CoChat
Sign Up
Cited by 54Neuroinflammation and Neurodegeneration MechanismsImmune cells in cancerAcute Ischemic Stroke Management

CD8 signaling in microglia/macrophage M1 polarization in a rat model of cerebral ischemia

Open access
Boddaert, Jan, Bielen, Kenny, ’s Jongers, Bart, Manocha, Ekta, Yperzeele, Laetitia, Cras, Patrick, Pirici, Daniel, Kumar-Singh, Samir·2018·PLOS ONE
DOI 10.1371/journal.pone.0186937PMC PMC5771556
Open this paper in CoChat — free accountOpen PDF

Abstract

Classical or M1 activity of microglia/macrophages has been described in several neurodegenerative and brain inflammatory conditions and has also been linked to expansion of ischemic injury in post-stroke brain. While different pathways of M1 polarization have been suggested to occur in the post-stroke brain, the precise underlying mechanisms remain undefined. Using a transient middle cerebral artery occlusion (MCAO) rat model, we showed a progressive M2 to M1 polarization in the perilesional brain region with M1 cells becoming one of the dominant subsets by day 4 post-stroke. Comparing key receptors involved in M1 polarization (CD8, IFNγR, Clec4, FcγR, TLR3 and TLR4) and their signal transducers (Syk, Stat1, Irf3, and Traf6) at the day 4 time point, we showed a strong upregulation of CD8 along with SYK transducer in dissected perilesional brain tissue. We further showed that CD8 expression in the post-stroke brain was associated with activated (CD68+) macrophages and that progressive accumulation of CD8+CD68+ cells in the post-stroke brain coincided with increased iNOS (M1 marker) and reduced Arg1 (M2 marker) expression on these cells. In vitro ligand-based stimulation of the CD8 receptor caused increased iNOS expression and an enhanced capacity to phagocytose E. coli particles; and interestingly, CD8 stimulation was also able to repolarize IL4-treated M2 cells to an M1 phenotype. Our data suggest that increased CD8 signaling in the post-stroke brain is primarily associated with microglia/macrophages and can independently drive M1 polarization, and that modulation of CD8 signaling could be a potential target to limit secondary post-stroke brain damage.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1371/journal.pone.0186937

