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• W3093119237 abstract "•Reperfusion failure despite clot retrieval leads to unfavorable outcome in stroke•In the thrombin model of stroke, ≈30% capillaries remain occluded after thrombolysis•Capillaries are plugged by neutrophils, hindering blood flow•Neutrophil depletion facilitates capillary reperfusion and stroke recovery Despite successful clot retrieval in large vessel occlusion stroke, ∼50% of patients have an unfavorable clinical outcome. The mechanisms underlying this functional reperfusion failure remain unknown, and therapeutic options are lacking. In the thrombin-model of middle cerebral artery (MCA) stroke in mice, we show that, despite successful thrombolytic recanalization of the proximal MCA, cortical blood flow does not fully recover. Using in vivo two-photon imaging, we demonstrate that this is due to microvascular obstruction of ∼20%–30% of capillaries in the infarct core and penumbra by neutrophils adhering to distal capillary segments. Depletion of circulating neutrophils using an anti-Ly6G antibody restores microvascular perfusion without increasing the rate of hemorrhagic complications. Strikingly, infarct size and functional deficits are smaller in mice treated with anti-Ly6G. Thus, we propose neutrophil stalling of brain capillaries to contribute to reperfusion failure, which offers promising therapeutic avenues for ischemic stroke. Despite successful clot retrieval in large vessel occlusion stroke, ∼50% of patients have an unfavorable clinical outcome. The mechanisms underlying this functional reperfusion failure remain unknown, and therapeutic options are lacking. In the thrombin-model of middle cerebral artery (MCA) stroke in mice, we show that, despite successful thrombolytic recanalization of the proximal MCA, cortical blood flow does not fully recover. Using in vivo two-photon imaging, we demonstrate that this is due to microvascular obstruction of ∼20%–30% of capillaries in the infarct core and penumbra by neutrophils adhering to distal capillary segments. Depletion of circulating neutrophils using an anti-Ly6G antibody restores microvascular perfusion without increasing the rate of hemorrhagic complications. Strikingly, infarct size and functional deficits are smaller in mice treated with anti-Ly6G. Thus, we propose neutrophil stalling of brain capillaries to contribute to reperfusion failure, which offers promising therapeutic avenues for ischemic stroke. Stroke remains the primary cause of disability worldwide (Benjamin et al., 2019Benjamin E.J. Muntner P. Alonso A. Bittencourt M.S. Callaway C.W. Carson A.P. Chamberlain A.M. Chang A.R. Cheng S. Das S.R. et al.American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics SubcommitteeHeart Disease and Stroke Statistics-2019 Update: A Report From the American Heart Association.Circulation. 2019; 139: e56-e528Crossref PubMed Scopus (3090) Google Scholar; GBD 2016 Neurology Collaborators, 2019GBD 2016 Neurology CollaboratorsGlobal, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.Lancet Neurol. 2019; 18: 459-480Abstract Full Text Full Text PDF PubMed Scopus (679) Google Scholar). To date, intravenous thrombolysis with recombinant tissue plasminogen activator (t-PA) and catheter-based mechanical thrombectomy are the pillars of acute stroke therapy (Campbell et al., 2019Campbell B.C.V. De Silva D.A. Macleod M.R. Coutts S.B. Schwamm L.H. Davis S.M. Donnan G.A. Ischaemic stroke.Nat. Rev. Dis. Primers. 2019; 5: 70Crossref PubMed Scopus (104) Google Scholar). Recanalization of occluded vessels enhances oxygen and nutrient delivery to affected tissue, thus facilitating functional recovery from stroke (Panni et al., 2019Panni P. Gory B. Xie Y. Consoli A. Desilles J.P. Mazighi M. Labreuche J. Piotin M. Turjman F. Eker O.F. et al.ETIS (Endovascular Treatment in Ischemic Stroke) InvestigatorsAcute Stroke With Large Ischemic Core Treated by Thrombectomy.Stroke. 