. Weitman;Seth Z. Aschen;Alan Yan;B. Mehrara
中科院分区：
其他
文献类型：
--
作者：
Jamie C. Zampell;Sonia Elhadad;Tomer Avraham;E. Weitman;Seth Z. Aschen;Alan Yan;B. Mehrara

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淋巴水肿的发病机制尚不清楚。最近，我们发现淋巴液淤积增加了内源性危险信号的表达，这些分子影响淋巴修复(Zampbell JC，等人)。Am J Physiol Cell Physiol 300：C1107-C1121,2011)。内源性危险信号激活Toll样受体(TLR)2、4和9，并根据生理环境诱导动态平衡或有害反应。本研究的目的是确定TLRs在调节组织对淋巴液淤滞的反应中的作用。使用了一种淋巴水肿的外科模型，在该模型中，野生型或TLR2、4或9基因敲除(KO)的小鼠接受了尾部淋巴切除。术后6周，与野生型动物相比，TLR KO组大鼠尾部肿胀明显增加(P<0.01)，TLR4组最明显(P&lt；0.01)。TLR缺乏导致间质和淋巴转运减少，淋巴管结构异常，毛细血管减少(减少40-50%；P&lt；0.001)。TLRKO的淋巴水肿性组织表现为白细胞浸润增加(P&lt；0.001)，包括更多的CD3+细胞(P&lt；0.05，TLR4和TLR9KO)，而F4/80+巨噬细胞的浸润减少(P&lt；0.05，所有组均P&lt；0.05)。此外，对分离的巨噬细胞的分析显示，在TLR2缺乏的动物中，血管内皮生长因子-C(P&lt；0.01)和Lyve-1(P&lt；0.05)的mRNA减少了两倍。最后，TLR缺乏与I型胶原沉积增加和转化生长因子-β1表达增加有关(P&lt；0.01，TLR4和TLR9KO)，促进真皮纤维化。总而言之，TLR缺乏会恶化组织对淋巴液淤积的反应，并与淋巴管生成减少、纤维化增加和巨噬细胞浸润减少有关。这些发现表明，包括TLR信号在内的先天免疫反应在淋巴修复和淋巴水肿的发病机制中发挥了作用。
Mechanisms regulating lymphedema pathogenesis remain unknown. Recently, we have shown that lymphatic fluid stasis increases endogenous danger signal expression, and these molecules influence lymphatic repair (Zampbell JC, et al. Am J Physiol Cell Physiol 300: C1107-C1121, 2011). Endogenous danger signals activate Toll-like receptors (TLR) 2, 4, and 9 and induce homeostatic or harmful responses, depending on physiological context. The purpose of this study was to determine the role of TLRs in regulating tissue responses to lymphatic fluid stasis. A surgical model of lymphedema was used in which wild-type or TLR2, 4, or 9 knockout (KO) mice underwent tail lymphatic excision. Six weeks postoperatively, TLR KOs demonstrated markedly increased tail edema compared with wild-type animals (50-200% increase; P < 0.01), and this effect was most pronounced in TLR4 KOs (P < 0.01). TLR deficiency resulted in decreased interstitial and lymphatic transport, abnormal lymphatic architecture, and fewer capillary lymphatics (40-50% decrease; P < 0.001). Lymphedematous tissues of TLR KOs demonstrated increased leukocyte infiltration (P < 0.001 for TLR4 KOs), including higher numbers of infiltrating CD3+ cells (P < 0.05, TLR4 and TLR9 KO), yet decreased infiltrating F4/80+ macrophages (P < 0.05, all groups). Furthermore, analysis of isolated macrophages revealed twofold reductions in VEGF-C (P < 0.01) and LYVE-1 (P < 0.05) mRNA from TLR2-deficient animals. Finally, TLR deficiency was associated with increased collagen type I deposition and increased transforming growth factor-β1 expression (P < 0.01, TLR4 and TLR9 KO), contributing to dermal fibrosis. In conclusion, TLR deficiency worsens tissue responses to lymphatic fluid stasis and is associated with decreased lymphangiogenesis, increased fibrosis, and reduced macrophage infiltration. These findings suggest a role for innate immune responses, including TLR signaling, in lymphatic repair and lymphedema pathogenesis.