敗血症起因於宿主對於細菌感染產生極高的發炎反應，進而造成器官衰竭和死亡。凝血酶調節素屬於第一型穿膜醣蛋白，能夠與凝血酶結合並活化蛋白質C，進而終止凝血反應。文獻指出單核球及巨噬細胞能夠表現凝血酶調節素，但對於凝血酶調節素在單核球及巨噬細胞中的功能並不清楚。在此研究中，我們利用核糖核酸干擾技術以及特定組織基因剔除小鼠來研究凝血酶調節素在單核球及巨噬細胞中所扮演的角色。我們發現在單核球中的凝血酶調節素能夠透過其類凝集素區域與革蘭氏陰性菌細胞壁中的脂多醣結合，並且抑制凝血酶調節素在人類單核球中的表現，可以減弱脂多醣所引起的發炎激素產生以及訊息傳遞。此外，凝血酶調節素與脂多醣在細胞表面上結合並且與CD14/類鐸受體4/骨髓分化因子-2形成複合體。我們亦發現抑制單核球中凝血酶調節素的表現會降低革蘭氏陰性菌克雷白氏肺炎桿菌所引起的細胞激素產生，顯示單核球中的凝血酶調節素對於革蘭氏陰性菌所引起的發炎反應扮演著重要的角色。為了研究單核球中的凝血酶調節素在體內的功能，我們建立了特定在髓細胞剔除凝血酶調節素的小鼠，並且發現在髓細胞缺乏凝血酶調節素的小鼠在刺激克雷白氏肺炎桿菌及闌尾結紮穿刺術後，發炎反應以及細菌擴散等敗血症狀能夠有效的被抑制，並且具有較高的存活率，而其被抑制的細菌擴散是因為早期嗜中性白血球的浸潤增加所造成。我們也觀察到缺乏凝血酶調節素的巨噬細胞具有較高的化學趨性，起因於趨化素受體在缺乏凝血酶調節素的巨噬細胞中表現增加，進而造成與細胞遷移相關的訊息傳遞增強以及增加纖維性肌動蛋白聚合的能力。我們亦發現在缺乏凝血酶調節素的巨噬細胞中巨噬細胞甘露醣受體以及介質白素-10的表現也會增加，顯示其具有M2巨噬細胞的特性。此外，黑色素瘤的生長會在髓細胞缺乏凝血酶調節素的小鼠中有增加的趨勢，且此現象與巨噬細胞的滲透能力增加有關。因此，綜合以上的結果，凝血酶調節素不僅能參與在脂多醣及革蘭氏陰性菌所引起的發炎反應，也會調控巨噬細胞的化學趨性能力，進而影響黑色素瘤的生長。

Sepsis results from host hyperinflammatory response to bacterial infection, causing multiple organ failure and high mortality. Thrombomodulin (TM), a type I transmembrane glycoprotein, functions as an anticoagulant factor by forming complex with thrombin. TM-thrombin complex further activates protein C to terminate blood coagulation. Although the expression of TM in monocytes and macrophages has been found, the function of monocytic TM is still unclear. In this study, we used the RNA interference technique and tissue-specific knockout mice to investigate the role of TM in monocytes and macrophages in vitro and in vivo. We found that monocytic membrane-bound TM interacted with Gram-negative bacterial cell wall component, lipopolysaccharide (LPS), through its lectin-like domain, and TM knockdown in human monocytic cells attenuated LPS-induced cytokine production and signaling pathways. Furthermore, monocytic TM bound to LPS on cell surface and interacted with CD14/Toll-like receptor 4/myeloid differentiation factor-2 complex. We also found that monocytic TM knockdown reduced cytokine production induced by Gram-negative bacteria Klebsiella pneumoniae, suggesting that monocytic TM plays an important role in Gram-negative bacteria-induced inflammation. To investigate the role of monocytic TM in vivo, the myeloid-specific TM-deficient mice were established and were found to display improved survival that resulted from the attenuation of septic syndrome, including reduced systemic inflammatory response and resistance to bacterial dissemination, after K. pneumoniae infection or cecal ligation and puncture surgery. The inhibition of bacterial dissemination in mice with a deficiency of myeloid TM may be caused by the early increase in neutrophil infiltration. Increased macrophage chemotactic ability, resulting from elevated activation of migration-related signaling pathways and F-actin polymerization, was also observed in TM-deficient macrophages isolated from LysMcre/TMflox/flox mice. Up-regulated expression of chemokine receptors in TM-deficient macrophages may be the cause of enhanced chemotaxis. Notably, TM-deficient macrophages displayed M2-like polarization, since up-regulated expression of macrophage mannose receptor and interleukin-10 was found in TM-deficient macrophages. Enhanced melanoma tumor growth in LysMcre/TMflox/flox mice may result from the increase in macrophage infiltration. In conclusion, these data suggest that TM not only participates in LPS- and Gram-negative bacteria-induced inflammation but also regulates macrophage chemotaxis in melanoma tumor growth.

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