Abstract

BackgroundS100A9 protein (myeloid-related protein MRP14, also referred to as calgranulin B) is a reliable marker of inflammation, an important proinflammatory factor of innate immunity and acts as an additional antimicrobial peptide in the innate immune system. Evidence indicates that S100A9 contributes to Alzheimer’s disease (AD) pathology, although the precise mechanisms are not clear.MethodsWe were interested to study the mechanisms of S100A9 release upon Aβ1-42 stimulation, the potential roles of extracellular S100A9 depletion in Aβ-induced cytotoxicity, and the interaction with innate immune response in THP-1 monocytic cells that have been challenged with mostly Aβ1-42 monomers instead of oligomers. We used protein preparation, Ca2+ influx fluorescence imaging, MTT assay, siRNA knockdown, colony forming units (CFUs) assay and western blotting techniques to perform our study.ResultsAβ1-42 monomers elicited a marked decrease of S100A9 release into the cell culture supernatant in a dose-dependent manner in human THP-1 monocytes. This reduction of S100A9 release was accompanied by an increase of intracellular Ca2+ level. Aβ1-42-mediated decrease of S100A9 release was not associated with Aβ1-42-induced cytotoxicity as measured by MTT reduction assay. This observation was confirmed with the recombinant S100A9, which had little effect on Aβ1-42-induced cytotoxicity. Moreover, depletion of S100A9 with siRNA did not significantly evoke the cell toxicity. On the other hand, Aβ1-42-induced extracellular S100A9 depletion resulted in decreased antimicrobial activity of the culture supernatant after Aβ1-42 stimulation. Immunodepletion of S100A9 with anti-S100A9 also decreased the antimicrobial peptide activity of the vehicle treated culture supernatant. Consistently, the recombinant S100A9 clearly elicited the antimicrobial peptide activity in vitro, confirming the observed antimicrobial activity of S100A9 in the culture supernatant.ConclusionCollectively, our findings suggest that the mostly monomeric form of Aβ1-42 negatively regulates the innate immune system by down-regulating the secretion of S100A9, which is likely a main mediator of antimicrobial activity in the conditioned media of human THP-1 monocytes.

Highlights

  • S100A9 protein is a reliable marker of inflammation, an important proinflammatory factor of innate immunity and acts as an additional antimicrobial peptide in the innate immune system

  • We focused our research on the mechanisms of S100A9 release upon stimulation with mostly Aβ1-42 monomers, the potential roles of extracellular S100A9 depletion in Amyloid beta (Aβ)-induced cytotoxicity, and the interaction with innate immune response in THP-1 monocytic cells that have been challenged with Aβ1-42 monomers instead of oligomers

  • To clarify the pathological mechanism related to S100A9 in Alzheimer’s disease (AD), we measured the extracellular release of S100A9 in response to stimulation with Aβ1-42 in human THP-1 monocytes

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Summary

Introduction

S100A9 protein (myeloid-related protein MRP14, referred to as calgranulin B) is a reliable marker of inflammation, an important proinflammatory factor of innate immunity and acts as an additional antimicrobial peptide in the innate immune system. Evidence indicates that S100A9 contributes to Alzheimer’s disease (AD) pathology, the precise mechanisms are not clear. Altered or excessive signaling in these injury defense systems contributes to neuroinflammation and the irreversible degeneration of brain cells [4]. Extensive innate immune gene activation reflecting chronic innate immune activation could accompany brain aging, increasing vulnerability to cognitive decline and neurodegeneration, consistent with the emerging idea of a critical involvement of inflammation in the earliest stages of AD [5]. Clinical pharmaceutical trials aimed at modulating the immune system in AD have largely focused on dampening down central proinflammatory innate immunity and the manipulation of systemic immunity, and its communication with the central nervous system (CNS) [6]

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