Prevention of LPS-induced microglia activation, cytokine production and sickness behavior with TLR4 receptor interfering peptides.
Prevention of LPS-induced microglia activation, cytokine production and sickness behavior with TLR4 receptor interfering peptides.
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DOI：
10.1371/journal.pone.0060388
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
MacVicar BA
中科院分区：
文献类型：
--
作者：
Hines DJ;Choi HB;Hines RM;Phillips AG;MacVicar BA
先天免疫受体 Toll-like 4 (TLR4) 是脂多糖 (LPS) 激活的受体，众所周知，TLR4-LPS 相互作用会诱导先天免疫反应，引发疾病行为。在大脑中，TLR4 在大脑小胶质细胞中高度表达，大脑中该通路激活导致的过度炎症与抑郁症和神经退行性疾病有关。我们假设阻断 LPS 诱导的 TLR4 激活将阻止大脑中的下游免疫信号传导并抑制疾病行为的诱导。我们使用干扰肽来阻断 TLR4 激活，并证实了它们在防止 LPS 治疗通常诱导的第二信使激活和细胞因子产生方面的功效。此外，这些肽阻断了通常由 LPS 诱导的小胶质细胞的形态变化。我们还证明，腹膜内 (i.p.) 注射 Tat-TLR4 干扰肽可预防 LPS 诱导的疾病行为，如在家笼行为和颅内自我刺激范例中所评估的那样。这些新合成的肽抑制 TLR4 信号传导，从而防止炎症刺激引起的行为和动机变化。这些肽突出显示了疾病行为中 TLR4 的滚动和小胶质细胞形态的变化，因此在限制特定中枢神经系统病理中过度炎症的有害影响方面可能具有治疗价值。
The innate immune receptor Toll-like 4 (TLR4) is the receptor activated by lipopolysaccharide (LPS), and TLR4-LPS interaction is well known to induce an innate immune response, triggering sickness behavior. Within the brain, TLR4 is highly expressed in brain microglia, and excessive inflammation resulting from activation of this pathway in the brain has been implicated in depressive disorders and neurodegenerative pathologies. We hypothesized that blocking LPS-induced activation of TLR4 would prevent downstream immune signaling in the brain and suppress the induction of sickness behavior. We used interfering peptides to block TLR4 activation and confirmed their efficacy in preventing second messenger activation and cytokine production normally induced by LPS treatment. Further, these peptides blocked morphological changes in microglia that are typically induced by LPS. We also demonstrated that intraperitoneal (i.p.) injection of Tat-TLR4 interfering peptides prevented LPS-induced sickness behavior, as assessed in home cage behavior and with the intracranial self-stimulation paradigm. These newly synthesised peptides inhibit TLR4 signaling thereby preventing changes in behavior and motivation caused by inflammatory stimuli. These peptides highlight the roll of TLR4 and microglia morphology changes in sickness behavior, and thus may be of therapeutic value in limiting the deleterious impact of excessive inflammation in specific CNS pathologies.
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影响因子：
4.2
作者：
Buttini, M;Limonta, S;Boddeke, HWGM
通讯作者：
Boddeke, HWGM
影响因子：
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作者：
Nimmerjahn, A;Kirchhoff, F;Helmchen, F
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Helmchen, F
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作者：
Mulligan, SJ;MacVicar, BA
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MacVicar, BA
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Littman, DR
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作者：
Loiarro, Maria;Capolunghi, Federica;Sette, Claudio
通讯作者：
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