CaSR Antagonist (Calcilytic) NPS 2143 Hinders the Release of Neuroinflammatory IL-6, Soluble ICAM-1, RANTES, and MCP-2 from Aβ-Exposed Human Cortical Astrocytes
Available evidence shows that human cortical neurons’ and astrocytes’ calcium-sensing receptors (CaSRs) bind Amyloid-beta (Aβ) oligomers triggering the overproduction/oversecretion of several Alzheimer’s disease (AD) neurotoxinseffects calcilytics suppress. We asked whether AβCaSR signaling might al...
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doaj-b2477a5b2b7a4ceb892d11d85f5942702020-11-25T02:36:17ZengMDPI AGCells2073-44092020-06-0191386138610.3390/cells9061386CaSR Antagonist (Calcilytic) NPS 2143 Hinders the Release of Neuroinflammatory IL-6, Soluble ICAM-1, RANTES, and MCP-2 from Aβ-Exposed Human Cortical AstrocytesAnna Chiarini0Ubaldo Armato1Peng Hu2Ilaria Dal Prà3Human Histology and Embryology Section, Department of Surgery, Dentistry, Pediatrics and Gynecology, Medical School, University of Verona, Veneto, 37134 Verona, ItalyHuman Histology and Embryology Section, Department of Surgery, Dentistry, Pediatrics and Gynecology, Medical School, University of Verona, Veneto, 37134 Verona, ItalyHuman Histology and Embryology Section, Department of Surgery, Dentistry, Pediatrics and Gynecology, Medical School, University of Verona, Veneto, 37134 Verona, ItalyHuman Histology and Embryology Section, Department of Surgery, Dentistry, Pediatrics and Gynecology, Medical School, University of Verona, Veneto, 37134 Verona, ItalyAvailable evidence shows that human cortical neurons’ and astrocytes’ calcium-sensing receptors (CaSRs) bind Amyloid-beta (Aβ) oligomers triggering the overproduction/oversecretion of several Alzheimer’s disease (AD) neurotoxinseffects calcilytics suppress. We asked whether AβCaSR signaling might also play a direct pro-neuroinflammatory role in AD. Cortical nontumorigenic adult human astrocytes (NAHAs) in vitro were untreated (controls) or treated with Aβ<sub>25-35</sub>±NPS 2143 (a calcilytic) and any proinflammatory agent in their protein lysates and growth media assayed via antibody arrays, enzyme-linked immunosorbent assays (ELISAs), and immunoblots. Results show Aβ•CaSR signaling upregulated the synthesis and release/shedding of proinflammatory interleukin (IL)-6, intercellular adhesion molecule-1 (ICAM-1) (holoprotein and soluble [s] fragment), Regulated upon Activation, normal T cell Expressed and presumably Secreted (RANTES), and monocyte chemotactic protein (MCP)-2. Adding NPS 2143 (i) totally suppressed IL-6′s oversecretion while remarkably reducing the other agents’ over-release; and (ii) more effectively than Aβ alone increased over controls the four agents’ distinctive intracellular accumulation. Conversely, NPS 2143 did not alter Aβ-induced surges in IL-1β, IL-3, IL-8, and IL-16 secretion, consequently revealing their Aβ•CaSR signaling-independence. Finally, Aβ<sub>25-35</sub>±NPS 2143 treatments left unchanged MCP-1′s and TIMP-2′s basal expression. Thus, NAHAs Aβ•CaSR signaling drove four proinflammatory agents’ over-release that NPS 2143 curtailed. Therefore, calcilytics would also abate NAHAs’ Aβ•CaSR signaling direct impact on AD’s neuroinflammation.https://www.mdpi.com/2073-4409/9/6/1386astrocyteshumancalcium-sensing receptorIL-6ICAM-1RANTES |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Anna Chiarini Ubaldo Armato Peng Hu Ilaria Dal Prà |
spellingShingle |
