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Tumour Necrosis Factor-α Inhibition Improves Stroke Outcome in a Mouse Model of Rheumatoid Arthritis


Bonetti, N R; Diaz-Cañestro, C; Liberale, L; Crucet, M; Akhmedov, A; Merlini, M; Reiner, M F; Gobbato, S; Stivala, S; Kollias, G; Ruschitzka, F; Lüscher, T F; Beer, J H; Camici, G G (2019). Tumour Necrosis Factor-α Inhibition Improves Stroke Outcome in a Mouse Model of Rheumatoid Arthritis. Scientific Reports, 9(1):2173.

Abstract

Rheumatoid Arthritis (RA) is a chronic inflammatory disorder where incidence and severity of myocardial infarction are increased. Data on the incidence and outcome of stroke are conflicting. Thus, we investigated outcome after Ischemia/Reperfusion (I/R) brain injury in a mouse model of RA and assessed for the role of the tumour necrosis factor-α (TNF-α) inhibitor Infliximab herein. We used a TNF-α reliant mouse model of RA. RA and wildtype (WT) animals were treated with vehicle (RA/WT) or Infliximab (RA Infliximab) for 4 weeks, before undergoing I/R brain injury. RA-animals displayed larger strokes and poorer neurological performance. Immunohistochemistry on brain sections revealed increased numbers of resident and peripheral innate immune cells (microglia and macrophages); increased Blood-Brain-Barrier (BBB)-disruption; decreased levels of the tight junction proteins (TJPs) claudin-5 and occludin; increased expression of matrix-metalloproteinases (MMP)-3 and -9 and enhanced lipid peroxidation. Treatment with Infliximab corrected these alterations. We show that RA associates to worse stroke-outcome via exacerbated BBB degradation by decrease of the TJPs claudin-5 and occludin. We identified MMPs-3 and -9 and increased oxidative stress as potential mediators thereof. Increased numbers of resident and peripheral innate immune cells (microglia and macrophages) may in turn contribute to all these effects. Infliximab-treatment restored the phenotype of RA-mice to baseline. Our data provide evidence clearly linking RA to adverse stroke-outcome in mice and indicate an approved TNF-α inhibitor as a potential strategy to reduce stroke-burden in this setting.

Abstract

Rheumatoid Arthritis (RA) is a chronic inflammatory disorder where incidence and severity of myocardial infarction are increased. Data on the incidence and outcome of stroke are conflicting. Thus, we investigated outcome after Ischemia/Reperfusion (I/R) brain injury in a mouse model of RA and assessed for the role of the tumour necrosis factor-α (TNF-α) inhibitor Infliximab herein. We used a TNF-α reliant mouse model of RA. RA and wildtype (WT) animals were treated with vehicle (RA/WT) or Infliximab (RA Infliximab) for 4 weeks, before undergoing I/R brain injury. RA-animals displayed larger strokes and poorer neurological performance. Immunohistochemistry on brain sections revealed increased numbers of resident and peripheral innate immune cells (microglia and macrophages); increased Blood-Brain-Barrier (BBB)-disruption; decreased levels of the tight junction proteins (TJPs) claudin-5 and occludin; increased expression of matrix-metalloproteinases (MMP)-3 and -9 and enhanced lipid peroxidation. Treatment with Infliximab corrected these alterations. We show that RA associates to worse stroke-outcome via exacerbated BBB degradation by decrease of the TJPs claudin-5 and occludin. We identified MMPs-3 and -9 and increased oxidative stress as potential mediators thereof. Increased numbers of resident and peripheral innate immune cells (microglia and macrophages) may in turn contribute to all these effects. Infliximab-treatment restored the phenotype of RA-mice to baseline. Our data provide evidence clearly linking RA to adverse stroke-outcome in mice and indicate an approved TNF-α inhibitor as a potential strategy to reduce stroke-burden in this setting.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Cardiology
04 Faculty of Medicine > Center for Molecular Cardiology
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Health Sciences > Multidisciplinary
Language:English
Date:18 February 2019
Deposited On:21 Aug 2019 10:01
Last Modified:16 Apr 2020 00:03
Publisher:Nature Publishing Group
ISSN:2045-2322
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1038/s41598-019-38670-z
PubMed ID:30778120

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