Anti-inflammatory effects of ADAMTS-4 in a mouse model of ischemic stroke.
ADAMTS-4 (a disintegrin and metalloproteinase with thrombospondin motifs type 4) is a metalloprotease capable to degrade chondroitin sulfate proteoglycans leading to cartilage destruction during arthritis or to neuroplasticity during spinal cord injury (SCI). Although ADAMTS-4 is an inflammatory-regulated enzyme, its role during inflammation has never been investigated. The aim of this study was to investigate the role of ADAMTS-4 in neuroinflammation. First, we evidenced an increase of ADAMTS-4 expression in the ischemic brain hemisphere of mouse and human patients suffering from ischemic stroke. Then, we described that ADAMTS-4 has predominantly an anti-inflammatory effect in the CNS. Treatment of primary microglia or astrocyte cultures with low doses of a human recombinant ADAMTS-4 prior to LPS exposure decreased NO production and the synthesis/release of pro-inflammatory cytokines including NOS2, CCL2, TNF-α, IL-1β and MMP-9. Accordingly, when cell cultures were transfected with silencing siRNA targeting ADAMTS-4 prior to LPS exposure, the production of NO and the synthesis/release of pro-inflammatory cytokines were increased. Finally, the feasibility of ADAMTS-4 to modulate neuroinflammation was investigated in vivo after permanent middle cerebral artery occlusion in mice. Although ADAMTS-4 treatment did not influence the lesion volume, it decreased astrogliosis and macrophage infiltration, and increased the number of microglia expressing arginase-1, a marker of alternatively activated cells with inflammation inhibiting functions. Additionally, ADAMTS-4 increased the production of IL-10 and IL-6 in the peri-ischemic area. By having anti-inflammatory and neuroregenerative roles, ADAMTS-4 may represent an interesting target to treat acute CNS injuries, such as ischemic stroke, SCI or traumatic brain injury. GLIA 2016;64:1492-1507.
Department of Neurobiology, a. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio University of Eastern Finland, Kuopio, P.O. Box 1627, Finland.
Sighild
S
Lemarchant
Department of Neurobiology, a. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio University of Eastern Finland, Kuopio, P.O. Box 1627, Finland.
Hiramani
H
Dunghana
Department of Neurobiology, a. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio University of Eastern Finland, Kuopio, P.O. Box 1627, Finland.
Yuriy
Y
Pomeshchik
Department of Neurobiology, a. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio University of Eastern Finland, Kuopio, P.O. Box 1627, Finland.
Henri
H
Leinonen
Department of Neurobiology, a. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio University of Eastern Finland, Kuopio, P.O. Box 1627, Finland.
Natalia
N
Kolosowska
Department of Neurobiology, a. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio University of Eastern Finland, Kuopio, P.O. Box 1627, Finland.
Paula
P
Korhonen
Department of Neurobiology, a. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio University of Eastern Finland, Kuopio, P.O. Box 1627, Finland.
Katja M
KM
Kanninen
Neurovascular Research Laboratory, Vall D'Hebron Research Institute (VHIR), Universitat Autònoma De Barcelona, Barcelona, Spain.
Teresa
T
García-Berrocoso
Neurovascular Research Laboratory, Vall D'Hebron Research Institute (VHIR), Universitat Autònoma De Barcelona, Barcelona, Spain.
Joan
J
Montaner
Department of Neurobiology, a. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio University of Eastern Finland, Kuopio, P.O. Box 1627, Finland.
Tarja
T
Malm
Department of Neurobiology, a. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio University of Eastern Finland, Kuopio, P.O. Box 1627, Finland.
Jari
J
Koistinaho
D000071121:ADAMTS4 Protein / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D016753:Interleukin-10 / Q000378:metabolism; D007511:Ischemia / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D017628:Microglia / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000378:metabolism; D020521:Stroke / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C556062:IL10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D000071121:ADAMTS4 Protein; C000603919:Adamts4 protein, mouse
ADAMTS-4; astrocyte; microglia; neuroinflammation; stroke