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The role of peripheral monocytes and macrophages in ischemic stroke

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Abstract

After acute ischemic stroke (AIS), peripheral monocytes infiltrate into the lesion site within 24 h, peak at 3 to 7 days, and then differentiate into macrophages. Traditionally, monocytes/macrophages (MMs) are thought to play a deleterious role in AIS. Depletion of MMs in the acute phase can alleviate brain injury induced by ischemia. However, several studies have shown that MMs have anti-inflammatory functions, participate in angiogenesis, phagocytose necrotic neurons, and promote neurovascular repair. Therefore, MMs play dual roles in ischemic stroke, depending mainly upon the MM microenvironment and the window of time post-stroke. Because activated microglia and MMs are similar in morphology and function, previous studies have often investigated them together. However, recent studies have used special methods to distinguish MMs from microglia and have found that MMs have properties which differ from microglia. Here, we review the unique role of MMs and the interaction between MMs and neurovascular units, including neurons, astrocytes, microglia, and microvessels. Future therapeutics targeting MMs should regulate the polarization and subset transformation of the MMs at different stages of AIS rather than comprehensively suppressing MM infiltration and differentiation. In addition, more studies are needed to elucidate the cellular and molecular mechanisms of MM subsets and polarization during ischemic stroke.

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References

  1. Rock KL, Latz E, Ontiveros F, Kono H (2010) The sterile inflammatory response. Annu Rev Immunol 28:321–342. https://doi.org/10.1146/annurev-immunol-030409-101311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Dirnagl U, Iadecola C, Moskowitz MA (1999) Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 22(9):391–397. https://doi.org/10.1016/s0166-2236(99)01401-0

    Article  CAS  PubMed  Google Scholar 

  3. Fagan SC, Hess DC, Hohnadel EJ, Pollock DM, Ergul A (2004) Targets for vascular protection after acute ischemic stroke. Stroke 35(9):2220–2225. https://doi.org/10.1161/01.STR.0000138023.60272.9e

    Article  CAS  PubMed  Google Scholar 

  4. Jin R, Yang G, Li G (2010) Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. J Leukoc Biol 87(5):779–789. https://doi.org/10.1189/jlb.1109766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Jin R, Liu L, Zhang S, Nanda A, Li G (2013) Role of inflammation and its mediators in acute ischemic stroke. J Cardiovasc Transl Res 6(5):834–851. https://doi.org/10.1007/s12265-013-9508-6

    Article  PubMed  Google Scholar 

  6. Chiba T, Umegaki K (2013) Pivotal roles of monocytes/macrophages in stroke. Mediat Inflamm 2013:759103–759110. https://doi.org/10.1155/2013/759103

    Article  Google Scholar 

  7. Fang W, Zhai X, Han D, Xiong X, Wang T, Zeng X, He S, Liu R, Miyata M, Xu B, Zhao H (2018) CCR2-dependent monocytes/macrophages exacerbate acute brain injury but promote functional recovery after ischemic stroke in mice. Theranostics 8(13):3530–3543. https://doi.org/10.7150/thno.24475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Rajan WD, Wojtas B, Gielniewski B, Gieryng A, Zawadzka M, Kaminska B (2019) Dissecting functional phenotypes of microglia and macrophages in the rat brain after transient cerebral ischemia. Glia 67(2):232–245. https://doi.org/10.1002/glia.23536

    Article  PubMed  Google Scholar 

  9. Kong X, Gao J (2017) Macrophage polarization: a key event in the secondary phase of acute spinal cord injury. J Cell Mol Med 21(5):941–954. https://doi.org/10.1111/jcmm.13034

    Article  PubMed  Google Scholar 

  10. Kanazawa M, Ninomiya I, Hatakeyama M, Takahashi T, Shimohata T (2017) Microglia and monocytes/macrophages polarization reveal novel therapeutic mechanism against stroke. Int J Mol Sci 18(10). https://doi.org/10.3390/ijms18102135

  11. Pedragosa J, Miró-Mur F, Otxoa-de-Amezaga A, Justicia C, Ruíz-Jaén F, Ponsaerts P, Pasparakis M, Planas AM (2020) CCR2 deficiency in monocytes impairs angiogenesis and functional recovery after ischemic stroke in mice. J Cereb Blood Flow Metab:271678X20909055. https://doi.org/10.1177/0271678x20909055

  12. Auffray C, Sieweke MH, Geissmann F (2009) Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu Rev Immunol 27:669–692. https://doi.org/10.1146/annurev.immunol.021908.132557

    Article  CAS  PubMed  Google Scholar 

  13. Tsou C-L, Peters W, Si Y, Slaymaker S, Aslanian AM, Weisberg SP, Mack M, Charo IF (2007) Critical roles for CCR2 and MCP-3 in monocyte mobilization from bone marrow and recruitment to inflammatory sites. J Clin Investig 117(4):902–909. https://doi.org/10.1172/jci29919

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hettinger J, Richards DM, Hansson J, Barra MM, Joschko A-C, Krijgsveld J, Feuerer M (2013) Origin of monocytes and macrophages in a committed progenitor. Nat Immunol 14(8):821–830. https://doi.org/10.1038/ni.2638

    Article  CAS  PubMed  Google Scholar 

  15. Murray PJ, Wynn TA (2011) Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 11(11):723–737. https://doi.org/10.1038/nri3073

    Article  CAS  PubMed  Google Scholar 

  16. Swirski FK, Libby P, Aikawa E, Alcaide P, Luscinskas FW, Weissleder R, Pittet MJ (2007) Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J Clin Investig 117(1):195–205. https://doi.org/10.1172/jci29950

