Impaired Signaling of NF-κB and NRF2 in CX3CR1-Deficient Microglia: Implications in Tauopathies

Castro-Sánchez, Sara; García-Yagüe, Ángel Juan; Kügler, Sebastian; Lastres‐Becker, Isabel

doi:10.1101/346304

Cited by 4 publications

(6 citation statements)

References 61 publications

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“…The activated phenotype of microglia is known to trigger demyelination, dysregulation of neurotransmission, and synaptic pruning via phagocytic and migratory transformation (Kenny et al, 2006;Domercq et al, 2013;Lively and Schlichter, 2013;Zabel et al, 2016;Vilalta and Brown, 2018;Castro-Sánchez et al, 2019;Liu et al, 2021). As expected, pretreatment with PSE completely attenuated the LPS-induced effects on phagocytosis and migration (Figures 4A-C, Supplementary Figure S3A).…”

Section: Discussionsupporting

confidence: 59%

Succinum extracts inhibit microglial-derived neuroinflammation and depressive-like behaviors

Kang

Baek²,

Son³

et al. 2022

Front. Pharmacol.

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Microglia are emerging as important targets for the treatment of neuropsychiatric disorders. The phagocytic microglial phenotype and the resulting neuroinflammation lead to synaptic loss and neuronal cell death. To explore potential candidates that inhibit microglial hyperactivation, we first investigated ten candidate extracts of traditional Chinese medicine (TCM) using lipopolysaccharide (LPS)-stimulated BV2 microglial cells. Among the candidates, Pinus spp. succinum extract (PSE) was superior; thus, we further investigated its pharmacological activity and underlying mechanisms both in vitro and in vivo. Pretreatment with PSE (10, 20, and 40 μg/ml) attenuated the increases in inflammatory factors (nitric oxide and tumor necrosis factor-α), translocation of nuclear factor-kappa B (NF-κB), and phenotypic transformations (phagocytic and migratory) in a dose-dependent manner. These inhibitory effects of PSE on microglia were supported by its regulatory effects on the CX3C chemokine receptor 1 (CX3CR1)/nuclear factor erythroid-2-related factor 2 (Nrf2) pathway. In particular, intragastric administration of PSE (100 mg/kg) considerably improved sickness, anxiety, and depressive-like behaviors in mice subjected to chronic restraint stress (CRS). Our results suggest that PSE has strong antineuroinflammatory and antidepressant properties, and the underlying mechanisms may involve not only the regulation of NF-κB translocation but also the normalization of the CX3CR1/Nrf2 pathway.

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Section: Discussionsupporting

confidence: 59%

Succinum extracts inhibit microglial-derived neuroinflammation and depressive-like behaviors

Kang

Baek²,

Son³

et al. 2022

Front. Pharmacol.

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“…A recent study has shown that CX3CL1 induces NF- κ B activation in microglial cells and impaired NF-κB signaling in microglia removed from CX3CR1-deficient mice indicated that NF- κ B is involved in CX3CR1 signaling, but there are limited studies related to vascular injury mediated by CX3CR1. 45,46(preprint)…”

Section: Discussionmentioning

confidence: 99%

Anti Human CX3CR1 VHH Molecule Attenuates Venous Neointimal Hyperplasia of Arteriovenous Fistula in Mouse Model

Misra

Kilari

Yang

et al. 2021

JASN

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BackgroundFractalkine receptor 1 (CX3CR1) mediates macrophage infiltration and accumulation, causing venous neointimal hyperplasia (VNH)/venous stenosis (VS) in arteriovenous fistula (AVF). The effect of blocking CX3CR1 using an anti–human variable VHH molecule (hCX3CR1 VHH, BI 655088) on VNH/VS was determined using a humanized mouse in which the human CX3CR1 (hCX3CR1) gene was knocked in (KI).MethodsWhole-transcriptomic RNA sequencing with bioinformatics analysis was used on human stenotic AVF samples, C57BL/6J, hCX3CR1 KI mice with AVF and CKD, and in in vitro experiments to identify the pathways involved in preventing VNH/VS formation after hCX3CR1 VHH administration.ResultsAccumulation of CX3CR1 and CD68 was significantly increased in stenotic human AVFs. In C57BL/6J mice with AVF, there was increased Cx3cr1, Cx3cl1, Cd68, and Tnf-α gene expression, and increased immunostaining of CX3CR1 and CD68. In hCX3CR1-KI mice treated with hCX3CR1 VHH molecule (KI-A), compared with vehicle controls (KI-V), there was increased lumen vessel area and patency, and decreased neointima in the AVF outflow veins. RNA-seq analysis identified TNF-α and NF-κB as potential targets of CX3CR1 inhibition. In KI-A–treated vessels compared with KI-V, there was decreased gene expression of Tnf-α, Mcp-1, and Il-1β; with reduction of Cx3cl1, NF-κB, and Cd68; decreased M1, Ly6C, smooth muscle cells, fibroblast-activated protein, fibronectin, and proliferation; and increased TUNEL and M2 staining. In cell culture, monocytes stimulated with PMA and treated with hCX3CR1 VHH had decreased TNF-α, CD68, proliferation, and migration.ConclusionsCX3CR1 blockade reduces VNH/VS formation by decreasing proinflammatory cues.

