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• W2914037133 abstract "HomeStrokeVol. 50, No. 3Neutrophils, the Felons of the Brain Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBNeutrophils, the Felons of the BrainCan They be Rehabilitated to Yield Benefit After Stroke? Jaroslaw Aronowski, MD, PhD and Meaghan A. Roy-O’Reilly, PhD Jaroslaw AronowskiJaroslaw Aronowski Correspondence to Jaroslaw Aronowski, MD, PhD, Department of Neurology, University of Texas, McGovern Medical School, 6431 Fannin St, Houston, TX 77030. Email E-mail Address: [email protected] From the Department of Neurology, University of Texas Health Science Center, McGovern Medical School, Houston. Search for more papers by this author and Meaghan A. Roy-O’ReillyMeaghan A. Roy-O’Reilly From the Department of Neurology, University of Texas Health Science Center, McGovern Medical School, Houston. Search for more papers by this author Originally published24 Jan 2019https://doi.org/10.1161/STROKEAHA.118.021563Stroke. 2019;50:e42–e43This article is commented on by the following:Polymorphonuclear Neutrophils Play a Decisive Role for Brain Injury and Neurological Recovery PoststrokeNeutrophils in Acute Stroke PathophysiologyOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 24, 2019: Ahead of Print See related articles, p e40, e44Polymorphonuclear neutrophils (PMNs) are short-lived but powerful immune cells, providing an early and robust inflammatory response after tissue damage. While the defensive role of PMNs in antimicrobial immunity has long been studied, recent attention has focused on the role of these cells in sterile inflammation after tissue injury.After stroke, PMNs are rapidly recruited to the injured brain. PMNs have been hypothesized to worsen stroke pathology via several mechanisms, including (1) physical blockade within the microvascular network, further reducing cerebral blood flow and (2) direct entry into the brain parenchyma, followed by the release of granules containing antimicrobial enzymes and chemical species that could further injury brain tissue.1–3 Based on these assumptions, the prevention of PMN entry into the brain after stroke has been extensively studied as a therapeutic target.3–5 Although PMN suppressing therapies showed benefit in numerous preclinical studies, subsequent clinical trials in stroke patients showed no overall benefit.3,6Recently, a growing body of evidence has suggested that PMNs, like other immune cells, may exhibit some level of functional plasticity, analogous to Th1/Th2 (for T cells), M1/M2 (for macrophages/microglia; Mφ).7 The N1 PMN phenotype refers to PMNs with stronger proinflammatory/oxidative properties, which possess effective antitumor and antimicrobial actions and may cause greater detrimental effects in the stroke-affected brain. Assuming that the majority of circulating neutrophils are normally in the N1 state, to maximize their ability to effectively engage in antimicrobial activities, the PMNs entering the brain early after stroke may be primarily detrimental. Conversely, the N2 PMN phenotype is characterized by reduced proinflammatory properties and a higher content of beneficial molecules.7–11As such, it is possible that the effect of PNMs on stroke outcome could depend on N1/N2 ratio, which may change with time after stroke, reducing the detrimental effects of infiltrating PMNs—or potentially even conferring benefit to the damaged tissue. Potential mechanisms of PMN-mediated benefit in stroke may involve (1) modification of other cells like macrophages (Mφ) and microglia to an