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Geissmann F, Auffray C, Palframan R, Wirrig C, Ciocca A, Campisi L, Narni-Mancinelli E, Lauvau G (2008) Blood monocytes: distinct subsets, how they relate to dendritic cells, and their possible roles in the regulation of T-cell responses. Immunol Cell Biol 86(5):398–408. https://doi.org/10.1038/icb.2008.19

    Article  CAS  PubMed  Google Scholar 

  18. Ginhoux F, Jung S (2014) Monocytes and macrophages: developmental pathways and tissue homeostasis. Nat Rev Immunol 14(6):392–404. https://doi.org/10.1038/nri3671

    Article  CAS  PubMed  Google Scholar 

  19. Geissmann F, Jung S, Littman DR (2003) Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19(1):71–82. https://doi.org/10.1016/s1074-7613(03)00174-2

    Article  CAS  PubMed  Google Scholar 

  20. Prinz M, Priller J (2010) Tickets to the brain: role of CCR2 and CX3CR1 in myeloid cell entry in the CNS. J Neuroimmunol 224:80–84. https://doi.org/10.1016/j.jneuroim.2010.05.015

    Article  CAS  PubMed  Google Scholar 

  21. Imai T, Hieshima K, Haskell C, Baba M, Nagira M, Nishimura M, Kakizaki M, Takagi S, Nomiyama H, Schall TJ, Yoshie O (1997) Identification and molecular characterization of fractalkine receptor CX3CR1, which mediates both leukocyte migration and adhesion. Cell 91(4):521–530. https://doi.org/10.1016/s0092-8674(00)80438-9

    Article  CAS  PubMed  Google Scholar 

  22. Auffray C, Fogg D, Garfa M, Elain G, Join-Lambert O, Kayal S, Sarnacki S, Cumano A, Lauvau G, Geissmann F (2007) Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science 317(5838):666–670. https://doi.org/10.1126/science.1142883

    Article  CAS  PubMed  Google Scholar 

  23. Swirski FK, Wildgruber M, Ueno T, Figueiredo J-L, Panizzi P, Iwamoto Y, Zhang E, Stone JR, Rodriguez E, Chen JW, Pittet MJ, Weissleder R, Nahrendorf M (2010) Myeloperoxidase-rich Ly-6C+ myeloid cells infiltrate allografts and contribute to an imaging signature of organ rejection in mice. J Clin Investig 120(7):2627–2634. https://doi.org/10.1172/jci42304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Terry RL, Getts DR, Deffrasnes C, van Vreden C, Campbell IL, King NJC (2012) Inflammatory monocytes and the pathogenesis of viral encephalitis. J Neuroinflammation 9:270. https://doi.org/10.1186/1742-2094-9-270

    Article  PubMed  PubMed Central  Google Scholar 

  25. García-Culebras A, Durán-Laforet V, Peña-Martínez C, Ballesteros I, Pradillo JM, Díaz-Guzmán J, Lizasoain I, Moro MA (2018) Myeloid cells as therapeutic targets in neuroinflammation after stroke: specific roles of neutrophils and neutrophil-platelet interactions. J Cereb Blood Flow Metab 38(12):2150–2164. https://doi.org/10.1177/0271678x18795789

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Mildner A, Mack M, Schmidt H, Brück W, Djukic M, Zabel MD, Hille A, Priller J, Prinz M (2009) CCR2+Ly-6Chi monocytes are crucial for the effector phase of autoimmunity in the central nervous system. Brain 132:2487–2500. https://doi.org/10.1093/brain/awp144

    Article  PubMed  Google Scholar 

  27. Sunderkötter C, Nikolic T, Dillon MJ, Van Rooijen N, Stehling M, Drevets DA, Leenen PJM (2004) Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response. J Neuroinflammation 172(7):4410–4417. https://doi.org/10.4049/jimmunol.172.7.4410

    Article  Google Scholar 

  28. Lin SL, Castaño AP, Nowlin BT, Lupher ML Jr, Duffield JS (2009) Bone marrow Ly6Chigh monocytes are selectively recruited to injured kidney and differentiate into functionally distinct populations. J Immunol 183(10):6733–6743. https://doi.org/10.4049/jimmunol.0901473

    Article  CAS  PubMed  Google Scholar 

  29. Hanna RN, Carlin LM, Hubbeling HG, Nackiewicz D, Green AM, Punt JA, Geissmann F, Hedrick CC (2011) The transcription factor NR4A1 (Nur77) controls bone marrow differentiation and the survival of Ly6C- monocytes. Nat Immunol 12(8):778–785. https://doi.org/10.1038/ni.2063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Swirski FK, Nahrendorf M, Etzrodt M, Wildgruber M, Cortez-Retamozo V, Panizzi P, Figueiredo J-L, Kohler RH, Chudnovskiy A, Waterman P, Aikawa E, Mempel TR, Libby P, Weissleder R, Pittet MJ (2009) Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 325(5940):612–616. https://doi.org/10.1126/science.1175202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Leuschner F, Panizzi P, Chico-Calero I, Lee WW, Ueno T, Cortez-Retamozo V, Waterman P, Gorbatov R, Marinelli B, Iwamoto Y, Chudnovskiy A, Figueiredo J-L, Sosnovik DE, Pittet MJ, Swirski FK, Weissleder R, Nahrendorf M (2010) Angiotensin-converting enzyme inhibition prevents the release of monocytes from their splenic reservoir in mice with myocardial infarction. Circ Res 107(11):1364–1373. https://doi.org/10.1161/circresaha.110.227454

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Garcia-Bonilla L, Brea D, Benakis C, Lane DA, Murphy M, Moore J, Racchumi G, Jiang X, Iadecola C, Anrather J (2018) Endogenous protection from ischemic brain injury by preconditioned monocytes. J Neurosci 38(30):6722–6736. https://doi.org/10.1523/jneurosci.0324-18.2018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Seifert HA, Hall AA, Chapman CB, Collier LA, Willing AE, Pennypacker KR (2012) A transient decrease in spleen size following stroke corresponds to splenocyte release into systemic circulation. J NeuroImmune Pharmacol 7(4):1017–1024. https://doi.org/10.1007/s11481-012-9406-8

    Article  PubMed  PubMed Central  Google Scholar 

  34. Kim E, Yang J, Beltran CD, Cho S (2014) Role of spleen-derived monocytes/macrophages in acute ischemic brain injury. J Cereb Blood Flow Metab 34(8):1411–1419. https://doi.org/10.1038/jcbfm.2014.101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Courties G, Herisson F, Sager HB, Heidt T, Ye Y, Wei Y, Sun Y, Severe N, Dutta P, Scharff J, Scadden DT, Weissleder R, Swirski FK, Moskowitz MA, Nahrendorf M (2015) Ischemic stroke activates hematopoietic bone marrow stem cells. Circ Res 116(3):407–417. https://doi.org/10.1161/circresaha.116.305207

    Article  CAS  PubMed  Google Scholar 

  36. Chu HX, Broughton BRS, Kim HA (2015) Evidence That Ly6Chi Monocytes Are Protective in Acute Ischemic Stroke by Promoting M2 Macrophage Polarization. Stroke 46:1929–1937. https://doi.org/10.1161/STROKEAHA.115.009426

    Article  CAS  PubMed  Google Scholar 

  37. Che X, Ye W, Panga L, Wu DC, Yang GY (2001) Monocyte chemoattractant protein-1 expressed in neurons and astrocytes during focal ischemia in mice. Brain Res 902(2):171–177. https://doi.org/10.1016/s0006-8993(01)02328-9

    Article  CAS  PubMed  Google Scholar 

  38. Chu HX, Arumugam TV, Gelderblom M, Magnus T, Drummond GR, Sobey CG (2014) Role of CCR2 in inflammatory conditions of the central nervous system. J Cereb Blood Flow Metab 34(9):1425–1429. https://doi.org/10.1038/jcbfm.2014.120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Dimitrijevic OB, Stamatovic SM, Keep RF, Andjelkovic AV (2007) Absence of the chemokine receptor CCR2 protects against cerebral ischemia/reperfusion injury in mice. Stroke 38(4):1345–1353. https://doi.org/10.1161/01.STR.0000259709.16654.8f

    Article  CAS  PubMed  Google Scholar 

  40. Schilling M, Strecker J-K, Ringelstein EB, Schäbitz W-R, Kiefer R (2009) The role of CC chemokine receptor 2 on microglia activation and blood-borne cell recruitment after transient focal cerebral ischemia in mice. Brain Res 1289:79–84. https://doi.org/10.1016/j.brainres.2009.06.054

    Article  CAS  PubMed  Google Scholar 

  41. Schuette-Nuetgen K, Strecker J-K, Minnerup J, Ringelstein EB, Schilling M (2012) MCP-1/CCR-2-double-deficiency severely impairs the migration of hematogenous inflammatory cells following transient cerebral ischemia in mice. Exp Neurol 233(2):849–858. https://doi.org/10.1016/j.expneurol.2011.12.011

    Article  CAS  PubMed  Google Scholar 

  42. Gliem M, Mausberg AK, Lee J-I, Simiantonakis I, van Rooijen N, Hartung H-P, Jander S (2012) Macrophages prevent hemorrhagic infarct transformation in murine stroke models. Ann Neurol 71(6):743–752. https://doi.org/10.1002/ana.23529

    Article  CAS  PubMed  Google Scholar 

  43. Michaud J-P, Pimentel-Coelho PM, Tremblay Y, Rivest S (2014) The impact of Ly6Clow monocytes after cerebral hypoxia-ischemia in adult mice. J Cereb Blood Flow Metab 34(7):e1–e9. https://doi.org/10.1038/jcbfm.2014.80

    Article  CAS  PubMed  Google Scholar 

  44. Garcia-Bonilla L, Faraco G, Moore J, Murphy M, Racchumi G, Srinivasan J, Brea D, Iadecola C, Anrather J (2016) Spatio-temporal profile, phenotypic diversity, and fate of recruited monocytes into the post-ischemic brain. J Neuroinflammation 13(1):285. https://doi.org/10.1186/s12974-016-0750-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Werner Y, Mass E, Kumar PA, Ulas T, Händler K, Horne A, Klee K, Lupp A, Schütz D, Saaber F, Redecker C, Schultze JL, Geissmann F, Stumm R (2020) Cxcr4 distinguishes HSC-derived monocytes from microglia and reveals monocyte immune responses to experimental stroke. Nat Neurosci 23(3):351–362. https://doi.org/10.1038/s41593-020-0585-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Miró-Mur F, Pérez-de-Puig I, Ferrer-Ferrer M, Urra X, Justicia C, Chamorro A, Planas AM (2016) Immature monocytes recruited to the ischemic mouse brain differentiate into macrophages with features of alternative activation. Brain Behav Immun 53:18–33. https://doi.org/10.1016/j.bbi.2015.08.010

    Article  CAS  PubMed  Google Scholar 

  47. Gelderblom M, Leypoldt F, Steinbach K, Behrens D, Choe C-U, Siler DA, Arumugam TV, Orthey E, Gerloff C, Tolosa E, Magnus T (2009) Temporal and spatial dynamics of cerebral immune cell accumulation in stroke. Stroke 40(5):1849–1857. https://doi.org/10.1161/strokeaha.108.534503

    Article  PubMed  Google Scholar 

  48. Garcia-Bonilla L, Moore JM, Racchumi G, Zhou P, Butler JM, Iadecola C, Anrather J (2014) Inducible nitric oxide synthase in neutrophils and endothelium contributes to ischemic brain injury in mice. J Immunol 193(5):2531–2537. https://doi.org/10.4049/jimmunol.1400918

    Article  CAS  PubMed  Google Scholar 

  49. Wattananit S, Tornero D, Graubardt N, Memanishvili T, Monni E, Tatarishvili J, Miskinyte G, Ge R, Ahlenius H, Lindvall O, Schwartz M, Kokaia Z (2016) Monocyte-derived macrophages contribute to spontaneous long-term functional recovery after stroke in mice. J Neurosci 36(15):4182–4195. https://doi.org/10.1523/jneurosci.4317-15.2016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zarruk JG, Greenhalgh AD, David S (2018) Microglia and macrophages differ in their inflammatory profile after permanent brain ischemia. Exp Neurol 301:120–132. https://doi.org/10.1016/j.expneurol.2017.08.011

    Article  CAS  PubMed  Google Scholar 

  51. Schilling M, Besselmann M, Müller M, Strecker JK, Ringelstein EB, Kiefer R (2005) Predominant phagocytic activity of resident microglia over hematogenous macrophages following transient focal cerebral ischemia: an investigation using green fluorescent protein transgenic bone marrow chimeric mice. Exp Neurol 196(2):290–297. https://doi.org/10.1016/j.expneurol.2005.08.004

    Article  CAS  PubMed  Google Scholar 

  52. Wong LM, Myers SJ, Tsou CL, Gosling J, Arai H, Charo IF (1997) Organization and differential expression of the human monocyte chemoattractant protein 1 receptor gene. Evidence for the role of the carboxyl-terminal tail in receptor trafficking. J Biol Chem 272(2):1038–1045. https://doi.org/10.1074/jbc.272.2.1038

    Article  CAS  PubMed  Google Scholar 

  53. Geissmann F, Manz MG, Jung S, Sieweke MH, Merad M, Ley K (2010) Development of monocytes, macrophages, and dendritic cells. Science 327(5966):656–661. https://doi.org/10.1126/science.1178331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Lee PY, Li Y, Kumagai Y, Xu Y, Weinstein JS, Kellner ES, Nacionales DC, Butfiloski EJ, van Rooijen N, Akira S, Sobel ES, Satoh M, Reeves WH (2009) Type I interferon modulates monocyte recruitment and maturation in chronic inflammation. Am J Pathol 175(5):2023–2033. https://doi.org/10.2353/ajpath.2009.090328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Sica A, Erreni M, Allavena P, Porta C (2015) Macrophage polarization in pathology. Cell Mol Life Sci 72(21):4111–4126. https://doi.org/10.1007/s00018-015-1995-y

    Article  CAS  PubMed  Google Scholar 

  56. Wynn TA, Chawla A, Pollard JW (2013) Macrophage biology in development, homeostasis and disease. Nature 496(7446):445–455. https://doi.org/10.1038/nature12034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Dai H, Lan P, Zhao D, Abou-Daya K, Liu W, Chen W, Friday AJ, Williams AL, Sun T, Chen J, Chen W, Mortin-Toth S, Danska JS, Wiebe C, Nickerson P, Li T, Mathews LR, Turnquist HR, Nicotra ML, Gingras S, Takayama E, Kubagawa H, Shlomchik MJ, Oberbarnscheidt MH, Li XC, Lakkis FG (2020) PIRs mediate innate myeloid cell memory to nonself MHC molecules. Science. 368:1122–1127. https://doi.org/10.1126/science.aax4040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Girard S, Brough D, Lopez-Castejon G, Giles J, Rothwell NJ, Allan SM (2013) Microglia and macrophages differentially modulate cell death after brain injury caused by oxygen-glucose deprivation in organotypic brain slices. Glia 61(5):813–824. https://doi.org/10.1002/glia.22478

    Article  PubMed  PubMed Central  Google Scholar 

  59. Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8(12):958–969. https://doi.org/10.1038/nri2448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Yang J, Zhang L, Yu C, Yang X-F, Wang H (2014) Monocyte and macrophage differentiation: circulation inflammatory monocyte as biomarker for inflammatory diseases. Biomark Res 2(1):1. https://doi.org/10.1186/2050-7771-2-1

    Article  PubMed  PubMed Central  Google Scholar 

  61. Hu X, Li P, Guo Y, Wang H, Leak RK, Chen S, Gao Y, Chen J (2012) Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke 43(11):3063–3070. https://doi.org/10.1161/strokeaha.112.659656

    Article  CAS  PubMed  Google Scholar 

  62. Perego C, Fumagalli S, Zanier ER, Carlino E, Panini N, Erba E, De Simoni M-G (2016) Macrophages are essential for maintaining a M2 protective response early after ischemic brain injury. Neurobiol Dis 96:284–293. https://doi.org/10.1016/j.nbd.2016.09.017

    Article  CAS  PubMed  Google Scholar 

  63. Ginhoux F, Schultze JL, Murray PJ, Ochando J, Biswas SK (2016) New insights into the multidimensional concept of macrophage ontogeny, activation and function. Nat Immunol 17(1):34–40. https://doi.org/10.1038/ni.3324

