Mechanism of Anti-Inflammatory Activity of TLR4-Interacting SPA4 Peptide.
Mechanism of Anti-Inflammatory Activity of TLR4-Interacting SPA4 Peptide.
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DOI：
10.4049/immunohorizons.2100067
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发表时间：
2021-08-24
期刊：
影响因子：
--
通讯作者：
Chataut N
中科院分区：
文献类型：
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作者：
Awasthi S;Kumar G;Ramani V;Awasthi V;Rodgers KK;Xie J;Beierle J;Kyere-Davies G;Singh B;Rahman N;Chowdhury AA;Chataut N
TLR 4相互作用的SPA 4肽抑制炎症。我们评估了SPA 4肽的结构和理化性质以及与TLR 4-MD 2的结合。我们还研究了用LPS攻击并用SPA 4肽处理的细胞系统和小鼠模型中的全转录组水平、细胞形态、活力、分泌的细胞因子和趋化因子以及细胞内流的变化。我们的结果表明，SPA 4肽不改变细胞活力和大小，仅适度影响细胞的转录组。计算对接和渲染表明，SPA 4肽插入LPS诱导的TLR 4-MD 2复合物。D-2氨基酸和SPA 4肽的NYTXXXRG-12-19基序的丙氨酸突变的结果表明，它们在与TLR 4结合和降低针对LPS刺激的细胞因子应答中起作用。此外，治疗性施用的SPA 4肽显著抑制LPS攻击小鼠的细胞和支气管肺泡灌洗液中细胞因子和趋化因子的分泌水平。结果表明，SPA 4肽嵌入LPS诱导的TLR 4复合物和抑制炎症的信号传导。
The TLR4-interacting SPA4 peptide suppresses inflammation. We assessed the structural and physicochemical properties and binding of SPA4 peptide to TLR4–MD2. We also studied the changes at the whole transcriptome level, cell morphology, viability, secreted cytokines and chemokines, and cell influx in cell systems and mouse models challenged with LPS and treated with SPA4 peptide. Our results demonstrated that the SPA4 peptide did not alter the cell viability and size and only moderately affected the transcriptome of the cells. Computational docking and rendering suggested that the SPA4 peptide intercalates with LPS-induced TLR4–MD2 complex. Results with alanine mutations of D-2 amino acid and NYTXXXRG-12–19 motif of SPA4 peptide suggested their role in binding to TLR4 and in reducing the cytokine response against LPS stimulus. Furthermore, therapeutically administered SPA4 peptide significantly suppressed the secreted levels of cytokines and chemokines in cells and bronchoalveolar lavage fluids of LPS-challenged mice. The results suggest that the SPA4 peptide intercalates with LPS-induced TLR4 complex and signaling for the suppression of inflammation.