Osama M. El-Sayed, BS, Nicholas A. Dewyer, MD, Catherine E

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Intact Toll-like receptor 9 signaling in neutrophils modulates normal thrombogenesis in mice Osama M. El-Sayed, BS, Nicholas A. Dewyer, MD, Catherine E. Luke, LVT, Megan Elfline, MS, Adriana Laser, MD, Cory Hogaboam, PhD, Steven L. Kunkel, PhD, Peter K. Henke, MD Journal of Vascular Surgery Volume 64, Issue 5, Pages 1450-1458.e1 (November 2016) DOI: 10.1016/j.jvs.2015.08.070 Copyright © 2015 Society for Vascular Surgery Terms and Conditions

Fig 1 A, Larger thrombi are present in stasis venous thrombosis (VT) at 6 hours and 2 days in Toll-like receptor 9 knockout (Tlr9−/−) mice compared with wild-type (WT) mice (n = 6-10) but not in nonstasis (electrolytic induction model [EIM]) Tlr9−/− compared with WT (n = 4-6). B, Thrombus interleukin 1-α (IL-1α) was reduced in Tlr9−/− mice compared with WT controls (n = 5). C, Thrombus uric acid concentration was increased in Tlr9−/− mice compared with WT controls (n = 6-7). D, Thrombus TUNEL+ cell counts in five high-power fields (5hpf) are shown. At 2 days, Tlr9−/− thrombi contained an increased number of TUNEL+ cells compared with WT controls (n = 4). Histology representative photos with TUNEL+ cells fluorescing green and 4′,6-diamidino-2-phenylindole (DAPI) fluorescing blue (magnification ×100; scale bar = 100 μm) in WT and Tlr9−/− thrombus (arrows denote dual-staining cells). E, Activated polymorphonuclear neutrophils (PMNs; Ly6G+) were increased in Tlr9−/− thrombi compared with WT thrombi (n = 5). F, Two histology image examples show greater Ly6G+ cells labeled in brown (arrows) in Tlr9−/− and WT (magnification ×100; scale bar = 100 μm). Data are mean ± standard deviation. ∗P < .05. Journal of Vascular Surgery 2016 64, 1450-1458.e1DOI: (10.1016/j.jvs.2015.08.070) Copyright © 2015 Society for Vascular Surgery Terms and Conditions

Fig 2 Venous thrombi in Toll-like receptor 9 knockout (Tlr9−/−) mice have increased neutrophil extracellular trap (NET) markers by Western immunoblotting and less antithrombogenic inhibitor compared with wild-type (WT) controls. A, Citrullinated histones (H3-Cit). B, Peptidylarginine deiminase 4 (PAD4). C, Elastase. D, Tissue factor pathway inhibitor (TFPI; n = 4-6). Data are mean ± standard deviation. ∗P < .05. Journal of Vascular Surgery 2016 64, 1450-1458.e1DOI: (10.1016/j.jvs.2015.08.070) Copyright © 2015 Society for Vascular Surgery Terms and Conditions

Fig 3 A, The number of neutrophil extracellular trap-positive (NET+) polymorphonuclear neutrophils (PMNs) was increased in Toll-like receptor 9 knockout (Tlr9−/−) mice compared with wild-type (WT) controls (n = 4-6). B, NET immunofluorescence histograph examples show costaining with PMNs of 4′,6-diamidino-2-phenylindole (DAPI), citrullinated histone (cit-H3), and Ly6G (arrows; magnification ×1000). C, Deoxyribonuclease (DNAse) I treatment (Tx) did not affect stasis venous thrombosis (VT) in WT or Tlr9−/− mice at 2 days (n = 6-8). D, Thrombus size was not altered in stasis VT in peptidylarginine deiminase 4 knockout (PAD4−/−) mice compared with WT mice (n = 6-8). Data are mean ± standard deviation. ∗P < .05. Journal of Vascular Surgery 2016 64, 1450-1458.e1DOI: (10.1016/j.jvs.2015.08.070) Copyright © 2015 Society for Vascular Surgery Terms and Conditions

Fig 4 Cellular polymorphonuclear neutrophil (PMN) processes in thrombogenesis. A, PMN antibody depletion (treatment [Tx]) significantly reduced venous thrombus (VT) size in Toll-like receptor 9 knockout (Tlr9−/−) mice compared with wild-type (WT) controls (n = 5). B-D, Thrombus elastase (B) and citrullinated histones (cit-H3; C) were reduced in Tlr9−/− mice with PMN depletion, whereas tissue factor pathway inhibitor (TFPI; D) was increased (n = 4-6). IgG, Immunoglobulin G. E, Intrathrombus PMNs were reduced in Tlr9−/− mice with treatment (n = 3-5). Example of hematoxylin and eosin-stained thrombus sections (magnification ×200; arrows indicate PMNs). Data are mean ± standard deviation. ∗P < .05. Journal of Vascular Surgery 2016 64, 1450-1458.e1DOI: (10.1016/j.jvs.2015.08.070) Copyright © 2015 Society for Vascular Surgery Terms and Conditions

Supplementary Fig (online only) Very early (6 hours) thrombi in Toll-like receptor 9 knockout (Tlr9−/−) mice have altered size and composition. A, Thrombus citrullinated histones (H3-Cit) were not significantly different between wild-type (WT) and Tlr9−/− thrombi. B, Thrombus elastase was greater in Tlr9−/− than in WT mice. C, Less tissue factor pathway inhibitor (TFPI) was present in Tlr9−/− compared with WT thrombi (n = 5-6). Data are mean ± standard deviation. ∗P < .05. Journal of Vascular Surgery 2016 64, 1450-1458.e1DOI: (10.1016/j.jvs.2015.08.070) Copyright © 2015 Society for Vascular Surgery Terms and Conditions