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.
Similar content being viewed by others
References
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
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
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
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
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
Chiba T, Umegaki K (2013) Pivotal roles of monocytes/macrophages in stroke. Mediat Inflamm 2013:759103–759110. https://doi.org/10.1155/2013/759103
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Pekny M, Nilsson M (2005) Astrocyte activation and reactive gliosis. Glia 50(4):427–434. https://doi.org/10.1002/glia.20207
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Funding
This study was financially supported by the Natural Science Foundation of Liaoning Province (No. 20170541053).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no competing interest.
Ethical approval
Not applicable.
Informed consent
Not applicable.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10072-020-04777-9