    Article  CAS  PubMed  Google Scholar 

  64. Kronenberg G, Uhlemann R, Richter N, Klempin F, Wegner S, Staerck L, Wolf S, Uckert W, Kettenmann H, Endres M, Gertz K (2018) Distinguishing features of microglia- and monocyte-derived macrophages after stroke. Acta Neuropathol 135(4):551–568. https://doi.org/10.1007/s00401-017-1795-6

    Article  CAS  PubMed  Google Scholar 

  65. Ajmo CT Jr, Vernon DOL, Collier L, Hall AA, Garbuzova-Davis S, Willing A, Pennypacker KR (2008) The spleen contributes to stroke-induced neurodegeneration. J Neurosci Res 86(10):2227–2234. https://doi.org/10.1002/jnr.21661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Ma Y, Li Y, Jiang L, Wang L, Jiang Z, Wang Y, Zhang Z, Yang G-Y (2016) Macrophage depletion reduced brain injury following middle cerebral artery occlusion in mice. J Neuroinflammation 13:38. https://doi.org/10.1186/s12974-016-0504-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Ostrowski RP, Schulte RW, Nie Y, Ling T, Lee T, Manaenko A, Gridley DS, Zhang JH (2012) Acute splenic irradiation reduces brain injury in the rat focal ischemic stroke model. Transl Stroke Res 3(4):473–481. https://doi.org/10.1007/s12975-012-0206-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Schmidt A, Strecker J-K, Hucke S, Bruckmann N-M, Herold M, Mack M, Diederich K, Schäbitz W-R, Wiendl H, Klotz L, Minnerup J (2017) Targeting different monocyte/macrophage subsets has no impact on outcome in experimental stroke. Stroke 48(4):1061–1069. https://doi.org/10.1161/strokeaha.116.015577

    Article  CAS  PubMed  Google Scholar 

  69. Ritzel RM, Patel AR, Grenier JM, Crapser J, Verma R, Jellison ER, McCullough LD (2015) Functional differences between microglia and monocytes after ischemic stroke. J Neuroinflammation 12:106. https://doi.org/10.1186/s12974-015-0329-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Rupalla K, Allegrini PR, Sauer D, Wiessner C (1998) Time course of microglia activation and apoptosis in various brain regions after permanent focal cerebral ischemia in mice. Acta Neuropathol 96(2):172–178. https://doi.org/10.1007/s004010050878

    Article  CAS  PubMed  Google Scholar 

  71. Denes A, Vidyasagar R, Feng J, Narvainen J, McColl BW, Kauppinen RA, Allan SM (2007) Proliferating resident microglia after focal cerebral ischaemia in mice. J Cereb Blood Flow Metab 27(12):1941–1953. https://doi.org/10.1038/sj.jcbfm.9600495

    Article  CAS  PubMed  Google Scholar 

  72. Sedgwick JD, Schwender S, Imrich H, Dörries R, Butcher GW, ter Meulen V (1991) Isolation and direct characterization of resident microglial cells from the normal and inflamed central nervous system. Proc Natl Acad Sci U S A 88(16):7438–7442. https://doi.org/10.1073/pnas.88.16.7438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Tanaka R, Komine-Kobayashi M, Mochizuki H, Yamada M, Furuya T, Migita M, Shimada T, Mizuno Y, Urabe T (2003) Migration of enhanced green fluorescent protein expressing bone marrow-derived microglia/macrophage into the mouse brain following permanent focal ischemia. Neuroscience 117(3):531–539. https://doi.org/10.1016/s0306-4522(02)00954-5

    Article  CAS  PubMed  Google Scholar 

  74. Ginhoux F, Lim S, Hoeffel G, Low D, Huber T (2013) Origin and differentiation of microglia. Front Cell Neurosci 7:45. https://doi.org/10.3389/fncel.2013.00045

    Article  PubMed  PubMed Central  Google Scholar 

  75. Prinz M, Priller J (2014) Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat Rev Neurosci 15(5):300–312. https://doi.org/10.1038/nrn3722

    Article  CAS  PubMed  Google Scholar 

  76. Kierdorf K, Katzmarski N, Haas CA, Prinz M (2013) Bone marrow cell recruitment to the brain in the absence of irradiation or parabiosis bias. PLoS One 8(3):e58544. https://doi.org/10.1371/journal.pone.0058544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Bauer J, Huitinga I, Zhao W, Lassmann H, Hickey WF, Dijkstra CD (1995) The role of macrophages, perivascular cells, and microglial cells in the pathogenesis of experimental autoimmune encephalomyelitis. Glia 15(4):437–446. https://doi.org/10.1002/glia.440150407

    Article  CAS  PubMed  Google Scholar 

  78. Duffield JS, Forbes SJ, Constandinou CM, Clay S, Partolina M, Vuthoori S, Wu S, Lang R, Iredale JP (2005) Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Investig 115(1):56–65. https://doi.org/10.1172/jci22675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Laterza C, Wattananit S, Uoshima N, Ge R, Pekny R, Tornero D, Monni E, Lindvall O, Kokaia Z (2017) Monocyte depletion early after stroke promotes neurogenesis from endogenous neural stem cells in adult brain. Exp Neurol 297:129–137. https://doi.org/10.1016/j.expneurol.2017.07.012

    Article  CAS  PubMed  Google Scholar 

  80. Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, Mehler MF, Conway SJ, Ng LG, Stanley ER, Samokhvalov IM, Merad M (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330(6005):841–845. https://doi.org/10.1126/science.1194637

