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Novel apoE receptor mimetics reduce LPS-induced microglial inflammation.

ABSTRACT: Apolipoprotein E (apoE) and apoE-mimetic peptides exert prominent anti-inflammatory effects. We determined the anti-inflammatory effects of novel apoE receptor mimetics, composed of the LDL receptor-binding domain of apoE (aa 133-152, ApoEp) or ApoEp with 6 lysines (6KApoEp) or 6 aspartates added at the N-terminus (6DApoEp). BV2 microglia and human THP-1 monocytes were treated with lipopolysaccharide (LPS) in the absence or presence of ApoEp, 6KApoEp or 6DApoEp, followed by determination of pro-inflammatory tumor necrosis factor ? (TNF?) and interleukin-6 (IL-6) release by ELISA. As signaling intermediates of inflammation, Signal Transducer and Activator of Transcription 3 (STAT3), Janus-Activated Kinase2 (JAK2) and p38 and p44/42 MAPK phosphorylation levels were determined by Western blot analysis. In addition, we isolated splenocytes from female htau mice treated with 6KApoEp or 6K for 28 weeks, followed by determination of concanavalinA (conA)-mediated interferon gamma (IFN?) release. 6KApoEp starting at 2.5 µM significantly reduced LPS-mediated TNF? and IL-6 secretion in BV2 and THP-1 cells in a dose-dependent manner. In BV2 cells, 6KApoEp reduced TNF? secretion more effectively than 6DApoEp and ApoEp, which was blocked by PCSK9 treatment, suggesting a role for LDL receptors. 6KApoEp also inhibited LPS-induced p44/42 MAPK, JAK2 and STAT3 phosphorylation, while enhancing p38 MAPK phosphorylation. In addition, conA induced significantly less IFN? release in splenocytes derived from htau mice treated with 6KApoEp compared with those treated with 6K. Thus, 6KApoEp most effectively reduces LPS-mediated neuroinflammation by interacting with LDL receptors, thus representing a novel anti-inflammatory agent for treatment of neurodegenerative disease.

SUBMITTER: Wang L

PROVIDER: S-EPMC6731434 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Novel apoE receptor mimetics reduce LPS-induced microglial inflammation.

Wang Likun L Hou Huayan H Zi Dan D Habib Ahsan A Tan Jun J Sawmiller Darrell D

American journal of translational research 20190815 8

Apolipoprotein E (apoE) and apoE-mimetic peptides exert prominent anti-inflammatory effects. We determined the anti-inflammatory effects of novel apoE receptor mimetics, composed of the LDL receptor-binding domain of apoE (aa 133-152, ApoEp) or ApoEp with 6 lysines (6KApoEp) or 6 aspartates added at the N-terminus (6DApoEp). BV2 microglia and human THP-1 monocytes were treated with lipopolysaccharide (LPS) in the absence or presence of ApoEp, 6KApoEp or 6DApoEp, followed by determination of pro- ...[more]

PMID: 31497223

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Project description:Background: Specific microglia responses are thought to contribute to the development and progression of neurodegenerative diseases, including Parkinson’s disease (PD). However, the phenotypic acquisition of microglial cells and their role during the underlying neuroinflammatory processes remain largely elusive. Here, according to the multiple-hit hypothesis, which stipulates that PD etiology is determined by a combination of genetics and various environmental risk factors, we investigate microglial transcriptional programs and morphological adaptations under PARK7/DJ-1 deficiency, a genetic cause of PD, during lipopolysaccharide (LPS)-induced inflammation. Methods: Using a combination of single-cell RNA-sequencing, bulk RNA-sequencing, multicolor flow cytometry and immunofluorescence analyses, we comprehensively compared microglial cell phenotypic characteristics in PARK7/DJ-1 knock-out (KO) with wildtype littermate mice following 6- or 24-hour intraperitoneal injection with LPS. For translational perspectives, we conducted corresponding analyses in human PARK7/DJ-1 mutant induced pluripotent stem cell (iPSC)-derived microglia and murine bone marrow-derived macrophages (BMDMs). Results: By excluding the contribution of other immune brain resident and peripheral cells, we show that microglia acutely isolated from PARK7/DJ-1 KO mice display a distinct phenotype, specially related to type II interferon and DNA damage response signaling, when compared with wildtype microglia, in response to LPS. We also detected discrete signatures in human PARK7/DJ-1 mutant iPSC-derived microglia and BMDMs from PARK7/DJ-1 KO mice. These specific transcriptional signatures were reflected at the morphological level, with microglia in LPS-treated PARK7/DJ-1 KO mice showing a less amoeboid cell shape compared to wildtype mice, both at 6 and 24 hours after acute inflammation, as also observed in BMDMs. Conclusions: Taken together, our results show that, under inflammatory conditions, PARK7/DJ-1 deficiency skews microglia towards a distinct phenotype characterized by downregulation of genes involved in type II interferon signaling and a less prominent amoeboid morphology compared to wildtype microglia. These findings suggest that the underlying oxidative stress associated with the lack of PARK7/DJ-1 affects microglia neuroinflammatory responses, which may play a causative role in PD onset and progression.

Dataset Information

Novel apoE receptor mimetics reduce LPS-induced microglial inflammation.

Publications

Novel apoE receptor mimetics reduce LPS-induced microglial inflammation.

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