anti-inflammatory healing phenotype, (2) PMN self-limitation of proinflammatory factors, or (3) direct secretion of beneficial factors. Some recent examples of these PMN behaviors after stroke are outlined below.Mature segmented neutrophils egress out of bone marrow to the blood circulation where they have short half-life (13–19 hours),12 meaning that all circulating PMNs are normally replaced within ≈ 1 day of their release. After tissue injury, including stroke, PMNs are recruited to the side of injury within hours, and continue for days, where they release some of their granule contents. Typically, PMNs then die via apoptosis and are consequently removed via Mφ-mediated efferocytosis (phagocytosis-mediated engulfment of apoptotic cells), which is essential to prevent PMN secondary necrosis with subsequent release of cytotoxic and proinflammatory PMN content.13The efferocytosis of PMNs has been shown to induce an anti-inflammatory phenotype in the microglia and Mφ that phagocytose them.13 Thus, PMN death through apoptosis is believed to act as a signal for Mφ to acquire the M2 phenotype that is essential for efficient phagocytosis and improved healing.13–15 PMNs have also been shown to phagocytose themselves, a type of cannibalism which results in increased production of TGF-β (transforming growth factor β) by the engulfing PMN.16 TGF-β is a cytokine that acts as an inducer of N2 polarization7 and has been shown to reduce neuroinflammation and improve recovery after intracerebral hemorrhage (ICH).17 Thus, the proper clearance of apoptotic PMNs may assist in the resolution of inflammation and the promotion of tissue repair.Activation of the PPARγ (peroxisome proliferator-activated receptor-γ) promotes the conversion of Mφ to a healing (M2) phenotype.14 Cuartero et al recently showed that mice subjected to cerebral ischemia and treated with a PPARγ agonist, rosiglitazone, experienced enhanced PMN infiltration into the brain, and increased proportion of N2 (Ym1+; a prototypic marker of M2 phenotype) anti-inflammatory PMNs and reduced infarct volume.18 Importantly, Ym1+ PMNs were more effectively phagocytosed by Mφ, and systemic depletion of PMNs before stroke abolished the neuroprotective effect of PPARγ agonist treatment.Under in vitro conditions, PMNs stimulated with proinflammatory TNF-α or lipopolysaccharide produce and secrete anti-inflammatory (s)IL-1RA (natural inhibitor of the proinflammatory IL-1β) at much higher rates than they produce IL-1β,19,20 suggesting a potential mechanism for self-limitation of the proinflammatory PMN response. Interestingly, Ahmed et al showed that pretreatment with lipopolysaccharide reduced ischemic brain injury in mice despite the increased presence of PMNs in the brain.21PMN precursor proliferation and maturation takes place in the bone marrow, where the chemical composition of PMN granules is established by local environmental cues. We have recently shown that IL-27 generated in response to ICH can modify the production of granule components in maturing bone marrow PMNs.11 Excitingly, we have shown that IL-27 may downregulate PMN levels of tissue-damaging enzymes (NADPH oxidase, iNOS [inducible nitric oxide synthase], and MMP [matrix metalloproteinase]-9) and upregulate the production of potentially beneficial molecules for ICH resolution, including iron-sequestering lactoferrin (PMNs are the primary source of blood lactoferrin) and hemoglobin-neutralizing haptoglobin. Both lactoferrin and haptoglobin have potent protective effects in the ICH-injured brain.5,20 We proposed that