CaSR Antagonist (Calcilytic) NPS 2143 Hinders the Release of Neuroinflammatory IL-6, Soluble ICAM-1, RANTES, and MCP-2 from A?-Exposed Human Cortical Astrocytes.

ABSTRACT: Available evidence shows that human cortical neurons' and astrocytes' calcium-sensing receptors (CaSRs) bind Amyloid-beta (A?) oligomers triggering the overproduction/oversecretion of several Alzheimer's disease (AD) neurotoxinseffects calcilytics suppress. We asked whether A?CaSR 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 A?25-35?±?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 A?•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 A? alone increased over controls the four agents' distinctive intracellular accumulation. Conversely, NPS 2143 did not alter A?-induced surges in IL-1?, IL-3, IL-8, and IL-16 secretion, consequently revealing their A?•CaSR signaling-independence. Finally, A?25-35?±?NPS 2143 treatments left unchanged MCP-1's and TIMP-2's basal expression. Thus, NAHAs A?•CaSR signaling drove four proinflammatory agents' over-release that NPS 2143 curtailed. Therefore, calcilytics would also abate NAHAs' A?•CaSR signaling direct impact on AD's neuroinflammation.

SUBMITTER: Chiarini A 

PROVIDER: S-EPMC7349863 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature