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Peroxidase-Mimicking Nanoassembly Mitigates Lipopolysaccharide-Induced Endotoxemia and Cognitive Damage in the Brain by Impeding Inflammatory Signaling in Macrophages
Nano Letters ( IF 9.6 ) Pub Date : 2018-09-24 00:00:00 , DOI: 10.1021/acs.nanolett.8b02785 Santhosh Kalash Rajendrakumar 1 , Vishnu Revuri 2 , Manikandan Samidurai 1, 3 , Adityanarayan Mohapatra 1 , Jae Hyuk Lee 4 , Palanivel Ganesan 5 , Jihoon Jo 3 , Yong-Kyu Lee 2 , In-Kyu Park 1
Nano Letters ( IF 9.6 ) Pub Date : 2018-09-24 00:00:00 , DOI: 10.1021/acs.nanolett.8b02785 Santhosh Kalash Rajendrakumar 1 , Vishnu Revuri 2 , Manikandan Samidurai 1, 3 , Adityanarayan Mohapatra 1 , Jae Hyuk Lee 4 , Palanivel Ganesan 5 , Jihoon Jo 3 , Yong-Kyu Lee 2 , In-Kyu Park 1
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Oxidative stress during sepsis pathogenesis remains the most-important factor creating imbalance and dysregulation in immune-cell function, usually observed following initial infection. Hydrogen peroxide (H2O2), a potentially toxic reactive oxygen species (ROS), is excessively produced by pro-inflammatory immune cells during the initial phases of sepsis and plays a dominant role in regulating the pathways associated with systemic inflammatory immune activation. In the present study, we constructed a peroxide scavenger mannosylated polymeric albumin manganese dioxide (mSPAM) nanoassembly to catalyze the decomposition of H2O2 responsible for the hyper-activation of pro-inflammatory immune cells. In a detailed manner, we investigated the role of mSPAM nanoassembly in modulating the expression and secretion of pro-inflammatory markers elevated in bacterial lipopolysaccharide (LPS)-mediated endotoxemia during sepsis. Through a facile one-step solution-phase approach, hydrophilic bovine serum albumin reduced manganese dioxide (BM) nanoparticles were synthesized and subsequently self-assembled with cationic mannosylated disulfide cross-linked polyethylenimine (mSP) to formulate mSPAM nanoassembly. In particular, we observed that the highly stable mSPAM nanoassembly suppressed HIF1α expression by scavenging H2O2 in LPS-induced macrophage cells. Initial investigation revealed that a significant reduction of free radicals by the treatment of mSPAM nanoassembly has reduced the infiltration of neutrophils and other leukocytes in a local endotoxemia animal model. Furthermore, therapeutic studies in a systemic endotoxemia model demonstrated that mSPAM treatment reduced TNF-α and IL-6 inflammatory cytokines in serum, in turn circumventing organ damage done by the inflammatory macrophages. Interestingly, we also observed that the reduction of these inflammatory cytokines by mSPAM nanoassembly further prevented IBA-1 immuno-positive microglial cell activation in the brain and consequently improved the cognitive function of the animals. Altogether, the administration of mSPAM nanoassembly scavenged H2O2 and suppressed HIF1α expression in LPS-stimulated macrophages and thereby inhibited the progression of local and systemic inflammation as well as neuroinflammation in an LPS-induced endotoxemia model. This mSPAM nanoassembly system could serve as a potent anti-inflammatory agent, and we further anticipate its successful application in treating various inflammation-related diseases.