2019; 50: 1164-1171Crossref PubMed Scopus (25) Google Scholar). However, there is accumulating evidence that clot removal and vessel recanalization do not always go along with tissue reperfusion, a phenomenon called “no-reflow” (Dalkara and Arsava, 2012Dalkara T. Arsava E.M. Can restoring incomplete microcirculatory reperfusion improve stroke outcome after thrombolysis?.J. Cereb. Blood Flow Metab. 2012; 32: 2091-2099Crossref PubMed Scopus (107) Google Scholar; Espinosa de Rueda et al., 2015Espinosa de Rueda M. Parrilla G. Manzano-Fernández S. García-Villalba B. Zamarro J. Hernández-Fernández F. Sánchez-Vizcaino C. Carreón E. Morales A. Moreno A. Combined Multimodal Computed Tomography Score Correlates With Futile Recanalization After Thrombectomy in Patients With Acute Stroke.Stroke. 2015; 46: 2517-2522Crossref PubMed Scopus (25) Google Scholar; Soares et al., 2010Soares B.P. Tong E. Hom J. Cheng S.C. Bredno J. Boussel L. Smith W.S. Wintermark M. Reperfusion is a more accurate predictor of follow-up infarct volume than recanalization: a proof of concept using CT in acute ischemic stroke patients.Stroke. 2010; 41: e34-e40Crossref PubMed Scopus (119) Google Scholar). No-reflow in stroke refers to microvascular reperfusion failure and tissue damage despite successful recanalization of the larger occluded artery. The no-reflow phenomenon has not only been described in stroke, but also occurs in ischemic heart disease, representing a major obstacle to tissue and functional recovery (Allencherril et al., 2019Allencherril J. Jneid H. Atar D. Alam M. Levine G. Kloner R.A. Birnbaum Y. Pathophysiology, Diagnosis, and Management of the No-Reflow Phenomenon.Cardiovasc. Drugs Ther. 2019; 33: 589-597Crossref PubMed Scopus (11) Google Scholar; del Zoppo and Mabuchi, 2003del Zoppo G.J. Mabuchi T. Cerebral microvessel responses to focal ischemia.J. Cereb. Blood Flow Metab. 2003; 23: 879-894Crossref PubMed Scopus (472) Google Scholar). Why microvascular no-reflow occurs in stroke even after successful recanalization is poorly understood, and strategies to counteract this perfusion failure do not exist. Here, we measured distal capillary flow after recanalization in mice subjected to stroke to identify the extent and the underlying mechanisms of the no-reflow phenomenon. We used a thrombin model of stroke and thrombolysis (El Amki et al., 2012El Amki M. Lerouet D. Coqueran B. Curis E. Orset C. Vivien D. Plotkine M. Marchand-Leroux C. Margaill I. Experimental modeling of recombinant tissue plasminogen activator effects after ischemic stroke.Exp. Neurol. 2012; 238: 138-144Crossref PubMed Scopus (25) Google Scholar; Orset et al., 2007Orset C. Macrez R. Young A.R. Panthou D. Angles-Cano E. Maubert E. Agin V. Vivien D. Mouse model of in situ thromboembolic stroke and reperfusion.Stroke. 2007; 38: 2771-2778Crossref PubMed Scopus (127) Google Scholar) where a fibrin rich clot is induced in the MCA, which is later dissolved by intravenous t-PA infusion, closely mimicking the clinical scenario of ischemic stroke and intravenous thrombolysis. To characterize the degree and timing of reperfusion and no-reflow after thrombolysis, we monitored cortical perfusion using laser speckle contrast imaging (LSI) during stroke and thrombolysis with either t-PA or saline (control treatment) for 2 h (Figures 1A–1L). Thrombolysis was administered at 30 min after ischemia onset, which resembles an early treatment time window with high chances of successful recanalization (Orset et al., 2016Orset C. Haelewyn B. Allan S.M. Ansar S. Campos F. Cho T.H. Durand A. El Amki M. Fatar M. Garcia-Yébenes I. et al.Efficacy of Alteplase in a Mouse Model of Acute Ischemic Stroke: A Retrospective Pooled Analysis.Stroke. 