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Woo M-S, Yang J, Beltran C, Cho S (2016) Cell surface CD36 protein in monocyte/macrophage contributes to phagocytosis during the resolution phase of ischemic stroke in mice. J Biol Chem 291(45):23654–23661. https://doi.org/10.1074/jbc.M116.750018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Zheng Y, He R, Wang P, Shi Y, Zhao L, Liang J (2019) Exosomes from LPS-stimulated macrophages induce neuroprotection and functional improvement after ischemic stroke by modulating microglial polarization. Biomater Sci 7(5):2037–2049. https://doi.org/10.1039/c8bm01449c

    Article  CAS  PubMed  Google Scholar 

  83. An C, Shi Y, Li P, Hu X, Gan Y, Stetler RA, Leak RK, Gao Y, Sun B-L, Zheng P, Chen J (2014) Molecular dialogs between the ischemic brain and the peripheral immune system: dualistic roles in injury and repair. Prog Neurobiol 115:6–24. https://doi.org/10.1016/j.pneurobio.2013.12.002

    Article  CAS  PubMed  Google Scholar 

  84. Wang X, Xuan W, Zhu Z-Y, Li Y, Zhu H, Zhu L, Fu D-Y, Yang L-Q, Li P-Y, Yu W-F (2018) The evolving role of neuro-immune interaction in brain repair after cerebral ischemic stroke. CNS NeurosciTther 24(12):1100–1114. https://doi.org/10.1111/cns.13077

    Article  Google Scholar 

  85. Poon IKH, Lucas CD, Rossi AG, Ravichandran KS (2014) Apoptotic cell clearance: basic biology and therapeutic potential. Nat Rev Immunol 14(3):166–180. https://doi.org/10.1038/nri3607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Zhang W, Zhao J, Wang R, Jiang M, Ye Q, Smith AD, Chen J, Shi Y (2019) Macrophages reprogram after ischemic stroke and promote efferocytosis and inflammation resolution in the mouse brain. CNS NeurosciTther 25(12):1329–1342. https://doi.org/10.1111/cns.13256

    Article  CAS  Google Scholar 

  87. Wang R, Liu Y, Ye Q, Hassan SH, Zhao J, Li S, Hu X, Leak RK, Rocha M, Wechsler LR, Chen J, Shi Y (2020) RNA sequencing reveals novel macrophage transcriptome favoring neurovascular plasticity after ischemic stroke. J Cereb Blood Flow Metab 40(4):720–738. https://doi.org/10.1177/0271678x19888630

    Article  CAS  PubMed  Google Scholar 

  88. Cao L, He C (2013) Polarization of macrophages and microglia in inflammatory demyelination. J Neurosci Bull 29(2):189–198. https://doi.org/10.1007/s12264-013-1324-0

    Article  CAS  Google Scholar 

  89. Rolls A, Shechter R, London A, Segev Y, Jacob-Hirsch J, Amariglio N, Rechavi G, Schwartz M (2008) Two faces of chondroitin sulfate proteoglycan in spinal cord repair: a role in microglia/macrophage activation. PLoS Med 5(8):e171. https://doi.org/10.1371/journal.pmed.0050171

    Article  PubMed  PubMed Central  Google Scholar 

  90. Mabbott NA, Baillie JK, Hume DA, Freeman TC (2010) Meta-analysis of lineage-specific gene expression signatures in mouse leukocyte populations. Immunobiology 215:724–736. https://doi.org/10.1016/j.imbio.2010.05.012

    Article  CAS  PubMed  Google Scholar 

  91. Yin Y, Henzl MT, Lorber B, Nakazawa T, Thomas TT, Jiang F, Langer R, Benowitz LI (2006) Oncomodulin is a macrophage-derived signal for axon regeneration in retinal ganglion cells. Nat Neurosci 9(6):843–852. https://doi.org/10.1038/nn1701

    Article  CAS  PubMed  Google Scholar 

  92. Urakawa N, Utsunomiya S, Nishio M, Shigeoka M, Takase N, Arai N, Kakeji Y, Koma Y-i, Yokozaki H (2015) GDF15 derived from both tumor-associated macrophages and esophageal squamous cell carcinomas contributes to tumor progression via Akt and Erk pathways. Lab Investig 95(5):491–503. https://doi.org/10.1038/labinvest.2015.36

    Article  CAS  PubMed  Google Scholar 

  93. Nahrendorf M, Swirski FK, Aikawa E, Stangenberg L, Wurdinger T, Figueiredo J-L, Libby P, Weissleder R, Pittet MJ (2007) The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J Exp Med 204(12):3037–3047. https://doi.org/10.1084/jem.20070885

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Batchelor PE, Liberatore GT, Wong JY, Porritt MJ, Frerichs F, Donnan GA, Howells DW (1999) Activated macrophages and microglia induce dopaminergic sprouting in the injured striatum and express brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. J Neurosci 19(5):1708–1716. https://doi.org/10.1523/jneurosci.19-05-01708.1999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Meller R, Stevens SL, Minami M, Cameron JA, King S, Rosenzweig H, Doyle K, Lessov NS, Simon RP, Stenzel-Poore MP (2005) Neuroprotection by osteopontin in stroke. J Cereb Blood Flow Metab 25(2):217–225. https://doi.org/10.1038/sj.jcbfm.9600022

    Article  CAS  PubMed  Google Scholar 

  96. Liu C, Wu C, Yang Q, Gao J, Li L, Yang D, Luo L (2016) Macrophages mediate the repair of brain vascular rupture through direct physical adhesion and mechanical traction. Immunity 44(5):1162–1176. https://doi.org/10.1016/j.immuni.2016.03.008

