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

Abstract

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.

LRP1 deficiency in microglia blocks neuro‐inflammation in the spinal dorsal horn and neuropathic pain processing

“…Because, in cells of myeloid origin, membrane-anchored LRP1 expresses anti-inflammatory activity (Brifault et al, 2017;Gorovoy et al, 2010;Mantuano et al, 2016;May et al, 2013;Overton et al, 2007;Pocivavsek, Burns, & Rebeck, 2009;Pocivavsek, Mikhailenko, et al, 2009;Staudt et al, 2013;Yang et al, 2016), proteolytic shedding of LRP1 serves as a key reaction that converts the activity of LRP1 from anti-inflammatory to pro-inflammatory (Brifault et al, 2017;Gorovoy et al, 2010). However, to date, in in vivo model systems, only the anti-inflammatory activity of LRP1 has been observed (Chuang et al, 2016;Mantuano et al, 2016;Overton et al, 2007;Staudt et al, 2013).…”

Microglia amplify inflammatory activation of astrocytes in manganese neurotoxicity

“…Bay11 was chosen due to its established ability to inhibit of NF-κB including in primary microglia [39, 40]. Media was completely exchanged, and microglia were then treated per standard MCM protocol with either saline or 100 μM MnCl 2 .…”

TLR Crosstalk Activates LRP1 to Recruit Rab8a and PI3Kγ for Suppression of Inflammatory Responses

“…LRP1 is synthesized as a >600-kDa precursor with an 85-kDa transmembrane subunit produced by furin cleavage, and additional cleavage releases a soluble extracellular domain (Zurhove et al, 2008). Although previously unconnected with either Rab8a or PI3Kg, LRP1 has nevertheless been linked with TLRs through nuclear factor kB (NF-kB)-dependent signaling outputs, where, like Rab8a and PI3Kg, it is a negative regulator of inflammation (Mantuano et al, 2016;Xian et al, 2017;Yang et al, 2016).…”