2016; 47: 1312-1318Crossref PubMed Scopus (19) Google Scholar). Thrombin injection led to successful occlusion of the MCA at its M2 segment bifurcation. At the end of the 2-h observation time, complete recanalization was achieved with t-PA in all treated mice (Figure 1C). None of the saline-treated mice showed complete clot dissolution: partial recanalization occurred in 77.7%, whereas the MCA remained completely occluded in 22.3% (Figure 1C). Clot formation induced a steep drop in perfusion within the core of the lesion, and moderate hypoperfusion in the penumbra. Although there was some degree of spontaneous reperfusion in controls, t-PA treatment significantly raised reperfusion level to 61% ± 4.9% compared to 44% ± 3.5% in the core region (Figures 1G–1I) and 71% ± 7.9% versus 47% ± 2.7% in the penumbra (Figures 1J–1L). Notably, even with thrombolysis and complete clot dissolution, tissue reperfusion was far from complete. Considerable no-reflow was evident beyond the core of the lesion, extending into the penumbra. To identify changes in vessel diameter and blood flow underlying the no-reflow phenomenon, we imaged the affected distal (pial) MCA segments, using two-photon imaging, and confirmed a profound reduction in red blood cell (RBC) velocity along with a vasoconstriction to 46% ± 11.2% of pre-stroke diameter in saline-treated controls (Figure 1N-P). In t-PA-treated animals, RBC velocity within the distal MCA segment was restored to 80% ± 6.9% of baseline, whereas ischemia-induced MCA diameter reduction was attenuated (74% ± 10%). We further analyzed cortical vascular networks to identify potential obstacles to reperfusion within the more distal capillary bed in the lesion core as well as the penumbra. To eliminate the possibility that capillary stalls are simply due to adjacent large vessel occlusion, we confirmed that the occluding clot in the MCA-M2 was completely resolved before starting the measurements (60 min after t-PA; Figures S1A and S1B). We identified patent and stalled capillaries using two-photon microscopy by the presence or absence of streaking RBCs (Figures 2A and 2B ; Video S1). Unbiased sampling of cortical vasculature in 12 mice without stroke for 2 h revealed that spontaneous obstruction of capillaries was relatively rare (14 in 2,245 capillaries; ∼0.64%, see Figures S1C–S1E). https://www.cell.com/cms/asset/8114af43-6085-456f-b36a-e95f6d33b89a/mmc2.mp4Loading ... Download .mp4 (2.68 MB) Help with .mp4 files Video S1. Neutrophils Cause Capillary Stalls after Stroke, Related to Figure 2Video of a Z stack through the MCA region, where the focus shift in 1 μm steps from the top of the cranial window through the cortex and showing capillary stalls due to neutrophils. Presence of neutrophils is confirmed by dual staining with Rhodamine 6G and Hoechst 33342, as described in Figure 2E. Stalls are indicated by white circles. Blood plasma is stained with 70 kDa TexasRedDextran. Video is played at 15fps. We observed that after stroke and despite thrombolysis (no obstructions in arterioles), ∼35% of capillaries in the core and ∼15% of capillaries in the penumbra remained stalled (Figures 2D and 2E). We found stalled capillary segments of 4–10 μm diameter throughout a cortical depth of 300 μm. As cause of capillary stalling after stroke, we identified cells of 8–10 μm diameter resembling neutrophils, as confirmed by dual staining with Rhodamine 6G and Hoechst 33342 (Figure 2G; Video S1 and S4). Neutrophils started to drift along arterioles and venules immediately after ischemia induction, clogging smaller capillaries, thus leading to flow arrest (Videos S2 and S3). Stall points with neutrophils were counted as points where the first cell blocking the flow in an occluded capillary was a neutrophil (Figures 2G–2I; Video S4). Due to labeling and the direct visualization of stall morphology, in addition to stalls caused specifically by neutrophils, we were also able to discriminate between platelet aggregates or RBCs (Figures 2G–2J and S2). We found that after stroke, capillary stalls could be due to neutrophils, RBCs, and even platelet aggregates (Figures 2P and 