Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213, USA.
J Trauma Acute Care Surg. 2013 Jun;74(6):1454-61. doi: 10.1097/TA.0b013e3182905ed2.
Toll-like receptors (TLRs) detect endogenous ligands released after trauma and contribute to the proinflammatory response to injury. Posttraumatic mortality correlates with the extent of the immunoinflammatory response to injury that is composed 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, TLR4, and TLR9 in the early and delayed immunoinflammatory phenotype. Posttraumatic immune dysfunction was measured in our trauma model using the following parameters: ex vivo splenocyte proliferation, TH1 cytokine release, and iNOS (inducible nitric oxide synthase) induction within splenic myeloid-derived suppressor cells. 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 TLR9 signaling as was posttraumatic iNOS upregulation in splenic myeloid-derived suppressor cells. 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 TLR4 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, TLR4, and TLR9 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, results in TLR9-deficient mice establish that the upregulation of early proinflammatory markers do not always correlate with the extent of sustained immune dysfunction. This suggests potential for targeted therapies that could limit immune dysfunction through selective inhibition of receptor function following injury.
Toll 样受体 (TLR) 可识别创伤后释放的内源性配体，并有助于损伤的促炎反应。创伤后死亡率与损伤引起的免疫炎症反应的程度相关，该反应由固有免疫和适应性免疫反应的复杂调节组成。尽管 TLR 被认为可调节固有免疫反应，但它们在创伤性组织损伤后抑制淋巴细胞反应中的作用尚不清楚。
本研究使用涉及肌肉挤压伤和骨折成分注射的严重外周组织损伤的小鼠模型，来评估 TLR2、TLR4 和 TLR9 在早期和延迟免疫炎症表型中的作用。我们在创伤模型中使用以下参数评估创伤后免疫功能障碍：脾细胞体外增殖、TH1 细胞因子释放和脾髓源性抑制细胞中的诱导型一氧化氮合酶 (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 TLR4 和 TLR9 信号，而脾髓源性抑制细胞中的 iNOS 上调也依赖于 TLR4 和 TLR9 信号。TLR2 通过对脾细胞增殖的抑制作用仅起到部分作用。本研究还揭示了 TLR2 和 TLR4 参与创伤性组织损伤后初始全身炎症反应；然而，这种反应被发现与 TLR9 无关。
这些发现表明 TLR2、TLR4 和 TLR9 在创伤性组织损伤后 T 细胞相关免疫功能障碍中具有先前未被识别的作用。重要的是，本研究还表明 TLR 在创伤后初始促炎反应和适应性免疫反应中发挥不同且选择性的作用。此外，TLR9 缺陷型小鼠的结果表明，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。这表明通过在损伤后选择性抑制受体功能，可以进行靶向治疗以限制免疫功能障碍。
