LRP1 expression in microglia is protective during CNS autoimmunity

Chuang, Tzu-Ying; Guo, Yuxin; Seki, Shinsuke; Rosen, Abagail M.; Johanson, David M.; Mandell, James W.; Lucchinetti, Claudia F.; Gaultier, Alban

doi:10.1186/s40478-016-0343-2

Cited by 61 publications

(75 citation statements)

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“…Consistent with the study by Chuang et al in macrophage [51], our current study also found that LRP1 down-regulation in primary microglia not only leads to NF-κB activation in the absence of inflammatory stimuli but also enhances the LPS-induced NF-κB activity. Gaultier et al has described a potential mechanism through which LRP1 may suppress NF-κB activation in mouse macrophage.…”

Section: Discussionsupporting

confidence: 93%

“…In addition, recent work by Chuang et al demonstrated that in the brains of microglial Lrp1 conditional knockout mice, microglia adopt a pro-inflammatory phenotype characterized by amoeboid morphology, indicating that LRP1 may regulate microglial activation in vivo. Of note, their work also suggests that ablation of LRP1 in microglia, not in macrophage, had a significant impact on the disease severity of multiple sclerosis [51]. However, the regulation and function of LRP1 as well as related signaling pathways in microglia remain to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…LRP1 regulates the metabolism of over 40 extracellular ligands; however, existing microglial Lrp1 conditional knockout mouse model does not address the role of LRP1 as a receptor for diverse ligands [51]. Here we have explored the role of LRP1 antagonist RAP in microglial activation.…”

Section: Discussionmentioning

confidence: 99%

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LRP1 modulates the microglial immune response via regulation of JNK and NF-κB signaling pathways

Yang

Liu

Zheng

et al. 2016

J Neuroinflammation

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BackgroundNeuroinflammation is characterized by microglial activation and the increased levels of cytokines and chemokines in the central nervous system (CNS). Recent evidence has implicated both beneficial and toxic roles of microglia when over-activated upon nerve injury or in neurodegenerative diseases, including Alzheimer’s disease (AD). The low-density lipoprotein receptor-related protein 1 (LRP1) is a major receptor for apolipoprotein E (apoE) and amyloid-β (Aβ), which play critical roles in AD pathogenesis. LRP1 regulates inflammatory responses in peripheral tissues by modulating the release of inflammatory cytokines and phagocytosis. However, the roles of LRP1 in brain innate immunity and neuroinflammation remain unclear.MethodsIn this study, we determined whether LRP1 modulates microglial activation by knocking down Lrp1 in mouse primary microglia. LRP1-related functions in microglia were also assessed in the presence of LRP1 antagonist, the receptor-associated protein (RAP). The effects on the production of inflammatory cytokines were measured by quantitative real-time PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). Potential involvement of specific signaling pathways in LRP1-regulated functions including mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB) were assessed using specific inhibitors.ResultsWe found that knocking down of Lrp1 in mouse primary microglia led to the activation of both c-Jun N-terminal kinase (JNK) and NF-κB pathways with corresponding enhanced sensitivity to lipopolysaccharide (LPS) in the production of pro-inflammatory cytokines. Similar effects were observed when microglia were treated with LRP1 antagonist RAP. In addition, treatment with pro-inflammatory stimuli suppressed Lrp1 expression in microglia. Interestingly, NF-κB inhibitor not only suppressed the production of cytokines induced by the knockdown of Lrp1 but also restored the down-regulated expression of Lrp1 by LPS.ConclusionsOur study uncovers that LRP1 suppresses microglial activation by modulating JNK and NF-κB signaling pathways. Given that dysregulation of LRP1 has been associated with AD pathogenesis, our work reveals a critical regulatory mechanism of microglial activation by LRP1 that could be associated with other AD-related pathways thus further nominating LRP1 as a potential disease-modifying target for the treatment of AD.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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LRP1 modulates the microglial immune response via regulation of JNK and NF-κB signaling pathways