2Q). Interestingly, after thrombolysis, the majority of stalled capillary segments were due to neutrophil clogging (∼75% in the core and ∼60% in the penumbra) (Figures 2P and 2Q). https://www.cell.com/cms/asset/a80d8b53-f16c-4a34-bc73-18904a12b5e6/mmc5.mp4Loading ... Download .mp4 (1.31 MB) Help with .mp4 files Video S4. Neutrophils Cause Capillary Stalls after Stroke, Related to Figure 2Higher magnification z stacks (1 μm/step) showing capillary stalls due to neutrophils. Blood plasma is stained with 70 kDa TexasRedDextran. In patent capillaries, RBCs movement generate a black streaking pattern while stalled capillaries show no streaks. Video is played at 15 fps. https://www.cell.com/cms/asset/8d7dc43e-ee64-48dc-8368-4394dcdd4070/mmc3.mp4Loading ... Download .mp4 (8.1 MB) Help with .mp4 files Video S2. Neutrophils Rolling in Large Vessels in the Penumbra after Stroke, Related to Figure 2Frame-scan video of neutrophils rolling in 2 pial venules after stroke. Neutrophils are identified as round cells and simple staining with Rhodamine 6G (S2) or dual staining with Rhodamine 6G and Hoechst 33342. Blood plasma is stained with 70 kDa TexasRedDextran. Video is played at 15 fps. https://www.cell.com/cms/asset/0a840dbc-51c4-4944-b827-0e7073a60201/mmc4.mp4Loading ... Download .mp4 (6.34 MB) Help with .mp4 files Video S3. Neutrophils Rolling in Large Vessels in the Infarct Core after Stroke, Related to Figure 2Frame-scan video of neutrophils rolling in 2 pial venules after stroke. Neutrophils are identified as round cells and simple staining with Rhodamine 6G (S2) or dual staining with Rhodamine 6G and Hoechst 33342. Blood plasma is stained with 70 kDa TexasRedDextran. Video is played at 15 fps. To prove that neutrophils stalling capillaries contributed significantly to the no-reflow phenomenon, we applied the monoclonal anti-Ly6G antibody, which specifically depletes neutrophils (Daley et al., 2008Daley J.M. Thomay A.A. Connolly M.D. Reichner J.S. Albina J.E. Use of Ly6G-specific monoclonal antibody to deplete neutrophils in mice.J. Leukoc. Biol. 2008; 83: 64-70Crossref PubMed Scopus (745) Google Scholar), to a separate group of mice 24 h before stroke induction. Flow cytometry analysis confirmed that antibody treatment diminished circulating neutrophils by 97.5% (Figures 3A and 3B ). In anti-LyG6-treated mice, we found fewer capillary stall points within the core (5.1%) and the penumbra (2.7%) after stroke (Figure 3C). Strikingly, anti-Ly6G reduced capillary stalls caused by neutrophils and RBCs (Figures 3D–3G). We observed that in the few remaining stalled capillaries after anti-Ly6G treatment, the majority was caused by RBCs (Figures 3J and 3K). We then tested whether depleting neutrophils improved capillary flow and tissue perfusion, thereby reducing tissue damage. Treatment with anti-Ly6G antibody and t-PA thrombolysis significantly increased tissue reperfusion confirming the causal link between capillary stall and no-reflow (Figures 4A–4D). There was no difference in MCA constriction, but RBC velocity improved in the distal branches of the MCA (Figures 4E and 4F). Importantly, we found reduced ischemic tissue damage at day 7 after stroke in mice treated with anti-Ly6G antibody compared to control mice (Figure 4G). Finally, we evaluated whether mice that received the anti-Ly6G treatment showed a favorable outcome. Indeed, sensorimotor function assessed by sticky tape test was better after stroke in Ly6G-treated mice (Figures 4I–4L), while there was a trend for better performance in the neurological score (Figures 4M and 4N). Hemorrhagic transformation of ischemic stroke is a complication associated with large infarctions, which is more frequent after systemic thrombolysis (Emberson et al., 2014Emberson J. Lees K.R. Lyden P. Blackwell L. Albers G. Bluhmki E. Brott T. Cohen G. Davis S. Donnan G. et al.Stroke Thrombolysis Trialists’ Collaborative GroupEffect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials.Lancet. 