Selective roles for toll-like receptors 2, 4, and 9 in systemic inflammation and immune dysfunction following peripheral tissue injury.
Selective roles for toll-like receptors 2, 4, and 9 in systemic inflammation and immune dysfunction following peripheral tissue injury.
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DOI：
10.1097/ta.0b013e3182905ed2
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发表时间：
2013-06
期刊：
影响因子：
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通讯作者：
Billiar TR
中科院分区：
文献类型：
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作者：
Darwiche SS;Ruan X;Hoffman MK;Zettel KR;Tracy AP;Schroeder LM;Cai C;Hoffman RA;Scott MJ;Pape HC;Billiar TR
Toll样受体（TLR）检测创伤后释放的内源性配体，并有助于对损伤的促炎反应。创伤后死亡率与对损伤的免疫炎症反应的程度相关，所述免疫炎症反应由先天性和适应性免疫反应的复杂调节组成。尽管已知TLR调节先天性免疫应答，但其在创伤性组织损伤后抑制淋巴细胞应答中的作用尚不清楚。本研究使用了严重外周组织损伤的小鼠模型，包括肌肉挤压损伤和注射骨折成分，以评估TLR 2、4和9在早期和延迟免疫炎症表型中的作用。在我们的创伤模型中，使用以下参数测量创伤后免疫功能障碍：离体脾细胞增殖，Th 1细胞因子释放和脾髓源性抑制细胞（MDSC）内的iNOS诱导。通过循环白细胞介素-6水平和肝细胞损伤来确定全身炎症和肝损伤。损伤后脾细胞反应的抑制依赖于TLR 4和9信号传导，因为在脾MDSC中创伤后iNOS上调。发现TLR 2通过促进抑制脾细胞增殖仅具有部分作用。这项研究还揭示了TLR 2和4参与创伤性组织损伤的初始全身炎症反应，然而，这种反应被发现是TLR 9独立的。这些发现证实了以前未鉴定的TLR 2、4和9在创伤性组织损伤后T细胞相关免疫功能障碍中的作用。重要的是，这项研究还表明，TLR在创伤后的初始促炎反应和适应性免疫反应中发挥不同的选择性作用。此外，TLR 9缺陷小鼠的结果表明，早期促炎标志物的上调并不总是与持续免疫功能障碍的程度相关。这表明有可能通过选择性抑制损伤后的受体功能来限制免疫功能障碍的靶向治疗。
Toll-like receptors (TLRs) detect endogenous ligands released after trauma and contribute to the proinflammatory response to injury. Post-traumatic mortality correlates with the extent of the immuno-inflammatory response to injury which is comprised of a complex regulation of innate and adaptive immune responses. Although TLRs are known to modulate innate immune responses, their role in the suppression of lymphocyte responses following traumatic tissue injury is unclear. This study used a murine model of severe peripheral tissue injury, involving muscle crush injury and injection of fracture components, to evaluate the roles of TLR2, 4 and 9 in the early and delayed immuno-inflammatory phenotype. Post-traumatic immune dysfunction was measured in our trauma model using the following parameters: ex-vivo splenocyte proliferation, Th1 cytokine release and iNOS induction within splenic myeloid-derived suppressor cells (MDSC). Systemic inflammation and liver damage were determined by circulating interleukin-6 levels and hepatocellular injury. Suppression of splenocyte responses after injury was dependent on TLR4 and 9 signaling as was post-traumatic iNOS upregulation in splenic MDSC. TLR2 was found to have only a partial role through contribution to inhibition of splenocyte proliferation. This study also reveals the involvement of TLR2 and 4 in the initial systemic inflammatory response to traumatic tissue injury, however, this response was found to be TLR9-independent. These findings demonstrate the previously unidentified role of TLR2, 4 and 9 in the T-cell associated immune dysfunction following traumatic tissue injury. Importantly, this study also illustrates that TLRs play differing and selective roles in both the initial proinflammatory response and adaptive immune response after trauma. Furthermore, the results in the TLR9-deficient mice establishes that the upregulation of early pro-inflammatory markers do not always correlate with the extent of sustained immune dysfunction. This suggests potential for targeted therapies that could limit the immune dysfunction through selective inhibition of receptor function following injury.