Cites

3 of 3 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 47

  1. [1]Iadecola C, Anrather J. The immunology of stroke: from mechanisms to translation. Nature medicine. 2011 7 07; 17(7): 796– 808. doi: 10.1038/nm.2399 21738161 PMC3137275 · DOI · Paper page
  2. [2]Stoll G, Jander S, Schroeter M. Inflammation and glial responses in ischemic brain lesions. Progress in neurobiology. 1998 10; 56(2): 149– 71. 9760699
  3. [3]Sladojevic N, Stamatovic SM, Keep RF, Grailer JJ, Sarma JV, Ward PA, et al Inhibition of junctional adhesion molecule-A/LFA interaction attenuates leukocyte trafficking and inflammation in brain ischemia/reperfusion injury. Neurobiology of disease. 2014 7; 67: 57– 70. doi: 10.1016/j.nbd.2014.03.010 24657919 PMC4273560 · DOI
  4. [4]Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM. M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol. 2000 6 15; 164(12): 6166– 73. 10843666
  5. [5]Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG. Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. The Journal of Neuroscience. 2009 10 28; 29(43): 13435– 44. doi: 10.1523/JNEUROSCI.3257-09.2009 19864556 PMC2788152 · DOI · Paper page
  6. [6]Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, et al Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014 7 17; 41(1): 14– 20. doi: 10.1016/j.immuni.2014.06.008 25035950 PMC4123412 · DOI · Paper page
  7. [7]Clausen BH, Lambertsen KL, Babcock AA, Holm TH, Dagnaes-Hansen F, Finsen B. Interleukin-1beta and tumor necrosis factor-alpha are expressed by different subsets of microglia and macrophages after ischemic stroke in mice. Journal of neuroinflammation. 2008; 5: 46 doi: 10.1186/1742-2094-5-46 18947400 PMC2585073 · DOI
  8. [8]Xu Y, Qian L, Zong G, Ma K, Zhu X, Zhang H, et al Class A scavenger receptor promotes cerebral ischemic injury by pivoting microglia/macrophage polarization. Neuroscience. 2012 8 30; 218: 35– 48. doi: 10.1016/j.neuroscience.2012.05.036 22652221 · DOI
  9. [9]Frieler RA, Meng H, Duan SZ, Berger S, Schutz G, He Y, et al Myeloid-specific deletion of the mineralocorticoid receptor reduces infarct volume and alters inflammation during cerebral ischemia. Stroke. 2011 1; 42(1): 179– 85. doi: 10.1161/STROKEAHA.110.598441 21106954 PMC3042719 · DOI
  10. [10]Han Z, Shen F, He Y, Degos V, Camus M, Maze M, et al Activation of alpha-7 nicotinic acetylcholine receptor reduces ischemic stroke injury through reduction of pro-inflammatory macrophages and oxidative stress. PloS one. 2014; 9(8): e105711 doi: 10.1371/journal.pone.0105711 25157794 PMC4144901 · DOI
  11. [11]Gliem M, Schwaninger M, Jander S. Protective features of peripheral monocytes/macrophages in stroke. Biochimica et biophysica acta. 2016 3; 1862(3): 329– 38. doi: 10.1016/j.bbadis.2015.11.004 26584587 · DOI · Paper page
  12. [12]Wattananit S, Tornero D, Graubardt N, Memanishvili T, Monni E, Tatarishvili J, et al Monocyte-Derived Macrophages Contribute to Spontaneous Long-Term Functional Recovery after Stroke in Mice. The Journal of Neuroscience. 2016 4 13; 36(15): 4182– 95. doi: 10.1523/JNEUROSCI.4317-15.2016. 27076418 PMC6601783 · DOI
  13. [13]Prass K, Meisel C, Hoflich C, Braun J, Halle E, Wolf T, et al Stroke-induced immunodeficiency promotes spontaneous bacterial infections and is mediated by sympathetic activation reversal by poststroke T helper cell type 1-like immunostimulation. The Journal of Experimental Medicine. 2003 9 1; 198(5): 725– 36. doi: 10.1084/jem.20021098 12939340 PMC2194193 · DOI
  14. [14]Hu X, Li P, Guo Y, Wang H, Leak RK, Chen S, et al Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke. 2012 11; 43(11): 3063– 70. doi: 10.1161/STROKEAHA.112.659656 22933588 · DOI
  15. [15]Chernykh ER, Shevela EY, Starostina NM, Morozov SA, Davydova MN, Menyaeva EV, et al Safety and therapeutic potential of M2-macrophages in stroke treatment. Cell transplantation. 2015 12 14 doi: 10.3727/096368915X690279. 26671426 · DOI
  16. [16]Yang J, Ding S, Huang W, Hu J, Huang S, Zhang Y, et al Interleukin-4 Ameliorates the Functional Recovery of Intracerebral Hemorrhage Through the Alternative Activation of Microglia/Macrophage. Frontiers in neuroscience. 2016; 10: 61 doi: 10.3389/fnins.2016.00061 27013935 PMC4781843 · DOI
  17. [17]Hu X, Herrero C, Li WP, Antoniv TT, Falck-Pedersen E, Koch AE, et al Sensitization of IFN-gamma Jak-STAT signaling during macrophage activation. Nature immunology. 2002 9; 3(9): 859– 66. doi: 10.1038/ni828 12172544 · DOI
  18. [18]Hirji N, Lin TJ, Befus AD. A novel CD8 molecule expressed by alveolar and peritoneal macrophages stimulates nitric oxide production. Journal of immunology. 1997 2 15; 158(4): 1833– 40. 9029123
  19. [19]Toshchakov V, Jones BW, Perera PY, Thomas K, Cody MJ, Zhang S, et al TLR4, but not TLR2, mediates IFN-beta-induced STAT1alpha/beta-dependent gene expression in macrophages. Nature immunology. 2002 4; 3(4): 392– 8. doi: 10.1038/ni774 11896392 · DOI
  20. [20]Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. The Journal of Clinical Investigation. 2012 3; 122(3): 787– 95. doi: 10.1172/JCI59643 22378047 PMC3287223 · DOI · Paper page
  21. [22]Zhang Z, Artelt M, Burnet M, Trautmann K, Schluesener HJ. Early infiltration of CD8+ macrophages/microglia to lesions of rat traumatic brain injury. Neuroscience. 2006 8 25; 141(2): 637– 44. doi: 10.1016/j.neuroscience.2006.04.027 16725271 · DOI
  22. [23]Schroeter M, Jander S, Huitinga I, Stoll G. CD8+ phagocytes in focal ischemia of the rat brain: predominant origin from hematogenous macrophages and targeting to areas of pannecrosis. Acta neuropathologica. 2001 5; 101(5): 440– 8. 11484815
  23. [24]Bielen K, s Jongers B, Malhotra-Kumar S, Jorens PG, Goossens H, Kumar-Singh S. Animal models of hospital-acquired pneumonia: current practices and future perspectives. Ann Transl Med. 2017 3; 5(6): 132 doi: 10.21037/atm.2017.03.72 28462212 PMC5395468 · DOI