Yang

Liu

Zheng

et al. 2016

J Neuroinflammation

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“…Active EAE was performed as described previously (16). Briefly, male or female (sex-matched within experiments) C57BL/6 mice were immunized subcutaneously with 50 μg of myelin oligodendrocyte glycoprotein peptide 35–55 (MOG 35–55 ) (CSBIO #CS0681) emulsified at a 1:1 ratio in Complete Freud’s Adjuvant (Sigma Aldrich #F5881).…”

Section: Methodsmentioning

confidence: 99%

Lineage-Specific Metabolic Properties and Vulnerabilities of T Cells in the Demyelinating Central Nervous System

Seki

Stevenson

Rosen

et al. 2017

The Journal of Immunology

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Multiple Sclerosis (MS) is a disease characterized by immune-mediated destruction of central nervous system (CNS) myelin. Current MS therapies aim to block peripheral immune cells from entering the CNS. While these treatments limit new inflammatory activity in the CNS, no treatment effectively prevents long-term disease progression and disability accumulation in MS patients. One explanation for this paradox is that current therapies are ineffective at targeting immune responses already present in the CNS. To this end, we sought to understand the metabolic properties of T cells that mediate ongoing inflammation in the demyelinating CNS. Using experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice, a well-studied model of MS, we showed that the CD4+ and CD8+ T cells that invade the EAE CNS are highly glycolytic. This elevation of glycolysis is mediated by upregulated expression of the glycolytic machinery, and is essential for inflammatory responses to myelin. Surprisingly, we found that an inhibitor of glyceraldehyde-3 phosphate (GAPDH), 3-bromopyruvic acid (3-BrPa), blocks IFN-γ but not IL-17A production in immune cells isolated from the EAE CNS. Indeed, in vitro studies confirmed that the production of IFN-γ by differentiated Th1 cells is more sensitive to 3-BrPa than the production of IL-17A by Th17 cells. Finally, in transfer models of EAE, 3-BrPa robustly attenuates the encephalitogenic potential of EAE-driving immune cells. These data are one of the first to demonstrate the metabolic properties of T cells in the demyelinating CNS in vivo.

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“…Modulating phagocytosis may also contribute to LRP1's 80 previously described role in mediating an anti-inflammatory effect on microglia during EAE 176 .…”

Section: Introductionmentioning

confidence: 91%

Microglial LRP1 modulates neuroinflammation via control of the NF-κB pathway in autoimmunity

Chuang¹

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Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system (CNS), characterized by immune cell infiltration and inflammation.While T cells are known contributors to MS pathology, the precise function of CNS resident and peripheral infiltrating myeloid cells is more controversial. In this work I delineate the myeloid cell function of LRP1, a scavenger receptor crucial for myelin clearance and the inflammatory response, in the context of MS. I find that LRP1 expression is increased in the MS lesion in comparison to the surrounding healthy tissue.Using two genetic mouse models, I show that deletion of LRP1 in microglia, but not in peripheral macrophages, negatively impacts the progression of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. I further demonstrate that this increase in EAE disease severity is not due to haplodeficiency of the Cx3cr1 locus. Furthermore, microglia lacking LRP1 adopt a pro-inflammatory phenotype characterized by amoeboid morphology and increased production of the inflammatory mediator TNFα. I also show that LRP1 inhibits NF-κB activation in myeloid cells via a MyD88 dependent mechanism. Together, my data suggests that LRP1 functions in microglia to keep these cells in an anti-inflammatory and neuroprotective status during inflammatory insult, including experimental autoimmune encephalomyelitis and potentially in MS. I also initiated studies exploring the role of LRP1 as a phagocytic receptor of myelin during MS using a combination of in vitro and in vivo models. This work will provide a foundation for future studies regarding the role of LRP1 in mediating the crosstalk between phagocytosis and inflammation.ii

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LRP1 expression in microglia is protective during CNS autoimmunity

Cited by 61 publications

References 50 publications

LRP1 modulates the microglial immune response via regulation of JNK and NF-κB signaling pathways

LRP1 modulates the microglial immune response via regulation of JNK and NF-κB signaling pathways

Lineage-Specific Metabolic Properties and Vulnerabilities of T Cells in the Demyelinating Central Nervous System

Microglial LRP1 modulates neuroinflammation via control of the NF-κB pathway in autoimmunity

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