1–40 β‐amyloid protein fragment modulates the expression of CD44 and CD71 on the astrocytoma cell line in the presence of IL1β and TNFα

Speciale, Livianna; Ruzzante, Stefania; Calabrese, Emma; Saresella, Marina; Taramelli, Donatella; Mariani, Claudio; Bava, Laura; Longhi, Renato; Ferrante, Pasquale

doi:10.1002/jcp.10295

Cited by 11 publications

(7 citation statements)

References 35 publications

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“…One potentially simple explanation for glial cell innate immune activation in brain aging/AD could be a direct, cytokine-like effect of Aβ, which is thought to be produced largely by neurons ( Vassar et al, 1999 ; LeBlanc et al, 1997 ). This idea has been suggested before ( Bales et al, 2000 ), and there have been some reports of immune activation in response to Aβ ( Barrientos et al, 2015 ; Speciale et al, 2003 ; Gitter et al, 1995 ; Lotz et al, 2005 ). The general concept is also consistent with: 1) the fact that Aβ shares structural similarities (e.g., small amphipathic structure, expression in multiple tissues) with anti-microbial peptides like cathelicidin, which has been reported to stimulate pro-inflammatory cytokine secretion in glial cells ( Lee et al, 2015 ); 2) numerous studies showing that Aβ can induce pores in cell membranes ( Stewart and Radford, 2017 ), which is a common characteristic of immune-activating anti-microbial peptides; 3) reports that LPS (a classic innate immune stimulus) increases Aβ in the brain ( Zhu et al, 2014 ); and 4) growing evidence that, similar to pro-inflammatory cytokines, Aβ levels increase with aging in the human brain ( Denver and McClean, 2018 ; Rodrigue et al, 2009 ).…”

Section: Introductionmentioning

confidence: 72%

Amyloid beta acts synergistically as a pro-inflammatory cytokine

LaRocca

Cavalier

Roberts

et al. 2021

Neurobiology of Disease

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The amyloid beta (Aβ) peptide is believed to play a central role in Alzheimer’s disease (AD), the most common age-related neurodegenerative disorder. However, the natural, evolutionarily selected functions of Aβ are incompletely understood. Here, we report that nanomolar concentrations of Aβ act synergistically with known cytokines to promote pro-inflammatory activation in primary human astrocytes (a cell type increasingly implicated in brain aging and AD). Using transcriptomics (RNA-seq), we show that Aβ can directly substitute for the complement component C1q in a cytokine cocktail previously shown to induce astrocyte immune activation. Furthermore, we show that astrocytes synergistically activated by Aβ have a transcriptional signature similar to neurotoxic “A1” astrocytes known to accumulate with age and in AD. Interestingly, we find that this biological action of Aβ at low concentrations is distinct from the transcriptome changes induced by the high/supra-physiological doses of Aβ often used in in vitro studies. Collectively, our results suggest an important, cytokine-like function for Aβ and a novel mechanism by which it may directly contribute to the neuroinflammation associated with brain aging and AD.

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Section: Introductionmentioning

confidence: 72%

Amyloid beta acts synergistically as a pro-inflammatory cytokine

LaRocca

Cavalier

Roberts

et al. 2021

Neurobiology of Disease

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“…In human AD patients, increased CD44 gene expression in lymphocytes was observed, implicating strong participation of CD44 in peripheral immune responses along AD pathology [ 85 ]. Furthermore, astrocytes in human AD brains were described to express CD44 [ 86 ], and an astrocytoma cell line exposed to amyloid-beta increased CD44 expression in vitro [ 87 ]. Additionally, CD44 is highly involved in leukocyte trafficking to inflamed tissue ([ 88 ], reviewed in [ 89 ]) and is upregulated after activation of T-cells, remaining on the surface of memory T-cells [ 90 ].…”

Section: Discussionmentioning

confidence: 99%

Microglia prevent peripheral immune cell invasion and promote an anti-inflammatory environment in the brain of APP-PS1 transgenic mice