PMNs modified by IL-27 may be less damaging or even beneficial in the brain in the later stages of ICH. In agreement with this hypothesis, we found that depletion of PMNs 24 hours after ICH worsened functional outcome in mice.In conclusion, although PMNs are typically thought of as detrimental in sterile inflammation, we believe that PMNs can assist in the resolution of inflammation under certain conditions. The newly reported plasticity of neutrophils is particularly exciting, as their short-lived and early responding nature makes them ideal candidates for enhancing tissue repair and regeneration. Future studies should be conducted to determine whether PMNs clearance or function can be beneficially manipulated to enhance the resolution of inflammation and improve functional outcome in sterile inflammatory diseases such as stroke.Sources of FundingSupported by National Institutes of Health-National Institute of Neurological Disorders and Stroke, grants RO1NS096308 and R42NS090650.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Jaroslaw Aronowski, MD, PhD, Department of Neurology, University of Texas, McGovern Medical School, 6431 Fannin St, Houston, TX 77030. Email j.[email protected]tmc.eduReferences1. Kalimo H, del Zoppo GJ, Paetau A, Lindsberg PJ. Polymorphonuclear neutrophil infiltration into ischemic infarctions: myth or truth?Acta Neuropathol. 2013; 125:313–316. doi: 10.1007/s00401-013-1098-5CrossrefMedlineGoogle Scholar2. del Zoppo GJ, Schmid-Schönbein GW, Mori E, Copeland BR, Chang CM. Polymorphonuclear leukocytes occlude capillaries following middle cerebral artery occlusion and reperfusion in baboons.Stroke. 1991; 22:1276–1283.LinkGoogle Scholar3. Jickling GC, Liu D, Ander BP, Stamova B, Zhan X, Sharp FR. Targeting neutrophils in ischemic stroke: translational insights from experimental studies.J Cereb Blood Flow Metab. 2015; 35:888–901. doi: 10.1038/jcbfm.2015.45CrossrefMedlineGoogle Scholar4. Härtl R, Schürer L, Schmid-Schönbein GW, del Zoppo GJ. Experimental antileukocyte interventions in cerebral ischemia.J Cereb Blood Flow Metab. 1996; 16:1108–1119. doi: 10.1097/00004647-199611000-00004CrossrefMedlineGoogle Scholar5. Zhang RL, Chopp M, Li Y, Zaloga C, Jiang N, Jones ML, et al. Anti-ICAM-1 antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in the rat.Neurology. 1994; 44:1747–1751.CrossrefMedlineGoogle Scholar6. Veltkamp R, Gill D. Clinical trials of immunomodulation in ischemic stroke.Neurotherapeutics. 2016; 13:791–800. doi: 10.1007/s13311-016-0458-yCrossrefMedlineGoogle Scholar7. Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN.Cancer Cell. 2009; 16:183–194. doi: 10.1016/j.ccr.2009.06.017CrossrefMedlineGoogle Scholar8. Hermann DM, Kleinschnitz C, Gunzer M. Implications of polymorphonuclear neutrophils for ischemic stroke and intracerebral hemorrhage: predictive value, pathophysiological consequences and utility as therapeutic target.J Neuroimmunol. 2018; 321:138–143. doi: 10.1016/j.jneuroim.2018.04.015CrossrefMedlineGoogle Scholar9. García-Culebras A, Durán-Laforet V, Peña-Martínez C, Ballesteros I, Pradillo JM, Diaz-Guzman J, et al. Myeloid cells as therapeutic targets in neuroinflammation after stroke: specific roles of neutrophils and neutrophil-platelet interactions [published online August 21, 2018].J Cereb Blood Flow Metab. doi: 10.1177/0271678X18795789Google Scholar10. Zhao X, Ting SM, Sun G, Roy-O’Reilly M, Mobley AS, Bautista Garrido J, et al. Beneficial role of neutrophils through function of lactoferrin after intracerebral hemorrhage.Stroke. 