中文翻译：
模拟过氧化物酶的纳米组装通过阻止巨噬细胞中的炎症信号传递，减轻脂多糖诱导的内毒素血症和大脑中的认知损伤。
脓毒症发病机理中的氧化应激仍然是最重要的因素，通常会在初次感染后引起免疫细胞功能失衡和失调。过氧化氢（H 2 O 2）是一种潜在的有毒的活性氧（ROS），在脓毒症的初始阶段由促炎性免疫细胞过度产生，并在调节与全身性炎性免疫激活相关的途径中起主要作用。在本研究中，我们构建了一种过氧化物清除剂，甘露糖基化的聚合白蛋白二氧化锰（mSPAM）纳米组件，以催化H 2 O 2的分解负责促炎性免疫细胞的过度激活。以详细的方式，我们调查了mSPAM纳米组装在调节败血症过程中细菌脂多糖（LPS）介导的内毒素血症中升高的促炎性标志物的表达和分泌中的作用。通过一种简便的一步法溶液相方法，合成了亲水性牛血清白蛋白还原的二氧化锰（BM）纳米颗粒，然后与阳离子甘露糖基化的二硫键交联的聚乙烯亚胺（mSP）自组装，从而构建了mSPAM纳米组装。特别是，我们观察到高度稳定的mSPAM纳米组装通过清除H 2 O 2抑制了HIF1α表达。在LPS诱导的巨噬细胞中。初步研究表明，通过mSPAM纳米组装体处理可以显着减少自由基，从而减少了局部内毒素血症动物模型中嗜中性粒细胞和其他白细胞的浸润。此外，在系统性内毒素血症模型中的治疗研究表明，mSPAM治疗可降低血清中的TNF-α和IL-6炎性细胞因子，从而规避了炎性巨噬细胞对器官的损害。有趣的是，我们还观察到通过mSPAM纳米组装减少的这些炎性细胞因子进一步阻止了大脑中IBA-1免疫阳性小胶质细胞的活化，从而改善了动物的认知功能。总而言之，mSPAM纳米组装的管理清除了H 2 O 2并抑制LPS刺激的巨噬细胞中HIF1α的表达，从而抑制LPS诱导的内毒素血症模型中局部和全身炎症的进展以及神经炎症。该mSPAM纳米组装系统可以用作有效的消炎药，我们进一步预期了其在治疗各种炎症相关疾病中的成功应用。
更新日期：2018-09-24
中文翻译：
模拟过氧化物酶的纳米组装通过阻止巨噬细胞中的炎症信号传递，减轻脂多糖诱导的内毒素血症和大脑中的认知损伤。
脓毒症发病机理中的氧化应激仍然是最重要的因素，通常会在初次感染后引起免疫细胞功能失衡和失调。过氧化氢（H 2 O 2）是一种潜在的有毒的活性氧（ROS），在脓毒症的初始阶段由促炎性免疫细胞过度产生，并在调节与全身性炎性免疫激活相关的途径中起主要作用。在本研究中，我们构建了一种过氧化物清除剂，甘露糖基化的聚合白蛋白二氧化锰（mSPAM）纳米组件，以催化H 2 O 2的分解负责促炎性免疫细胞的过度激活。以详细的方式，我们调查了mSPAM纳米组装在调节败血症过程中细菌脂多糖（LPS）介导的内毒素血症中升高的促炎性标志物的表达和分泌中的作用。通过一种简便的一步法溶液相方法，合成了亲水性牛血清白蛋白还原的二氧化锰（BM）纳米颗粒，然后与阳离子甘露糖基化的二硫键交联的聚乙烯亚胺（mSP）自组装，从而构建了mSPAM纳米组装。特别是，我们观察到高度稳定的mSPAM纳米组装通过清除H 2 O 2抑制了HIF1α表达。在LPS诱导的巨噬细胞中。初步研究表明，通过mSPAM纳米组装体处理可以显着减少自由基，从而减少了局部内毒素血症动物模型中嗜中性粒细胞和其他白细胞的浸润。此外，在系统性内毒素血症模型中的治疗研究表明，mSPAM治疗可降低血清中的TNF-α和IL-6炎性细胞因子，从而规避了炎性巨噬细胞对器官的损害。有趣的是，我们还观察到通过mSPAM纳米组装减少的这些炎性细胞因子进一步阻止了大脑中IBA-1免疫阳性小胶质细胞的活化，从而改善了动物的认知功能。总而言之，mSPAM纳米组装的管理清除了H 2 O 2并抑制LPS刺激的巨噬细胞中HIF1α的表达，从而抑制LPS诱导的内毒素血症模型中局部和全身炎症的进展以及神经炎症。该mSPAM纳米组装系统可以用作有效的消炎药，我们进一步预期了其在治疗各种炎症相关疾病中的成功应用。
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