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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-12

AUTHORS

N. R. Bonetti, C. Diaz-Cañestro, L. Liberale, M. Crucet, A. Akhmedov, M. Merlini, M. F. Reiner, S. Gobbato, S. Stivala, G. Kollias, F. Ruschitzka, T. F. Lüscher, J. H. Beer, G. G. Camici

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. More... »

PAGES

2173

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41598-019-38670-z

DOI

http://dx.doi.org/10.1038/s41598-019-38670-z

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1112201246

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30778120


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