2014; 384: 1929-1935Abstract Full Text Full Text PDF PubMed Scopus (1284) Google Scholar). Although all animals treated with t-PA showed some evidence of hemorrhagic infarct transformation in their brains after reperfusion, this was strongly reduced in animals pre-treated with anti-Ly6G (28.5%) (Figures 4H and S3). To exclude a systemic effect of the antibody on stroke severity independent of thrombolysis, we treated another group of mice subjected to stroke but no t-PA with the anti-Ly6G antibody. We found no improvement in cerebral blood flow, lesion volume, or neurological outcome (Figure S4) in anti-Ly6G pre-treated mice without thrombolysis, suggesting that neutrophils, specifically, are associated with reflow and capillary stalls after recanalization. Fast and efficient recanalization strategies for stroke patients have evolved over the last years (Campbell et al., 2019Campbell B.C.V. De Silva D.A. Macleod M.R. Coutts S.B. Schwamm L.H. Davis S.M. Donnan G.A. Ischaemic stroke.Nat. Rev. Dis. Primers. 2019; 5: 70Crossref PubMed Scopus (104) Google Scholar). However, the microvascular no-reflow is a major problem for successful tissue reperfusion and recovery from stroke. Using LSI and two-photon imaging, we confirm that microvascular no-reflow impairs tissue reperfusion after stroke in mice. Despite successful large vessel recanalization through thrombolysis, stalling of ∼20%–30% of capillaries in the distal vascular network by neutrophils limited tissue reperfusion to only ∼60% of baseline. Therefore, intravenous thrombolysis with t-PA only partially restores perfusion of brain tissue distal to the occlusion site. We found areas with no-reflow extending beyond the severely hypoperfused (core) area reaching into the ischemic border zone (penumbra). The no-reflow of brain microvascular networks after ischemia was already described in 1968 (Ames et al., 1968Ames 3rd, A. Wright R.L. Kowada M. Thurston J.M. Majno G. Cerebral ischemia. II. The no-reflow phenomenon.Am. J. Pathol. 1968; 52: 437-453PubMed Google Scholar). It is likely that multiple mechanisms contribute to the microvascular no-reflow phenomenon, including endothelial cell dysfunction, embolization of clot fragments into more distal vessel segments, or death in “rigor” of pericytes (El Amki and Wegener, 2017El Amki M. Wegener S. Improving Cerebral Blood Flow after Arterial Recanalization: A Novel Therapeutic Strategy in Stroke.Int. J. Mol. Sci. 2017; 18: 2669Crossref Scopus (25) Google Scholar; Hall et al., 2014Hall C.N. Reynell C. Gesslein B. Hamilton N.B. Mishra A. Sutherland B.A. O’Farrell F.M. Buchan A.M. Lauritzen M. Attwell D. Capillary pericytes regulate cerebral blood flow in health and disease.Nature. 2014; 508: 55-60Crossref PubMed Scopus (883) Google Scholar; Hartings et al., 2017Hartings J.A. Shuttleworth C.W. Kirov S.A. Ayata C. Hinzman J.M. Foreman B. Andrew R.D. Boutelle M.G. Brennan K.C. Carlson A.P. et al.The continuum of spreading depolarizations in acute cortical lesion development: Examining Leão’s legacy.J. Cereb. Blood Flow Metab. 2017; 37: 1571-1594Crossref PubMed Scopus (153) Google Scholar; Ito et al., 2011Ito U. Hakamata Y. Kawakami E. Oyanagi K. Temporary [corrected] cerebral ischemia results in swollen astrocytic end-feet that compress microvessels and lead to delayed [corrected] focal cortical infarction.J. Cereb. Blood Flow Metab. 2011; 31: 328-338Crossref PubMed Scopus (43) Google Scholar; Wiseman et al., 2014Wiseman S. Marlborough F. Doubal F. Webb D.J. Wardlaw J. Blood markers of coagulation, fibrinolysis, endothelial dysfunction and inflammation in lacunar stroke versus non-lacunar stroke and non-stroke: systematic review and meta-analysis.Cerebrovasc. Dis. 2014; 37: 64-75Crossref PubMed Scopus (100) Google Scholar; Yemisci et al., 2009Yemisci M. Gursoy-Ozdemir Y. Vural A. Can A. Topalkara K. Dalkara T. Pericyte contraction induced by oxidative-nitrative stress impairs capillary reflow despite successful opening of an occluded cerebral artery.Nat. Med. 2009; 15: 1031-1037Crossref PubMed Scopus (403) Google Scholar; Zhang et al., 1999Zhang Z.G. Chopp M. Goussev A. Lu D. Morris D. Tsang W. Powers C. Ho K.L. Cerebral microvascular obstruction by fibrin is associated with upregulation of PAI-1 acutely after onset of focal embolic ischemia in rats.J. Neurosci. 