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

被引:35
作者
Bonetti, N. R. [1 ]
Diaz-Canestro, C. [1 ]
Liberale, L. [1 ,2 ]
Crucet, M. [1 ]
Akhmedov, A. [1 ]
Merlini, M. [3 ]
Reiner, M. F. [1 ]
Gobbato, S. [1 ]
Stivala, S. [1 ]
Kollias, G. [4 ]
Ruschitzka, F. [5 ]
Luescher, T. F. [1 ,6 ]
Beer, J. H. [1 ,7 ]
Camici, G. G. [1 ]
机构
[1] Univ Zurich, Ctr Mol Cardiol, Schlieren, Switzerland
[2] Univ Genoa, Dept Internal Med, Clin Internal Med 1, Genoa, Italy
[3] UCSF, Gladstone Inst Neurol Dis, San Francisco, CA USA
[4] Biomed Sci Res Ctr, Varkiza, Greece
[5] Univ Hosp Zurich, Univ Heart Ctr, Zurich, Switzerland
[6] Royal Brompton & Harefield Hosp Trust, London, England
[7] Cantonal Hosp Baden, Dept Internal Med, Baden, Switzerland
基金
瑞士国家科学基金会;
关键词
TNF-ALPHA; CARDIOVASCULAR MORBIDITY; INFLAMMATORY ARTHRITIS; ISCHEMIC-STROKE; MORTALITY; RISK; METAANALYSIS; ANTIBODY; DISEASE; EVENTS;
D O I
10.1038/s41598-019-38670-z
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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-alpha (TNF-alpha) inhibitor Infliximab herein. We used a TNF-alpha 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-alpha inhibitor as a potential strategy to reduce stroke-burden in this setting.
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页数:11
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共 65 条
  • [31] Rheumatoid arthritis is associated with a more severe presentation of acute coronary syndrome and worse short-term outcome
    Mantel, Angla
    Holmqvist, Marie
    Jernberg, Tomas
    Wallberg-Jonsson, Solveig
    Askling, Johan
    [J]. EUROPEAN HEART JOURNAL, 2015, 36 (48) : 3413 - 3422
  • [32] Reduced nitric oxide bioavailability mediates cerebroarterial dysfunction independent of cerebral amyloid angiopathy in a mouse model of Alzheimer's disease
    Merlini, Mario
    Shi, Yi
    Keller, Stephan
    Savarese, Gianluigi
    Akhmedov, Alexander
    Derungs, Rebecca
    Spescha, Remo D.
    Kulic, Luka
    Nitsch, Roger M.
    Luscher, Thomas F.
    Camici, Giovanni G.
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 2017, 312 (02): : H232 - H238
  • [33] Trends in cardiovascular mortality in patients with rheumatoid arthritis over 50 years: a systematic review and meta-analysis of cohort studies
    Meune, Christophe
    Touze, Emmanuel
    Trinquart, Ludovic
    Allanore, Yannick
    [J]. RHEUMATOLOGY, 2009, 48 (10) : 1309 - 1313
  • [34] The Science of Stroke: Mechanisms in Search of Treatments
    Moskowitz, Michael A.
    Lo, Eng H.
    Iadecola, Costantino
    [J]. NEURON, 2010, 67 (02) : 181 - 198
  • [35] 10 YEAR MORTALITY AND CAUSES OF DEATH IN PATIENTS WITH RHEUMATOID-ARTHRITIS
    MUTRU, O
    LAAKSO, M
    ISOMAKI, H
    KOOTA, K
    [J]. BMJ-BRITISH MEDICAL JOURNAL, 1985, 290 (6484): : 1797 - 1799
  • [36] Cardiovascular, rheumatologic, and pharmacologic predictors of stroke in patients with rheumatoid arthritis: A nested, case-control study
    Nadareishvili, Zurab
    Michaud, Kaleb
    Hallenbeck, John M.
    Wolfe, Frederick
    [J]. ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH, 2008, 59 (08): : 1090 - 1096
  • [37] Innate Immunity and Inflammation Post-Stroke: An α7-Nicotinic Agonist Perspective
    Neumann, Silke
    Shields, Nicholas J.
    Balle, Thomas
    Chebib, Mary
    Clarkson, Andrew N.
    [J]. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2015, 16 (12): : 29029 - 29046
  • [38] Fcγ receptors as regulators of immune responses
    Nimmerjahn, Falk
    Ravetch, Jeffrey V.
    [J]. NATURE REVIEWS IMMUNOLOGY, 2008, 8 (01) : 34 - 47
  • [39] Identification of Ischemic Regions in a Rat Model of Stroke
    Popp, Anke
    Jaenisch, Nadine
    Witte, Otto W.
    Frahm, Christiane
    [J]. PLOS ONE, 2009, 4 (03):
  • [40] Longitudinal assessment of synovial, lymph node, and bone volumes in inflammatory arthritis in mice by in vivo magnetic resonance Imaging and microfocal computed tomography
    Proulx, Steven T.
    Kwok, Edmund
    You, Zhigang
    Papuga, M. Owen
    Beck, Christopher A.
    Shealy, David J.
    Ritchlin, Christopher T.
    Awad, Hani A.
    Boyce, Brendan F.
    Xing, Lianping
    Schwarz, Edward M.
    [J]. ARTHRITIS AND RHEUMATISM, 2007, 56 (12): : 4024 - 4037