    Article  CAS  PubMed  Google Scholar 

  97. Tei N, Tanaka J, Sugimoto K, Nishihara T, Nishioka R, Takahashi H, Yano H, Matsumoto S, Ohue S, Watanabe H, Kumon Y, Ohnishi T (2013) Expression of MCP-1 and fractalkine on endothelial cells and astrocytes may contribute to the invasion and migration of brain macrophages in ischemic rat brain lesions. J Neurosci Res 91(5):681–693. https://doi.org/10.1002/jnr.23202

    Article  CAS  PubMed  Google Scholar 

  98. Pekny M, Nilsson M (2005) Astrocyte activation and reactive gliosis. Glia 50(4):427–434. https://doi.org/10.1002/glia.20207

    Article  PubMed  Google Scholar 

  99. Schroeter M, Schiene K, Kraemer M, Hagemann G, Weigel H, Eysel UT, Witte OW, Stoll G (1995) Astroglial responses in photochemically induced focal ischemia of the rat cortex. Exp Brain Res 106(1):1–6. https://doi.org/10.1007/bf00241351

    Article  CAS  PubMed  Google Scholar 

  100. Gliem M, Krammes K, Liaw L, van Rooijen N, Hartung H-P (2015) Macrophage-derived osteopontin induces reactive astrocyte polarization and promotes re-establishment of the blood brain barrier after ischemic stroke. Glia 63(4):2198–2207. https://doi.org/10.1177/0271678x19888630

    Article  CAS  PubMed  Google Scholar 

  101. Chabas D, Baranzini SE, Mitchell D, Bernard CC, Rittling SR, Denhardt DT, Sobel RA, Lock C, Karpuj M, Pedotti R, Heller R, Oksenberg JR, Steinman L (2001) The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science 294(5547):1731–1735. https://doi.org/10.1126/science.1062960

    Article  CAS  PubMed  Google Scholar 

  102. Schroeter M, Zickler P, Denhardt DT, Hartung H-P, Jander S (2006) Increased thalamic neurodegeneration following ischaemic cortical stroke in osteopontin-deficient mice. Brain 129:1426–1437. https://doi.org/10.1093/brain/awl094

    Article  PubMed  Google Scholar 

  103. Suzuki H, Hasegawa Y, Kanamaru K, Zhang JH (2010) Mechanisms of osteopontin-induced stabilization of blood-brain barrier disruption after subarachnoid hemorrhage in rats. Stroke 41(8):1783–1790. https://doi.org/10.1161/strokeaha.110.586537

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. van Velthoven CTJ, Heijnen CJ, van Bel F, Kavelaars A (2011) Osteopontin enhances endogenous repair after neonatal hypoxic-ischemic brain injury. Stroke 42(8):2294–2301. https://doi.org/10.1161/strokeaha.110.608315

    Article  PubMed  Google Scholar 

  105. Peng H, Ong YM, Shah WA, Holland PC, Carbonetto S (2013) Integrins regulate centrosome integrity and astrocyte polarization following a wound. Dev Neurobiol 73(5):333–353. https://doi.org/10.1002/dneu.22055

    Article  CAS  PubMed  Google Scholar 

  106. Hoda MN, Bhatia K, Hafez SS, Johnson MH, Siddiqui S, Ergul A, Zaidi SK, Fagan SC, Hess DC (2014) Remote ischemic perconditioning is effective after embolic stroke in ovariectomized female mice. Transl Stroke Res 5(4):484–490. https://doi.org/10.1007/s12975-013-0318-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Yang J, Balkaya M, Beltran C, Heo JH, Cho S (2019) Remote postischemic conditioning promotes stroke recovery by shifting circulating monocytes to CCR2 Proinflammatory subset. J Neurosci 39(39):7778–7789. https://doi.org/10.1523/jneurosci.2699-18.2019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Hato T, Zollman A, Plotkin Z, El-Achkar TM, Maier BF, Pay SL, Dube S, Cabral P, Yoshimoto M, McClintick J, Dagher PC (2018) Endotoxin preconditioning reprograms S1 tubules and macrophages to protect the kidney. J Am Soc Nephrol 29(1):104–117. https://doi.org/10.1681/asn.2017060624

    Article  CAS  PubMed  Google Scholar 

  109. Bao Y, Kim E, Bhosle S, Mehta H, Cho S (2010) A role for spleen monocytes in post-ischemic brain inflammation and injury. J Neuroinflammation 7:92. https://doi.org/10.1186/1742-2094-7-92

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Hou J, Yang X, Li S, Cheng Z, Wang Y, Zhao J, Zhang C, Li Y, Luo M, Ren H, Liang J, Wang J, Wang J, Qin J (2019) Accessing neuroinflammation sites: monocyte/neutrophil-mediated drug delivery for cerebral ischemia. Sci Adv 5(7):eaau8301. https://doi.org/10.1126/sciadv.aau8301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Taj SH, Kho W, Aswendt M, Collmann FM, Green C, Adamczak J, Tennstaedt A, Hoehn M (2016) Dynamic modulation of microglia/macrophage polarization by miR-124 after focal cerebral ischemia. J NeuroImmune Pharmacol 11(4):733–748. https://doi.org/10.1007/s11481-016-9700-y

    Article  Google Scholar 

  112. Fumagalli S, Perego C, Pischiutta F, Zanier ER, De Simoni M-G (2015) The ischemic environment drives microglia and macrophage function. Front Neurol 6:81. https://doi.org/10.3389/fneur.2015.00081