  24. [25]Bielen K, s Jongers B, Boddaert J, Raju TK, Lammens C, Malhotra-Kumar S, et al Biofilm-Induced Type 2 Innate Immunity in a Cystic Fibrosis Model of Pseudomonas aeruginosa. Front Cell Infect Microbiol. 2017; 7: 274 doi: 10.3389/fcimb.2017.00274 28680858 PMC5478716 · DOI
  25. [26]Wang-Fischer Y. Manual of Stroke Models in Rats: CRC Press Taylor and Francis Group (Melbourne, Australia). 2008. (ISBN 9780849395789)
  26. [27]Garcia JH, Wagner S, Liu KF, Hu XJ. Neurological deficit and extent of neuronal necrosis attributable to middle cerebral artery occlusion in rats. Statistical validation. Stroke. 1995 4; 26(4): 627– 34. 7709410
  27. [28]Kumar-Singh S, Pirici D, McGowan E, Serneels S, Ceuterick C, Hardy J, et al Dense-core plaques in Tg2576 and PSAPP mouse models of Alzheimer's disease are centered on vessel walls. The American journal of pathology. 2005 8; 167(2): 527– 43. doi: 10.1016/S0002-9440(10)62995-1. Epub 2005/07/29. eng. 16049337 PMC1603563 · DOI
  28. [29]Pirici D, Mogoanta L, Kumar-Singh S, Pirici I, Margaritescu C, Simionescu C, et al Antibody elution method for multiple immunohistochemistry on primary antibodies raised in the same species and of the same subtype. The journal of histochemistry and cytochemistry. 2009 6; 57(6): 567– 75. doi: 10.1369/jhc.2009.953240 19223296 PMC2690408 · DOI
  29. [30]Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nature protocols. 2008; 3(6): 1101– 8. 18546601
  30. [31]Kumar-Singh S, Theuns J, Van Broeck B, Pirici D, Vennekens K, Corsmit E, et al Mean age-of-onset of familial alzheimer disease caused by presenilin mutations correlates with both increased Abeta42 and decreased Abeta40. Human mutation. 2006 7; 27(7): 686– 95. doi: 10.1002/humu.20336 16752394 · DOI
  31. [32]Mosser DM, Zhang X. Activation of murine macrophages. Current protocols in immunology / edited by Coligan John E [ et al]. 2008 11; Chapter 14: Unit 14 2. PMC2822273 19016446
  32. [33]Hill JK, Gunion-Rinker L, Kulhanek D, Lessov N, Kim S, Clark WM, et al Temporal modulation of cytokine expression following focal cerebral ischemia in mice. Brain research. 1999 2 27; 820(1–2): 45– 54. 10023029
  33. [35]Li T, Pang S, Yu Y, Wu X, Guo J, Zhang S. Proliferation of parenchymal microglia is the main source of microgliosis after ischaemic stroke. Brain. 2013 12; 136(Pt 12): 3578– 88. doi: 10.1093/brain/awt287 24154617 · DOI · Paper page
  34. [36]Jander S, Schroeter M, D'Urso D, Gillen C, Witte OW, Stoll G. Focal ischaemia of the rat brain elicits an unusual inflammatory response: early appearance of CD8+ macrophages/microglia. The European Journal of Neuroscience. 1998 2; 10(2): 680– 8. 9749729
  35. [37]Zheng XF, Hong YX, Feng GJ, Zhang GF, Rogers H, Lewis MA, et al Lipopolysaccharide-induced M2 to M1 macrophage transformation for IL-12p70 production is blocked by Candida albicans mediated up-regulation of EBI3 expression. PloS one. 2013; 8(5): e63967 doi: 10.1371/journal.pone.0063967 23724011 PMC3664618 · DOI
  36. [38]Perego C, Fumagalli S, De Simoni MG. Temporal pattern of expression and colocalization of microglia/macrophage phenotype markers following brain ischemic injury in mice. Journal of neuroinflammation. 2011; 8: 174 doi: 10.1186/1742-2094-8-174 22152337 PMC3251548 · DOI
  37. [39]Desestret V, Riou A, Chauveau F, Cho TH, Devillard E, Marinescu M, et al In vitro and in vivo models of cerebral ischemia show discrepancy in therapeutic effects of M2 macrophages. PloS one. 2013; 8(6): e67063 doi: 10.1371/journal.pone.0067063 23825621 PMC3692438 · DOI
  38. [40]Schmidt A, Strecker JK, Hucke S, Bruckmann NM, Herold M, Mack M, et al Targeting Different Monocyte/Macrophage Subsets Has No Impact on Outcome in Experimental Stroke. Stroke. 2017 4; 48(4): 1061– 9. doi: 10.1161/STROKEAHA.116.015577 28292872 · DOI
  39. [42]Chao CC, Hu S, Molitor TW, Shaskan EG, Peterson PK. Activated microglia mediate neuronal cell injury via a nitric oxide mechanism. Journal of immunology. 1992 10 15; 149(8): 2736– 41.. 1383325
  40. [43]Araki E, Forster C, Dubinsky JM, Ross ME, Iadecola C. Cyclooxygenase-2 inhibitor ns-398 protects neuronal cultures from lipopolysaccharide-induced neurotoxicity. Stroke. 2001 10; 32(10): 2370– 5.. 11588328
  41. [44]Liu B, Hong JS. Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. The Journal of pharmacology and experimental therapeutics. 2003 1; 304(1): 1– 7. doi: 10.1124/jpet.102.035048 12490568 · DOI · Paper page
  42. [45]Gibbings DJ, Marcet-Palacios M, Sekar Y, Ng MC, Befus AD. CD8 alpha is expressed by human monocytes and enhances Fc gamma R-dependent responses. BMC immunology. 2007; 8: 12 doi: 10.1186/1471-2172-8-12 17678538 PMC2000912 · DOI
  43. [46]Baba T, Ishizu A, Iwasaki S, Suzuki A, Tomaru U, Ikeda H, et al CD4+/CD8+ macrophages infiltrating at inflammatory sites: a population of monocytes/macrophages with a cytotoxic phenotype. Blood. 2006 3 1; 107(5): 2004– 12. doi: 10.1182/blood-2005-06-2345 16269616 · DOI
  44. [47]Carnevale J, Ross L, Puissant A, Banerji V, Stone RM, DeAngelo DJ, et al SYK regulates mTOR signaling in AML. Leukemia. 2013 11; 27(11): 2118– 28. doi: 10.1038/leu.2013.89 23535559 PMC4028963 · DOI
  45. [48]Dan HC, Cooper MJ, Cogswell PC, Duncan JA, Ting JP, Baldwin AS. Akt-dependent regulation of NFκB is controlled by mTOR and Raptor in association with IKK. Genes & development. 2008 6 01; 22(11): 1490– 500. 18519641 PMC2418585
  46. [49]Harari OA, Liao JK. NF-kappaB and innate immunity in ischemic stroke. Ann N Y Acad Sci. 2010 10; 1207: 32– 40. doi: 10.1111/j.1749-6632.2010.05735.x 20955423 PMC3807097 · DOI
  47. [50]Lan X, Han X, Li Q, Li Q, Gao Y, Cheng T, et al Pinocembrin protects hemorrhagic brain primarily by inhibiting toll-like receptor 4 and reducing M1 phenotype microglia. Brain, behavior, and immunity. 2016 12 20. PMC5453178 28007523