Unger

Schernthaner

Marschallinger

et al. 2018

J Neuroinflammation

101

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BackgroundUndoubtedly, neuroinflammation is a major contributor to Alzheimer’s disease (AD) progression. Neuroinflammation is characterized by the activity of brain resident glial cells, in particular microglia, but also by peripheral immune cells, which infiltrate the brain at certain stages of disease progression. The specific role of microglia in shaping AD pathology is still controversially discussed. Moreover, a possible role of microglia in the interaction and recruitment of peripheral immune cells has so far been completely ignored.MethodsWe ablated microglia cells in 12-month-old WT and APP-PS1 transgenic mice for 4 weeks using the CSF1R inhibitor PLX5622 and analyzed its consequences to AD pathology and in particular to peripheral immune cell infiltration.ResultsPLX5622 treatment successfully reduced microglia numbers. Interestingly, it uncovered a treatment-resistant macrophage population (Iba1+/TMEM119−). These cells strongly expressed the phagocytosis marker CD68 and the lymphocyte activation, homing, and adhesion molecule CD44, specifically at sites of amyloid-beta plaques in the brains of APP-PS1 mice. In consequence, ablation of microglia significantly raised the number of CD3+/CD8+ T-cells and reduced the expression of anti-inflammatory genes in the brains of APP-PS1 mice.ConclusionWe conclude that in neurodegenerative conditions, chronically activated microglia might limit CD3+/CD8+ T-cell recruitment to the brain and that local macrophages connect innate with adaptive immune responses. Investigating the role of peripheral immune cells, their interaction with microglia, and understanding the link between innate and adaptive immune responses in the brain might be a future directive in treating AD pathology.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1304-4) contains supplementary material, which is available to authorized users.

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“…TNF-a is known to up-regulate CD44 expression in monocytes and astrocytes (21,22). We therefore investigated whether TNF-a had a similar effect in ovarian cancer cells.…”

Section: Tnf-a Modulates Cd44 Expression In Ovarian Cancer Cellsmentioning

confidence: 99%

Tumor Necrosis Factor-α Differentially Modulates CD44 Expression in Ovarian Cancer Cells

Muthukumaran

Miletti-González

Ravindranath

et al. 2006

Molecular Cancer Research

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Chronic inflammation is implicated in the pathophysiology of ovarian cancer. Tumor necrosis factor-A (TNF-A), a major inflammatory cytokine, is abundant in the ovarian cancer microenvironment. TNF-A modulates the expression of CD44 in normal T lymphocytes and CD44 is implicated in ovarian carcinogenesis and metastases. However, little is known about the role of TNF-A in CD44 expression of cancer cells. Recent clinical work using TNF-A inhibitors for the treatment of ovarian cancer makes the study of TNF-A interactions with CD44 crucial to determining treatment a success or a failure. We studied the effect of TNF-A on ovarian cancer cells viability, CD44 expression, and in vitro migration/invasion. Our results revealed that TNF-A differentially modulates the expression of CD44 in TNF-A-resistant ovarian cancer cells, affecting their in vitro migration, invasion, and binding to hyaluronic acid. TNF-A up-regulation of CD44 expression was dependent on the activation of c-Jun NH 2 -terminal kinase (JNK) and this activation was accompanied by an increase in their invasive phenotype. On the contrary, if TNF-A failed to induce JNK phosphorylation, the end result was down-regulation of both CD44 expression and the invasive phenotype. These results were confirmed by the use of JNK inhibitors and a TNF receptor competitive inhibitor.

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1–40 β‐amyloid protein fragment modulates the expression of CD44 and CD71 on the astrocytoma cell line in the presence of IL1β and TNFα

Cited by 11 publications

References 35 publications

Amyloid beta acts synergistically as a pro-inflammatory cytokine

Amyloid beta acts synergistically as a pro-inflammatory cytokine

Microglia prevent peripheral immune cell invasion and promote an anti-inflammatory environment in the brain of APP-PS1 transgenic mice

Tumor Necrosis Factor-α Differentially Modulates CD44 Expression in Ovarian Cancer Cells

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