Nerve growth factor regulates TNF-α production in mouse macrophages via MAP kinase activation

Barouch, Rina; Kazimirsky, Gila; Appel, Elena; Brodie, Chaya

doi:10.1189/jlb.69.6.1019

Cited by 52 publications

(5 citation statements)

References 44 publications

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“…Because p75 NTR has been identified in macrophages (Barouch et al, 2001; Caroleo et al, 2001; Samah et al, 2008; Meeker et al, 2015; Yu et al, 2022), we tested whether the p75 NTR -specific inhibitor, TAT-Pep5 (Yamashita and Tohyama, 2003), inhibits Tau-elicited responses in BMDMs. Fig.…”

Section: Resultsmentioning

confidence: 99%

LRP1 Triggers Pro-inflammatory Cell-signaling in Response to Extracellular Tau Independently of the NMDA Receptor

Azmoon,

Mantuano,

Poudel

et al. 2023

Preprint

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In Alzheimer’s Disease (AD) and other neurodegenerative diseases, microtubule-associated protein Tau forms abnormal intracellular aggregates. Mechanisms by which Tau may promote AD progression remain incompletely understood. Low Density Lipoprotein Receptor-related Protein-1 (LRP1) mediates the uptake of Tau, which is released into the extracellular spaces in the brain and may thereby promote seeding of Tau aggregates in new cells. Herein, we demonstrate that in macrophages, microglia, and astrocytes, extracellular Tau induces an LRP1-dependent pro-inflammatory response, characterized by NFκB activation and expression of diverse pro-inflammatory cytokines. Unlike other LRP1 ligands that elicit LRP1-dependent cell-signaling events, the response to Tau occurs independently of the NMDA Receptor. Instead, Tau-activated cell-signaling requires the low affinity Neurotrophin Receptor (p75NTR). The role of p75NTRin Tau-elicited cell-signaling was demonstrated by gene-silencing and/or with TAT-Pep5, in macrophages, astrocytes, and PC12 cells. Because RhoA is activated downstream of p75NTR, we studied two Rho kinase pharmacologic inhibitors, Y-27632 and Fasudil Hydrochloride, and demonstrated that both reagents block NFκB activation and cytokine expression in response to Tau. These results define Tau and its receptor assembly, which includes LRP1 and p75NTR, as a novel biochemical system that may regulate neuro-inflammation in AD and other neurodegenerative diseases. The ability of Rho kinase inhibitors to antagonize the Tau-LRP1/p75NTRpathway may represent a novel mechanism by which these agents demonstrate efficacy in Alzheimer’s Disease.Significance StatementIn Alzheimer’s Disease and other neurodegenerative diseases, microtubule-associated protein Tau forms abnormal intracellular aggregates that contribute to disease progression. When Tau is released by cells, it binds to the transmembrane receptor, LRP1, which is expressed by diverse cells in the CNS. LRP1 has a unique ability to couple endocytosis with activation of cell-signaling. We demonstrated that Tau-binding to LRP1 activates pro-inflammatory responses in macrophages, microglia, and astrocytes. p75 Neurotrophin Receptor served as an essential co-receptor. Targeting Rho kinase, downstream of p75NTR, blocked Tau-initiated pro-inflammatory responses. These results define a novel pathway by which Tau may regulate neuro-inflammation in Alzheimer’s Disease and other neurodegenerative diseases.

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Section: Resultsmentioning

confidence: 99%

LRP1 Triggers Pro-inflammatory Cell-signaling in Response to Extracellular Tau Independently of the NMDA Receptor

Azmoon,

Mantuano,

Poudel

et al. 2023

Preprint

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“…These cytokines, activate macrophages [25] and promote T cell activation and proliferation [42]. NGF also plays important roles in differentiation and proliferation of inflammatory cells [4,39,42]. In addition to its role in inflammatory cell differentiation, NGF is known to promote aggressive sprouting of sympathetic nerves.…”

Section: Discussionmentioning

confidence: 99%

Macrophage Depletion Suppresses Sympathetic Hyperinnervation following Myocardial Infarction

2008

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Myocardial infarction induces sympathetic axon sprouting adjacent to the necrotic region, and this has been implicated in the etiology of arrhythmias resulting in sudden cardiac death. Previous studies show that nerve growth factor (NGF) is essential for enhanced post-infarct sympathetic sprouting, but the cell types necessary to supply this neurotrophic protein are unknown. The objective of the present study was to determine whether macrophages, which are known to synthesize NGF, are necessary for post-infarct cardiac sympathetic sprouting. Ovariectomized female rats received left coronary artery ligation or sham operation, followed by intravenous injection of liposomes containing saline vehicle or clodronate, which kills macrophages. Shamoperated myocardium contained some sympathetic axons, few myofibroblasts and T cells and no CD-68-positive macrophages. In rats receiving saline liposomes through 7 days post-ligation, the posterolateral infarct border contained numerous myofibroblasts, macrophages and T cells, and sympathetic innervation was increased twofold. Treatment with clodronate liposomes reduced macrophage numbers by 69%, while myofibroblast area was reduced by 23% and T cell number was unaffected. Clodronate liposome treatment reduced sympathetic axon density to levels comparable to the uninfarcted heart. NGF protein content measured in western blots was reduced to 33% of that present in infarcts where rats received saline-containing liposomes. Tissue morphometry confirmed that NGF immunostaining was dramatically reduced, and this was attributable primarily to reduced macrophage content. These results show that macrophage

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“…In future studies, plasma Troponin I measurement 24hs after surgery should be performed as a standardized protocol in minimizing the bias caused by model. Besides, because OT can target pathogenic events in multiple cell types, these undefined cells may be inflammatory cells, such as macrophages (Barouch et al 2001), lymphocytes (Ralainirina et al 2012) or cardiomyocytes. Further studies are needed to clarify how the OT-OTR system may contribute to cardiac remodeling in other cell types.…”

Section: Limitationsmentioning

confidence: 99%

Oxytocin Attenuates Sympathetic Innervation with Inhibition of Cardiac Mast Cell Degranulation in Rats after Myocardial Infarction

Yin,

Wang,

Han

et al. 2024

J Pharmacol Exp Ther

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Nerve growth factor regulates TNF-α production in mouse macrophages via MAP kinase activation

Cited by 52 publications

References 44 publications

LRP1 Triggers Pro-inflammatory Cell-signaling in Response to Extracellular Tau Independently of the NMDA Receptor

LRP1 Triggers Pro-inflammatory Cell-signaling in Response to Extracellular Tau Independently of the NMDA Receptor

Macrophage Depletion Suppresses Sympathetic Hyperinnervation following Myocardial Infarction

Oxytocin Attenuates Sympathetic Innervation with Inhibition of Cardiac Mast Cell Degranulation in Rats after Myocardial Infarction

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