Antagonism of Integrin CD11b Affords Protection against Endotoxin Shock and Polymicrobial Sepsis via Attenuation of HMGB1 Nucleocytoplasmic Translocation and Extracellular Release
Antagonism of Integrin CD11b Affords Protection against Endotoxin Shock and Polymicrobial Sepsis via Attenuation of HMGB1 Nucleocytoplasmic Translocation and Extracellular Release
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整合素 CD11b 的拮抗作用通过减弱 HMGB1 核细胞质易位和细胞外释放来防止内毒素休克和多种微生物败血症
DOI：
10.4049/jimmunol.1701285
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发表时间：
2018-03-01
影响因子：
4.4
通讯作者：
Zhao, Zhihui
中科院分区：
文献类型：
--
作者：
Zhou, Huiting;Li, Yanhong;Zhao, Zhihui
高迁移率族蛋白1（HMGB 1）是一种染色质结合的核蛋白，在脓毒症中起着关键的“晚期”炎症介质的作用。整合素CD 11b是炎症细胞活化和迁移所必需的，从而介导炎症反应。然而，目前尚不清楚CD 11b是否参与脓毒症的发展。在这项研究中，我们报告说，CD 11b有助于LPS诱导的内毒素休克和微生物脓毒症，因为CD 11b阻断抗体或CD 11b抑制剂Gu-4对CD 11b的拮抗作用可保护小鼠免受LPS和微生物脓毒症相关的致死性，这与血清HMGB 1水平显著降低有关。与此一致，CD 11b缺陷小鼠对微生物脓毒症的抵抗力更强，血清HMGB 1水平比野生型小鼠低得多。药理学阻断和基因敲除/敲除小鼠巨噬细胞中的CD 11b阻碍LPS刺激的HMGB 1核质易位和细胞外释放。此外，沉默CD 11b中断了HMGB 1与核输出因子染色体区域维持1或经典蛋白激酶C的相互作用，并抑制了经典蛋白激酶C诱导的HMGB 1磷酸化，这是负责CD 11b阻断诱导的HMGB 1核质易位抑制和随后的细胞外释放的潜在潜在机制。因此，我们的研究结果强调，CD 11b有助于脓毒症的发展，主要是通过促进核质易位和HMGB 1的主动释放。
High mobility group box 1 (HMGB1), a chromatin-binding nuclear protein, plays a critical role in sepsis by acting as a key " late-phase" inflammatory mediator. Integrin CD11b is essential for inflammatory cell activation and migration, thus mediating inflammatory responses. However, it is unclear whether CD11b participates in the development of sepsis. In this study, we report that CD11b contributes to LPS-induced endotoxin shock and microbial sepsis, as antagonism of CD11b with the CD11b blocking Ab or CD11b inhibitor Gu-4 protects mice against LPS-and microbial sepsis-related lethality, which is associated with significantly diminished serum HMGB1 levels. Consistent with this, CD11b-deficient mice were more resistant to microbial sepsis with a much lower serum HMGB1 level compared with wild-type mice. Pharmacological blockage and genetic knockdown/knockout of CD11b in murine macrophages hampered LPS-stimulated HMGB1 nucleocytoplasmic translocation and extracellular release. Furthermore, silencing CD11b interrupted the interaction of HMGB1 with either a nuclear export factor chromosome region maintenance 1 or classical protein kinase C and inhibited classical protein kinase C-induced HMGB1 phosphorylation, the potential underlying mechanism(s) responsible for CD11b blockage-induced suppression of HMGB1 nucleocytoplasmic translocation and subsequent extracellular release. Thus, our results highlight that CD11b contributes to the development of sepsis, predominantly by facilitating nucleocytoplasmic translocation and active release of HMGB1.