1999; 19: 10898-10907Crossref PubMed Google Scholar). In the 1980s, leukocyte plugs were first observed in capillaries and smaller post-capillary venules after stroke ex vivo, but the functional role in stroke pathophysiology was not clear (Aspey et al., 1989Aspey B.S. Jessimer C. Pereira S. Harrison M.J. Do leukocytes have a role in the cerebral no-reflow phenomenon?.J. Neurol. Neurosurg. Psychiatry. 1989; 52: 526-528Crossref PubMed Scopus (38) Google Scholar; del Zoppo et al., 1991del Zoppo G.J. Schmid-Schönbein G.W. Mori E. Copeland B.R. Chang C.M. Polymorphonuclear leukocytes occlude capillaries following middle cerebral artery occlusion and reperfusion in baboons.Stroke. 1991; 22: 1276-1283Crossref PubMed Scopus (612) Google Scholar). Subsequent studies reported leukocyte rolling and accumulation in brain venules, arterioles, and capillaries after ischemia/reperfusion in filament models of stroke using intravital fluorescence microscopy (Ishikawa et al., 1999Ishikawa M. Sekizuka E. Sato S. Yamaguchi N. Inamasu J. Bertalanffy H. Kawase T. Iadecola C. Effects of moderate hypothermia on leukocyte- endothelium interaction in the rat pial microvasculature after transient middle cerebral artery occlusion.Stroke. 1999; 30: 1679-1686Crossref PubMed Scopus (69) Google Scholar; Ritter et al., 2000Ritter L.S. Orozco J.A. Coull B.M. McDonagh P.F. Rosenblum W.I. Leukocyte accumulation and hemodynamic changes in the cerebral microcirculation during early reperfusion after stroke.Stroke. 2000; 31: 1153-1161Crossref PubMed Scopus (149) Google Scholar) and suggested that leukocyte adhesion and rolling could contribute to reperfusion failure after stroke (del Zoppo et al., 1991del Zoppo G.J. Schmid-Schönbein G.W. Mori E. Copeland B.R. Chang C.M. Polymorphonuclear leukocytes occlude capillaries following middle cerebral artery occlusion and reperfusion in baboons.Stroke. 1991; 22: 1276-1283Crossref PubMed Scopus (612) Google Scholar). In a recent study, Erdener et al., 2020Erdener S.E. Tang J. Kilic K. Postnov D. Giblin J.T. Kura S. Chen I.A. Vayisoglu T. Sakadzic S. Schaffer C.B. et al.Dynamic capillary stalls in reperfused ischemic penumbra contribute to injury: A hyperacute role for neutrophils in persistent traffic jams.J. Cereb. Blood Flow Metab. 2020; (Published online April 1, 2020)https://doi.org/10.1177/0271678X20914179Crossref PubMed Scopus (15) Google Scholar detected an increased number of stalled capillaries in peri-infarct regions in a model of mechanical, distal MCA occlusion using optical coherence tomography, which confirms our findings. However, it was not possible to differentiate between different sources of capillary stalls or to evaluate their role in thrombolysis, which is a key reperfusion treatment in stroke patients. The ability to map capillary patency across the cortex during t-PA induced reperfusion allowed the in vivo demonstration of microcirculatory stalling and reperfusion failure, in line with previous histological reports (Hallenbeck et al., 1986Hallenbeck J.M. Dutka A.J. Tanishima T. Kochanek P.M. Kumaroo K.K. Thompson C.B. Obrenovitch T.P. Contreras T.J. Polymorphonuclear leukocyte accumulation in brain regions with low blood flow during the early postischemic period.Stroke. 1986; 17: 246-253Crossref PubMed Scopus (393) Google Scholar; Zhang et al., 1999Zhang Z.G. Chopp M. Goussev A. Lu D. Morris D. Tsang W. Powers C. Ho K.L. Cerebral microvascular obstruction by fibrin is associated with upregulation of PAI-1 acutely after onset of focal embolic ischemia in rats.J. Neurosci. 