Anna Chiarini Ubaldo Armato Peng Hu Ilaria Dal Prà CaSR Antagonist (Calcilytic) NPS 2143 Hinders the Release of Neuroinflammatory IL-6, Soluble ICAM-1, RANTES, and MCP-2 from Aβ-Exposed Human Cortical Astrocytes Cells astrocytes human calcium-sensing receptor IL-6 ICAM-1 RANTES |
author_facet |
Anna Chiarini Ubaldo Armato Peng Hu Ilaria Dal Prà |
author_sort |
Anna Chiarini |
title |
CaSR Antagonist (Calcilytic) NPS 2143 Hinders the Release of Neuroinflammatory IL-6, Soluble ICAM-1, RANTES, and MCP-2 from Aβ-Exposed Human Cortical Astrocytes |
title_short |
CaSR Antagonist (Calcilytic) NPS 2143 Hinders the Release of Neuroinflammatory IL-6, Soluble ICAM-1, RANTES, and MCP-2 from Aβ-Exposed Human Cortical Astrocytes |
title_full |
CaSR Antagonist (Calcilytic) NPS 2143 Hinders the Release of Neuroinflammatory IL-6, Soluble ICAM-1, RANTES, and MCP-2 from Aβ-Exposed Human Cortical Astrocytes |
title_fullStr |
CaSR Antagonist (Calcilytic) NPS 2143 Hinders the Release of Neuroinflammatory IL-6, Soluble ICAM-1, RANTES, and MCP-2 from Aβ-Exposed Human Cortical Astrocytes |
title_full_unstemmed |
CaSR Antagonist (Calcilytic) NPS 2143 Hinders the Release of Neuroinflammatory IL-6, Soluble ICAM-1, RANTES, and MCP-2 from Aβ-Exposed Human Cortical Astrocytes |
title_sort |
casr antagonist (calcilytic) nps 2143 hinders the release of neuroinflammatory il-6, soluble icam-1, rantes, and mcp-2 from aβ-exposed human cortical astrocytes |
publisher |
MDPI AG |
series |
Cells |
issn |
2073-4409 |
publishDate |
2020-06-01 |
description |
Available evidence shows that human cortical neurons’ and astrocytes’ calcium-sensing receptors (CaSRs) bind Amyloid-beta (Aβ) oligomers triggering the overproduction/oversecretion of several Alzheimer’s disease (AD) neurotoxinseffects calcilytics suppress. We asked whether AβCaSR signaling might also play a direct pro-neuroinflammatory role in AD. Cortical nontumorigenic adult human astrocytes (NAHAs) in vitro were untreated (controls) or treated with Aβ<sub>25-35</sub>±NPS 2143 (a calcilytic) and any proinflammatory agent in their protein lysates and growth media assayed via antibody arrays, enzyme-linked immunosorbent assays (ELISAs), and immunoblots. Results show Aβ•CaSR signaling upregulated the synthesis and release/shedding of proinflammatory interleukin (IL)-6, intercellular adhesion molecule-1 (ICAM-1) (holoprotein and soluble [s] fragment), Regulated upon Activation, normal T cell Expressed and presumably Secreted (RANTES), and monocyte chemotactic protein (MCP)-2. Adding NPS 2143 (i) totally suppressed IL-6′s oversecretion while remarkably reducing the other agents’ over-release; and (ii) more effectively than Aβ alone increased over controls the four agents’ distinctive intracellular accumulation. Conversely, NPS 2143 did not alter Aβ-induced surges in IL-1β, IL-3, IL-8, and IL-16 secretion, consequently revealing their Aβ•CaSR signaling-independence. Finally, Aβ<sub>25-35</sub>±NPS 2143 treatments left unchanged MCP-1′s and TIMP-2′s basal expression. Thus, NAHAs Aβ•CaSR signaling drove four proinflammatory agents’ over-release that NPS 2143 curtailed. Therefore, calcilytics would also abate NAHAs’ Aβ•CaSR signaling direct impact on AD’s neuroinflammation. |
topic |
astrocytes human calcium-sensing receptor IL-6 ICAM-1 RANTES |
url |
https://www.mdpi.com/2073-4409/9/6/1386 |
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