Chronic exposure to IL-6 induces a desensitized phenotype of the microglia
Recasens, Mireia (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)
Almolda Ardid, Beatriz (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)
Pérez-Clausell, Jeús (Universitat de Barcelona. Departament de Biologia Cel·lular, Fisiologia i Immunologia)
Campbell, Iain L. (University of Sydney. School of Life and Environmental Sciences and Charles Perkins Centre)
González, Berta (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)
Castellano López, Bernardo (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)

Date:	2021
Abstract:	When the homeostasis of the central nervous system (CNS) is altered, microglial cells become activated displaying a wide range of phenotypes that depend on the specific site, the nature of the activator, and particularly the microenvironment generated by the lesion. Cytokines are important signals involved in the modulation of the molecular microenvironment and hence play a pivotal role in orchestrating microglial activation. Among them, interleukin-6 (IL-6) is a pleiotropic cytokine described in a wide range of pathological conditions as a potent inducer and modulator of microglial activation, but with contradictory results regarding its detrimental or beneficial functions. The objective of the present study was to evaluate the effects of chronic IL-6 production on the immune response associated with CNS-axonal anterograde degeneration. The perforant pathway transection (PPT) paradigm was used in transgenic mice with astrocyte-targeted IL6-production (GFAP-IL6Tg). At 2, 3, 7, 14, and 21 days post-lesion, the hippocampal areas were processed for immunohistochemistry, flow cytometry, and protein microarray. An increase in the microglia/macrophage density was observed in GFAP-IL6Tg animals in non-lesion conditions and at later time-points after PPT, associated with higher microglial proliferation and a major monocyte/macrophage cell infiltration. Besides, in homeostasis, GFAP-IL6Tg showed an environment usually linked with an innate immune response, with more perivascular CD11b + /CD45 high /MHCII + /CD86 + macrophages, higher T cell infiltration, and higher IL-10, IL-13, IL-17, and IL-6 production. After PPT, WT animals show a change in microglia phenotype expressing MHCII and co-stimulatory molecules, whereas transgenic mice lack this shift. This lack of response in the GFAP-IL6Tg was associated with lower axonal sprouting. Chronic exposure to IL-6 induces a desensitized phenotype of the microglia. The online version contains supplementary material available at 10. 1186/s12974-020-02063-1.
Grants:	Ministerio de Ciencia e Innovación BFU2014-55459 Ministerio de Ciencia e Innovación BFU2017-87843-R
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Axonal sprouting ; Primed microglia ; T cell ; Monocyte ; MHCII
Published in:	Journal of neuroinflammation, Vol. 18 (january 2021) , ISSN 1742-2094

DOI: 10.1186/s12974-020-02063-1
PMID: 33482848

22 p, 6.8 MB

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