Cited by

Sorted by citations

Authors
Boddaert, J., Bielen, K., ’s Jongers, B., Manocha, E., Yperzeele, L., Cras, P., Pirici, D., & Kumar-Singh, S.
Affiliations
  • Antwerp University Hospital (BE)
  • University of Medicine and Pharmacy of Craiova (RO)
ORCID
Venue
PLOS ONE
Publisher
Public Library of Science (PLoS)
Published
2018-01-17
Volume
13
Issue
1
Pages
e0186937
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0186937
PMC
PMC5771556
OpenAlex
W2786860261
Cited by
54
References
3
Citations by year
2026: 3 · 2025: 5 · 2024: 3 · 2023: 6 · 2022: 9 · 2021: 9 · 2020: 9 · 2019: 8 · 2018: 2
FWCI
3.15
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • Universiteit Antwerpen (BOF/NOI/LP/DOCPRO 25813, BOF/NOI-FFP130265, GOA-s30729)
  • Romanian National Authority for Research and Innovation (PN-II-RU-TE-2014-4-0582)
  • Flemish Institute for Science and technology (IWT-SB111664)
  • Flemish Fund for Scientific Research (FWO- SB151525)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
Keywords
microglia, macrophages, M1 macrophage polarization, M2 polarization, cerebral ischemia, stroke, transient middle cerebral artery occlusion, Syk, inducible nitric oxide synthase, Arg1, phagocytosis, neuroinflammation
MeSH terms
Animals, Brain Ischemia, Disease Models, Animal, Female, Macrophages, Male, Cell Polarity, CD8 Antigens, Rats, Wistar, Microglia, Rats

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review