1999; 19: 10898-10907Crossref PubMed Google Scholar). Rapid upregulation of endothelial adhesion molecules (VCAM1, ICAM1, and P-selectin) during cerebral ischemia is likely involved, leading to an increased endothelium-neutrophil interaction and prolonged adhesion (Reglero-Real et al., 2016Reglero-Real N. Colom B. Bodkin J.V. Nourshargh S. Endothelial Cell Junctional Adhesion Molecules: Role and Regulation of Expression in Inflammation.Arterioscler. Thromb. Vasc. Biol. 2016; 36: 2048-2057Crossref PubMed Scopus (65) Google Scholar). When MCA occlusion is permanent, adhesion molecules are expressed in both core and penumbra (Gauberti et al., 2013Gauberti M. Montagne A. Marcos-Contreras O.A. Le Béhot A. Maubert E. Vivien D. Ultra-sensitive molecular MRI of vascular cell adhesion molecule-1 reveals a dynamic inflammatory penumbra after strokes.Stroke. 2013; 44: 1988-1996Crossref PubMed Scopus (63) Google Scholar). However, in transient stroke models, the increase of VCAM-1 expression may be restricted to the core (C57Bl6 mice) or involve the penumbra (Swiss mice), depending on the extent of collateral network, which is critical for maintaining blood flow in penumbral areas (El Amki et al., 2018El Amki M. Lerouet D. Garraud M. Teng F. Beray-Berthat V. Coqueran B. Barsacq B. Abbou C. Palmier B. Marchand-Leroux C. Margaill I. Improved Reperfusion and Vasculoprotection by the Poly(ADP-Ribose)Polymerase Inhibitor PJ34 After Stroke and Thrombolysis in Mice.Mol. Neurobiol. 2018; 55: 9156-9168Crossref PubMed Scopus (16) Google Scholar; Zhang and Faber, 2019Zhang H. Faber J.E. Transient versus Permanent MCA Occlusion in Mice Genetically Modified to Have Good versus Poor Collaterals.Med One. 2019; 4: e190024PubMed Google Scholar). BALB/c mice with their poor leptomeningeal collaterals are likely to have a similar inflammatory penumbral phenotype, which may further booster leucocyte stalls. Recently, clinical studies have provided evidence that elevated blood neutrophil count on admission is a biomarker for unfavorable outcome in stroke patients receiving thrombolysis (Chen et al., 2018Chen J. Zhang Z. Chen L. Feng X. Hu W. Ge W. Li X. Jin P. Shao B. Correlation of Changes in Leukocytes Levels 24 Hours after Intravenous Thrombolysis With Prognosis in Patients With Acute Ischemic Stroke.J. Stroke Cerebrovasc. Dis. 2018; 27: 2857-2862Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar; Malhotra et al., 2018Malhotra K. Goyal N. Chang J.J. Broce M. Pandhi A. Kerro A. Shahripour R.B. Alexandrov A.V. Tsivgoulis G. Differential leukocyte counts on admission predict outcomes in patients with acute ischaemic stroke treated with intravenous thrombolysis.Eur. J. Neurol. 2018; 25: 1417-1424Crossref PubMed Scopus (20) Google Scholar). This implies that indeed, neutrophils might be involved in amplifying tissue injury in stroke patients and in other neurological diseases, where chronic hypoperfusion augments neural decay (Cruz Hernández et al., 2019Cruz Hernández J.C. Bracko O. Kersbergen C.J. Muse V. Haft-Javaherian M. Berg M. Park L. Vinarcsik L.K. Ivasyk I. Rivera D.A. et al.Neutrophil adhesion in brain capillaries reduces cortical blood flow and impairs memory function in Alzheimer’s disease mouse models.Nat. Neurosci. 2019; 22: 413-420Crossref PubMed Scopus (98) Google Scholar). When we depleted neutrophils by targeted antibody treatment, tissue reperfusion was substantially improved in both core and penumbra. Importantly, anti-Ly6G treatment led to a pronounced attenuation of stroke-induced damage in our model of thrombin-occlusion and thrombolysis. It resulted in smaller stroke lesion volumes as well as less functional impairment at 7 days after stroke. The beneficial effect of anti-Ly6G treatment was not observed in mice without recanalization (stroke without t-PA thrombolysis), confirming that neutrophil depletion works through enhancement of microvascular perfusion, which requires that flow in the proximal arteries is reinstalled. Given the fact that neutrophils affect the coagulation cascade (Kambas et al., 2012Kambas K. Mitroulis I. Ritis K. The emerging role of neutrophils in thrombosis-the journey of TF through NETs.Front. Immunol. 