2018; 49:1241–1247. doi: 10.1161/STROKEAHA.117.020544LinkGoogle Scholar11. Zhao X, Ting SM, Liu CH, Sun G, Kruzel M, Roy-O’Reilly M, et al. Neutrophil polarization by IL-27 as a therapeutic target for intracerebral hemorrhage.Nat Commun. 2017; 8:602. doi: 10.1038/s41467-017-00770-7CrossrefMedlineGoogle Scholar12. Lahoz-Beneytez J, Elemans M, Zhang Y, Ahmed R, Salam A, Block M, et al. Human neutrophil kinetics: modeling of stable isotope labeling data supports short blood neutrophil half-lives.Blood. 2016; 127:3431–3438. doi: 10.1182/blood-2016-03-700336CrossrefMedlineGoogle Scholar13. Greenlee-Wacker MC. Clearance of apoptotic neutrophils and resolution of inflammation.Immunol Rev. 2016; 273:357–370. doi: 10.1111/imr.12453CrossrefMedlineGoogle Scholar14. Zhao X, Sun G, Zhang J, Strong R, Song W, Gonzales N, et al. Hematoma resolution as a target for intracerebral hemorrhage treatment: role for peroxisome proliferator-activated receptor gamma in microglia/macrophages.Ann Neurol. 2007; 61:352–362. doi: 10.1002/ana.21097CrossrefMedlineGoogle Scholar15. Hu X, Leak RK, Shi Y, Suenaga J, Gao Y, Zheng P, et al. Microglial and macrophage polarization—new prospects for brain repair.Nat Rev Neurol. 2015; 11:56–64. doi: 10.1038/nrneurol.2014.207CrossrefMedlineGoogle Scholar16. Steiger S, Harper JL. Neutrophil cannibalism triggers transforming growth factor β1 production and self regulation of neutrophil inflammatory function in monosodium urate monohydrate crystal-induced inflammation in mice.Arthritis Rheum. 2013; 65:815–823. doi: 10.1002/art.37822CrossrefMedlineGoogle Scholar17. Taylor RA, Chang CF, Goods BA, Hammond MD, Mac Grory B, Ai Y, et al. TGF-β1 modulates microglial phenotype and promotes recovery after intracerebral hemorrhage.J Clin Invest. 2017; 127:280–292. doi: 10.1172/JCI88647CrossrefMedlineGoogle Scholar18. Cuartero MI, Ballesteros I, Moraga A, Nombela F, Vivancos J, Hamilton JA, et al. N2 neutrophils, novel players in brain inflammation after stroke: modulation by the PPARγ agonist rosiglitazone.Stroke. 2013; 44:3498–3508. doi: 10.1161/STROKEAHA.113.002470LinkGoogle Scholar19. McColl SR, Paquin R, Ménard C, Beaulieu AD. Human neutrophils produce high levels of the interleukin 1 receptor antagonist in response to granulocyte/macrophage colony-stimulating factor and tumor necrosis factor alpha.J Exp Med. 1992; 176:593–598.CrossrefMedlineGoogle Scholar20. Malyak M, Smith MF, Abel AA, Arend WP. Peripheral blood neutrophil production of interleukin-1 receptor antagonist and interleukin-1 beta.J Clin Immunol. 1994; 14:20–30.CrossrefMedlineGoogle Scholar21. Ahmed SH, He YY, Nassief A, Xu J, Xu XM, Hsu CY, et al. Effects of lipopolysaccharide priming on acute ischemic brain injury.Stroke. 2000; 31:193–199.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Shi S, Vodovoz S, Xiu Y, Liu N, Jiang Y, Katakam P, Bix G, Dumont A and Wang X (2022) T-Lymphocyte Interactions with the Neurovascular Unit: Implications in Intracerebral Hemorrhage, Cells, 10.3390/cells11132011, 11:13, (2011) Dhanesha N, Patel R, Doddapattar P, Ghatge M, Flora G, Jain M, Thedens D, Olalde H, Kumskova M, Leira E and Chauhan A (2022) PKM2 promotes neutrophil activation and cerebral thromboinflammation: therapeutic implications for ischemic stroke, Blood, 10.1182/blood.2021012322, 139:8, (1234-1245), Online publication date: 24-Feb-2022. Aronowski J, Sansing L, Xi G and Zhang J (2022) Mechanisms of Damage After Cerebral Hemorrhage Stroke, 10.1016/B978-0-323-69424-7.00008-9, (92-102.e9), . Rayasam A, Jullienne A, Chumak T, Faustino J, Szu J, Hamer M, Ek C, Mallard C, Obenaus A and Vexler Z (2021) Viral mimetic triggers cerebral arteriopathy in juvenile brain via neutrophil elastase and NETosis, Journal of Cerebral Blood Flow & Metabolism, 10.1177/0271678X211032737, 41:12, (3171-3186), Online publication date: 1-Dec-2021. Chen W, Xie L, Yu F, Li Y, Chen C, Xie W, Huang T, Zhang Y, Zhang S and Li P (2021) Zebrafish as a Model for In-Depth Mechanistic Study for Stroke, Translational Stroke Research, 10.1007/s12975-021-00907-3, 12:5, (695-710), Online publication date: 1-Oct-2021. Chen C, Huang T, Zhai X, Ma Y, Xie L, Lu B, Zhang Y, Li Y, Chen Z, Yin J and Li P (2021) Targeting neutrophils as a novel therapeutic strategy after stroke, Journal of Cerebral Blood Flow & Metabolism, 10.1177/0271678X211000137, 41:9, (2150-2161), Online publication date: 1-Sep-2021. Liu Y, Wu Z, Qu J, Qiu D, Luo G, Yin H, Fang X, Wang F and Chen Y (2020) High neutrophil‐to‐lymphocyte ratio is a predictor of poor short‐term outcome in patients with mild acute ischemic stroke receiving intravenous thrombolysis, Brain and Behavior, 10.1002/brb3.1857, 10:12, Online publication date: 1-Dec-2020. Taroza S, Rastenytė D, Burkauskas J, Podlipskytė A, Kažukauskienė N, Patamsytė V and Mickuvienė N (2020) Deiodinases, organic anion transporter polypeptide polymorphisms and symptoms of anxiety and depression after ischemic stroke, Journal of Stroke and Cerebrovascular Diseases, 10.1016/j.jstrokecerebrovasdis.2020.105040, 29:9, (105040), Online publication date: 1-Sep-2020. Su Z, Chang Q, Drelich A, Shelite T, Judy B, Liu Y, Xiao J, Zhou C, He X, Jin Y, Saito T, Tang S, Soong L, Wakamiya M, Fang X, Bukreyev A, Ksiazek T, Russell W, Gong B and Blacksell S (2020) Annexin A2 depletion exacerbates the intracerebral microhemorrhage induced by acute rickettsia and Ebola virus infections, PLOS Neglected Tropical Diseases, 10.1371/journal.pntd.0007960, 14:7, (e0007960) Dhanesha N, Jain M, Tripathi A, Doddapattar P, Chorawala M, Bathla G, Nayak M, Ghatge M, Lentz S, Kon S and Chauhan A (2020) Targeting Myeloid-Specific Integrin α9β1 Improves Short- and Long-Term Stroke Outcomes in Murine Models With Preexisting Comorbidities by Limiting Thrombosis and Inflammation, Circulation Research, 126:12, (1779-1794), Online publication date: 5-Jun-2020.García-Culebras A, Durán-Laforet V, Peña-Martínez C, Moraga A, Ballesteros I, Cuartero M, de la Parra J, Palma-Tortosa S, Hidalgo A, Corbí A, Moro M and Lizasoain I (2019) Role of TLR4 (Toll-Like Receptor 4) in N1/N2 Neutrophil Programming After Stroke, Stroke, 50:10, (2922-2932), Online publication date: 1-Oct-2019. Barrios-Anderson A, Chen X, Nakada S, Chen R, Lim Y and Stonestreet B (2019) Inter-alpha Inhibitor Proteins Modulate Neuroinflammatory Biomarkers After Hypoxia-Ischemia in Neonatal Rats, Journal of Neuropathology & Experimental Neurology, 10.1093/jnen/nlz051, 78:8, (742-755), Online publication date: 1-Aug-2019. Related articlesPolymorphonuclear Neutrophils Play a Decisive Role for Brain Injury and Neurological Recovery PoststrokeDirk M. Hermann, et al. Stroke. 2019;50:e40-e41Neutrophils in Acute Stroke PathophysiologyWolf-Rüdiger Schäbitz, et al. Stroke. 2019;50:e44-e45 March 2019Vol 50, Issue 3 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/STROKEAHA.118.021563PMID: 30674235 Manuscript receivedAugust 27, 2018Manuscript acceptedOctober 10, 2018Originally publishedJanuary 24, 2019Manuscript revisedOctober 3, 2018 KeywordsstrokemicrovesselsbraininflammationmacrophagesPDF download Advertisement SubjectsIntracranial HemorrhageIschemic Stroke" @default.
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