AUTHOR=Nosaka Mizuho , Ishida Yuko , Kimura Akihiko , Kuninaka Yumi , Taruya Akira , Ozaki Mitsunori , Tanaka Atushi , Mukaida Naofumi , Kondo Toshikazu 

TITLE=Crucial Involvement of IL-6 in Thrombus Resolution in Mice via Macrophage Recruitment and the Induction of Proteolytic Enzymes

JOURNAL=Frontiers in Immunology

VOLUME=10

YEAR=2020

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.03150

DOI=10.3389/fimmu.2019.03150

ISSN=1664-3224

ABSTRACT=<p>After the ligation of the inferior vena cava (IVC) of wild-type (WT) mice, venous thrombi formed and grew progressively until 5 days and resolved thereafter. Concomitantly, intrathrombotic gene expression of <italic>Il6</italic> was enhanced later than 5 days after IVC ligation. IL-6 protein expression was detected mainly in F4/80-positive macrophages in thrombus. When <italic>Il6</italic>-deficient (<italic>Il6</italic><sup>−/−</sup>) mice were treated in the same manner, thrombus mass was significantly larger than in WT mice. Moreover, the recovery of thrombosed IVC blood flow was markedly delayed in <italic>Il6</italic><sup>−/−</sup> compared with WT mice. F4/80-positive macrophages in thrombus expressed proteolytic enzymes such as matrix metalloproteinase (<italic>Mmp</italic>) <italic>2, Mmp9</italic>, and urokinase-type plasminogen activator (<italic>Plau</italic>); and their mRNA expression was significantly reduced in <italic>Il6</italic><sup>−/−</sup> mice. Consistently, the administration of anti-IL-6 antibody delayed the thrombus resolution in WT mice, whereas IL-6 administration accelerated thrombus resolution in WT and <italic>Il6</italic><sup>−/−</sup> mice. Moreover, IL-6 <italic>in vitro</italic> enhanced <italic>Mmp2, Mmp9</italic>, and <italic>Plau</italic> mRNA expression in WT-derived peritoneal macrophages in a dose-dependent manner; and the enhancement was abrogated by a specific Stat3 inhibitor, Stattic. Thus, IL-6/Stat3 signaling pathway can promote thrombus resolution by enhancing <italic>Mmp2, Mmp9</italic>, and <italic>Plau</italic> expression in macrophages.</p>