Differential effects of toll-like receptor activation and differential mediation by MAP kinases of immune responses in microglial cells

Kwon, J., Arsenis, C., Suessmilch, M., McColl, A., Cavanagh, J. and Morris, B. J. (2022) Differential effects of toll-like receptor activation and differential mediation by MAP kinases of immune responses in microglial cells. Cellular and Molecular Neurobiology, 42(8), pp. 2655-2671. (doi: 10.1007/s10571-021-01127-x) (PMID:34297254) (PMCID:PMC9560989)

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Abstract

Microglial activation is believed to play a role in many psychiatric and neurodegenerative diseases. Based largely on evidence from other cell types, it is widely thought that MAP kinase (ERK, JNK and p38) signalling pathways contribute strongly to microglial activation following immune stimuli acting on toll-like receptor (TLR) 3 or TLR4. We report here that exposure of SimA9 mouse microglial cell line to immune mimetics stimulating TLR4 (lipopolysaccharide—LPS) or TLR7/8 (resiquimod/R848), results in marked MAP kinase activation, followed by induction of nitric oxide synthase, and various cytokines/chemokines. However, in contrast to TLR4 or TLR7/8 stimulation, very few effects of TLR3 stimulation by poly-inosine/cytidine (polyI:C) were detected. Induction of chemokines/cytokines at the mRNA level by LPS and resiquimod were, in general, only marginally affected by MAP kinase inhibition, and expression of TNF, Ccl2 and Ccl5 mRNAs, along with nitrite production, were enhanced by p38 inhibition in a stimulus-specific manner. Selective JNK inhibition enhanced Ccl2 and Ccl5 release. Many distinct responses to stimulation of TLR4 and TLR7 were observed, with JNK mediating TNF protein induction by the latter but not the former, and suppressing Ccl5 release by the former but not the latter. These data reveal complex modulation by MAP kinases of microglial responses to immune challenge, including a dampening of some responses. They demonstrate that abnormal levels of JNK or p38 signalling in microglial cells will perturb their profile of cytokine and chemokine release, potentially contributing to abnormal inflammatory patterns in CNS disease states.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Kwon, Jaedeok and Cavanagh, Professor Jonathan and McColl, Dr Alison and Suessmilch, Maria and Morris, Professor Brian
Authors: Kwon, J., Arsenis, C., Suessmilch, M., McColl, A., Cavanagh, J., and Morris, B. J.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
Research Centre:College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology
Journal Name:Cellular and Molecular Neurobiology
Publisher:Springer
ISSN:0272-4340
ISSN (Online):1573-6830
Published Online:23 July 2021
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Cellular and Molecular Neurobiology 42(8): 2655-2671
Publisher Policy:Reproduced under a Creative Commons Licence

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
308675Consortium of Neuroimmunology of Mood Disorders and Alzheimer's DiseaseJonathan CavanaghWellcome Trust (WELLCOTR)104025III - Immunology