2012; 3: 385Crossref PubMed Scopus (77) Google Scholar), it is reassuring that, even when treatment was combined with t-PA, we found no increase in hemorrhagic complications or mortality. While complete depletion of neutrophils is not a feasible treatment option for stroke patients due to their important and multiple roles in neuro-inflammation and repair, our results support the development of therapeutic strategies geared against neutrophil adhesion in stroke. Notably, our data suggest that such treatment concepts appear to be beneficial even in the hyper-acute phase of stroke and combined to the current reperfusion strategies. Because it requires 24 h to achieve neutrophil depletion with the anti-Ly6G antibody (Erdener et al., 2020Erdener S.E. Tang J. Kilic K. Postnov D. Giblin J.T. Kura S. Chen I.A. Vayisoglu T. Sakadzic S. Schaffer C.B. et al.Dynamic capillary stalls in reperfused ischemic penumbra contribute to injury: A hyperacute role for neutrophils in persistent traffic jams.J. Cereb. Blood Flow Metab. 2020; (Published online April 1, 2020)https://doi.org/10.1177/0271678X20914179Crossref PubMed Scopus (15) Google Scholar), this approach is not suited as an acute post-stroke treatment. Furthermore, Ly6G is expressed in mice and not in humans. Therefore, more research is required to identify translational therapeutic drug targets that counteract neutrophil stall" @default.
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• W3093119237 date "2020-10-01" @default.
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• W3093119237 title "Neutrophils Obstructing Brain Capillaries Are a Major Cause of No-Reflow in Ischemic Stroke" @default.
• W3093119237 cites W1546165821 @default.
• W3093119237 cites W1592252953 @default.
• W3093119237 cites W1809025926 @default.
• W3093119237 cites W1922537076 @default.
• W3093119237 cites W1965593262 @default.
• W3093119237 cites W1975938124 @default.
• W3093119237 cites W1976485053 @default.
• W3093119237 cites W1998200062 @default.
• W3093119237 cites W1999736533 @default.
• W3093119237 cites W2001552996 @default.
• W3093119237 cites W2026616100 @default.
• W3093119237 cites W2035569448 @default.
• W3093119237 cites W2060427223 @default.
• W3093119237 cites W2067093434 @default.
• W3093119237 cites W2067436359 @default.
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• W3093119237 cites W2117985944 @default.
• W3093119237 cites W2118610309 @default.
• W3093119237 cites W2121071682 @default.
• W3093119237 cites W2127366468 @default.
• W3093119237 cites W2128892154 @default.
• W3093119237 cites W2132515954 @default.
• W3093119237 cites W2143263703 @default.
• W3093119237 cites W2157827475 @default.
• W3093119237 cites W2159689462 @default.
• W3093119237 cites W2165568749 @default.
• W3093119237 cites W2285828294 @default.
• W3093119237 cites W2329112309 @default.
• W3093119237 cites W2471954838 @default.
• W3093119237 cites W2508485797 @default.
• W3093119237 cites W2754967293 @default.
• W3093119237 cites W2761237624 @default.
• W3093119237 cites W2771983204 @default.
• W3093119237 cites W2797889037 @default.
• W3093119237 cites W2810095031 @default.
• W3093119237 cites W2883733789 @default.
• W3093119237 cites W2895193908 @default.
• W3093119237 cites W2895897136 @default.
• W3093119237 cites W2911407981 @default.
• W3093119237 cites W2913705661 @default.
• W3093119237 cites W2937638951 @default.
• W3093119237 cites W2968139477 @default.
• W3093119237 cites W2970824372 @default.
• W3093119237 cites W3015000162 @default.
• W3093119237 cites W4211070880 @default.
• W3093119237 cites W70337943 @default.
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