    Article  PubMed  PubMed Central  Google Scholar 

  113. Amantea D, Certo M, Petrelli F, Tassorelli C, Micieli G, Corasaniti MT, Puccetti P, Fallarino F, Bagetta G (2016) Azithromycin protects mice against ischemic stroke injury by promoting macrophage transition towards M2 phenotype. Exp Neurol 275:116–125. https://doi.org/10.1016/j.expneurol.2015.10.012

    Article  CAS  PubMed  Google Scholar 

  114. Cai W, Liu S, Hu M, Sun X, Qiu W, Zheng S, Hu X, Lu Z (2018) Post-stroke DHA treatment protects against acute ischemic brain injury by skewing macrophage polarity toward the M2 phenotype. Transl Stroke Res 9(6):669–680. https://doi.org/10.1007/s12975-018-0662-7

    Article  CAS  PubMed  Google Scholar 

  115. Jiang M, Wang H, Jin M, Yang X, Ji H, Jiang Y, Zhang H, Wu F, Wu G, Lai X, Cai L, Hu R, Xu L, Li L (2018) Exosomes from MiR-30d-5p-ADSCs reverse acute ischemic stroke-induced, autophagy-mediated brain injury by promoting M2 microglial/macrophage polarization. Cell Physiol Biochem 47(2):864–878. https://doi.org/10.1159/000490078

    Article  CAS  PubMed  Google Scholar 

  116. Liu J, Nolte K, Brook G, Liebenstund L, Weinandy A, Höllig A, Veldeman M, Willuweit A, Langen K-J, Rossaint R, Coburn M (2019) Post-stroke treatment with argon attenuated brain injury, reduced brain inflammation and enhanced M2 microglia/macrophage polarization: a randomized controlled animal study. Crit Care 23(1):198. https://doi.org/10.1186/s13054-019-2493-7

    Article  PubMed  PubMed Central  Google Scholar 

  117. Kolosowska N, Keuters MH, Wojciechowski S, Keksa-Goldsteine V, Laine M, Malm T, Goldsteins G, Koistinaho J, Dhungana H (2019) Peripheral administration of IL-13 induces anti-inflammatory microglial/macrophage responses and provides Neuroprotection in ischemic stroke. Neurotherapeutics 16(4):1304–1319. https://doi.org/10.1007/s13311-019-00761-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Ye Y, Jin T, Zhang X, Zeng Z, Ye B, Wang J, Zhong Y, Xiong X, Gu L (2019) Meisoindigo protects against focal cerebral ischemia-reperfusion injury by inhibiting NLRP3 Inflammasome activation and regulating microglia/macrophage polarization via TLR4/NF-κB signaling pathway. Front Cell Neurosci 13:553. https://doi.org/10.3389/fncel.2019.00553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Yeh C-F, Chuang T-Y, Hung Y-W, Lan M-Y, Tsai C-H, Huang H-X, Lin Y-Y (2019) Inhibition of soluble epoxide hydrolase regulates monocyte/macrophage polarization and improves neurological outcome in a rat model of ischemic stroke. Neuroreport 30(8):567–572. https://doi.org/10.1097/wnr.0000000000001248

    Article  CAS  PubMed  Google Scholar 

  120. Chen C, Chu S-F, Ai Q-D, Zhang Z, Guan F-F, Wang S-S, Dong Y-X, Zhu J, Jian W-X, Chen N-H (2019) CKLF1 aggravates focal cerebral ischemia injury at early stage partly by modulating microglia/macrophage toward M1 polarization through CCR4. Cell Mol Neurobiol 39(5):651–669. https://doi.org/10.1007/s10571-019-00669-5

    Article  CAS  PubMed  Google Scholar 

  121. Hucke S, Floßdorf J, Grützke B, Dunay IR, Frenzel K, Jungverdorben J, Linnartz B, Mack M, Peitz M, Brüstle O, Kurts C, Klockgether T, Neumann H, Prinz M, Wiendl H, Knolle P, Klotz L (2012) Licensing of myeloid cells promotes central nervous system autoimmunity and is controlled by peroxisome proliferator-activated receptor γ. Brain 135:1586–1605. https://doi.org/10.1093/brain/aws058

    Article  PubMed  Google Scholar 

  122. Hu X, Leak RK, Shi Y, Suenaga J, Gao Y, Zheng P, Chen J (2015) Microglial and macrophage polarization—new prospects for brain repair. Nat Rev Neurol 11(1):56–64. https://doi.org/10.1038/nrneurol.2014.207

    Article  PubMed  Google Scholar 

  123. Wang Y, Luo Y, Yao Y, Ji Y, Feng L, Du F, Zheng X, Tao T, Zhai X, Li Y, Han P, Xu B, Zhao H (2020) MaclpilSilencing the lncRNA in pro-inflammatory macrophages attenuates acute experimental ischemic stroke via LCP1 in mice. J Cereb Blood Flow Metab 40(4):747–759. https://doi.org/10.1177/0271678x19836118

    Article  CAS  PubMed  Google Scholar 

  124. Lin J-N, Lin C-L, Lin M-C, Lai C-H, Lin H-H, Yang C-H, Kao C-H (2015) Increased risk of hemorrhagic and ischemic strokes in patients with splenic injury and Splenectomy: a Nationwide cohort study. Medicine 94(35):e1458. https://doi.org/10.1097/md.0000000000001458

    Article  PubMed  PubMed Central  Google Scholar 

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This study was financially supported by the Natural Science Foundation of Liaoning Province (No. 20170541053).

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Han, D., Liu, H. & Gao, Y. The role of peripheral monocytes and macrophages in ischemic stroke. Neurol Sci 41, 3589–3607 (2020). https://doi.org/10.1007/s10072-020-04777-9

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