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“…In 2018, controversial results were reported by the same group that CX3CR1 receptor signalling is involved in the synthesis of pro-inflammatory cytokines such as IL-1β, TNF-α, etc., mediated by MSK-1 and NFκB [91]. CX3CR1 signalling also triggered kinases such as ERK-1/2, p38 and JNK in immortal microglial (IMG) cells [91]. In addition, CX3CR1 deficient primary microglia had been observed with impaired NRF2, deficiency of phagocytosis and impaired microglial migration [92] (Fig.…”

Section: Cx3cr1/fractalkine Signalling-different Roles In Microgliamentioning

confidence: 96%

“…These nuclear transcription factors are involved in the synthesis of antioxidant enzymes, including heme oxygenase 1 and attenuate the proinflammatory phenotype in microglia [90]. In 2018, controversial results were reported by the same group that CX3CR1 receptor signalling is involved in the synthesis of pro-inflammatory cytokines such as IL-1β, TNF-α, etc., mediated by MSK-1 and NFκB [91]. CX3CR1 signalling also triggered kinases such as ERK-1/2, p38 and JNK in immortal microglial (IMG) cells [91].…”

Section: Cx3cr1/fractalkine Signalling-different Roles In Microgliamentioning

confidence: 99%

Interaction of Tau with the chemokine receptor, CX3CR1 and its effect on microglial activation, migration and proliferation

2020

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Alzheimer’s disease (AD) is a neurodegenerative disease that leads to progressive loss of memory and dementia. The pathological hallmarks of AD include extracellular accumulation of amyloid-β peptides forming senile plaques and intracellular accumulation of Tau oligomers and filamentous species. Tau is a microtubule-binding protein that stabilizes tubulin to form microtubules under physiological condition. In AD/ pathological condition, Tau detaches from microtubules and aggregates to form oligomers of different sizes and filamentous species such as paired helical filaments. Microglia are the resident brain macrophages that are involved in the phagocytosis of microbes, cellular debris, misfolded and aggregated proteins. Chemokine receptor, CX3CR1 is mostly expressed on microglia and is involved in maintaining the microglia in a quiescent state by binding to its ligand, fractalkine (CX3CL1), which is expressed in neurons as both soluble or membrane-bound state. Hence, under physiological conditions, the CX3CR1/CX3CL1 axis plays a significant role in maintaining the central nervous system (CNS) homeostasis. Further, CX3CR1/CX3CL1 signalling is involved in the synthesis of anti-inflammatory cytokines and also has a significant role in cytoskeletal rearrangement, migration, apoptosis and proliferation. In AD brain, the expression level of fractalkine is reduced, and hence Tau competes to interact with its receptor, CX3CR1. In microglia, phagocytosis and internalization of extracellular Tau species occurs in the presence of a chemokine receptor, CX3CR1 which binds directly to Tau and promotes its internalization. In this review, the pathophysiological roles of CX3CR1/fractalkine signalling in microglia and neurons at different stages of Alzheimer’s disease and the possible role of CX3CR1/Tau signalling has been widely discussed.

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Impaired Signaling of NF-κB and NRF2 in CX3CR1-Deficient Microglia: Implications in Tauopathies

Abstract: axis is essential in microglial activation associated with tauopathies and that polymorphisms have to be taken into account to development of therapeutic strategies.

Cited by 4 publications

References 61 publications

Succinum extracts inhibit microglial-derived neuroinflammation and depressive-like behaviors

Succinum extracts inhibit microglial-derived neuroinflammation and depressive-like behaviors

Anti Human CX3CR1 VHH Molecule Attenuates Venous Neointimal Hyperplasia of Arteriovenous Fistula in Mouse Model

Interaction of Tau with the chemokine receptor, CX3CR1 and its effect on microglial activation, migration and proliferation

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