Paterson Hugh M, Murphy Thomas J, Purcell Elizabeth J, Shelley Odhran, Kriynovich Sara J, Lien Egil, Mannick John A, Lederer James A
Department of Surgery, Brigham and Women's Hospital/Harvard Medical School, Boston, MA 02115, USA.
J Immunol. 2003 Aug 1;171(3):1473-83. doi: 10.4049/jimmunol.171.3.1473.
Severe injury causes a dramatic host response that disrupts immune homeostasis and predisposes the injured host to opportunistic infections. Because Toll-like receptors (TLRs) recognize conserved microbial Ags and endogenous danger signals that may be triggered by injury, we wanted to determine how injury influences TLR responses. Using an in vivo injury model, we demonstrate that injury significantly increased TLR2- and TLR4-induced IL-1beta, IL-6, and TNF-alpha production by spleen cells. This influence of injury on TLR reactivity was observed as early as 1 day after injury and persisted for at least 7 days. The outcome of similar studies performed using TLR4-mutant C57BL/10ScN/Cr mice revealed that TLR2 responses remained primed, thus suggesting that injury-induced priming can occur independently of endogenous TLR4 signaling. Increased TLR4 reactivity was also observed in vivo, because LPS-challenged injured mice demonstrated significantly higher cytokine expression levels in the lung, liver, spleen, and plasma. Macrophages and dendritic cells were the major source of these cytokines as judged by intracellular cytokine staining. Moreover, ex vivo studies using enriched macrophage and dendritic cell populations confirmed that T cells did not contribute to the enhanced TLR2 and TLR4 responses. The results of flow cytometry studies using TLR2- and TLR4-MD-2-specific Abs indicated that injury did not markedly alter cell surface TLR2 or TLR4-MD-2 expression. Taken together, these findings establish that injury primes the innate immune system for enhanced TLR2- and TLR4-mediated responses and provides evidence to suggest that augmented TLR reactivity might contribute to the development of heightened systemic inflammation following severe injury.
严重损伤会引发剧烈的宿主反应，破坏免疫稳态，使受伤宿主易发生机会性感染。由于Toll样受体（TLR）可识别保守的微生物抗原和可能由损伤触发的内源性危险信号，我们想要确定损伤如何影响TLR反应。使用体内损伤模型，我们证明损伤显著增加了脾脏细胞中TLR2和TLR4诱导的IL-1β、IL-6和TNF-α的产生。损伤对TLR反应性的这种影响在损伤后1天就已观察到，并持续至少7天。使用TLR4突变的C57BL/10ScN/Cr小鼠进行的类似研究结果显示，TLR2反应仍处于启动状态，这表明损伤诱导的启动可以独立于内源性TLR4信号发生。在体内也观察到TLR4反应性增加，因为脂多糖攻击的受伤小鼠在肺、肝、脾和血浆中表现出明显更高的细胞因子表达水平。通过细胞内细胞因子染色判断，巨噬细胞和树突状细胞是这些细胞因子的主要来源。此外，使用富集的巨噬细胞和树突状细胞群体进行的体外研究证实，T细胞对增强的TLR2和TLR4反应没有贡献。使用TLR2和TLR4-MD-2特异性抗体进行的流式细胞术研究结果表明，损伤并未显著改变细胞表面TLR2或TLR4-MD-2的表达。综上所述，这些发现表明损伤使先天性免疫系统启动，以增强TLR2和TLR4介导的反应，并提供证据表明增强的TLR反应性可能有助于严重损伤后全身炎症加剧的发展。
