Characterization and modulation of microglial phenotypes in an animal model of severe sepsis

We aim to characterize the kinetics of early and late microglial phenotypes after systemic inflammation in an animal model of severe sepsis and the effects of minocycline on these phenotypes. Rats were subjected to CLP, and some animals were treated with minocycline (10 ug/kg) by i.c.v. administrati...

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Autores:
Michels, Monique
Rocha Abatti, Mariane
Avila, Pricila
Vieira, Andriele
Borges, Heloisa
Carvalho Junior, Celso
Wendhausen, Diogo
Gasparotto, Juciano
Tiefensee Ribeiro, Camila
Moreira, José Cláudio Fonseca
Pens Gelain, Daniel
Dal‐Pizzol, Felipe
Tipo de recurso:
Article of journal
Fecha de publicación:
2019
Institución:
Corporación Universidad de la Costa
Repositorio:
REDICUC - Repositorio CUC
Idioma:
eng
OAI Identifier:
oai:repositorio.cuc.edu.co:11323/5646
Acceso en línea:
https://hdl.handle.net/11323/5646
https://repositorio.cuc.edu.co/
Palabra clave:
M1/M2
Microglia
Inflammation
Microglial polarization
Phenotypes
Sepsis
Rights
openAccess
License
CC0 1.0 Universal
id RCUC2_0b51df88a7ea8d48318f0a4be84f8046
oai_identifier_str oai:repositorio.cuc.edu.co:11323/5646
network_acronym_str RCUC2
network_name_str REDICUC - Repositorio CUC
repository_id_str
dc.title.spa.fl_str_mv Characterization and modulation of microglial phenotypes in an animal model of severe sepsis
title Characterization and modulation of microglial phenotypes in an animal model of severe sepsis
spellingShingle Characterization and modulation of microglial phenotypes in an animal model of severe sepsis
M1/M2
Microglia
Inflammation
Microglial polarization
Phenotypes
Sepsis
title_short Characterization and modulation of microglial phenotypes in an animal model of severe sepsis
title_full Characterization and modulation of microglial phenotypes in an animal model of severe sepsis
title_fullStr Characterization and modulation of microglial phenotypes in an animal model of severe sepsis
title_full_unstemmed Characterization and modulation of microglial phenotypes in an animal model of severe sepsis
title_sort Characterization and modulation of microglial phenotypes in an animal model of severe sepsis
dc.creator.fl_str_mv Michels, Monique
Rocha Abatti, Mariane
Avila, Pricila
Vieira, Andriele
Borges, Heloisa
Carvalho Junior, Celso
Wendhausen, Diogo
Gasparotto, Juciano
Tiefensee Ribeiro, Camila
Moreira, José Cláudio Fonseca
Pens Gelain, Daniel
Dal‐Pizzol, Felipe
dc.contributor.author.spa.fl_str_mv Michels, Monique
Rocha Abatti, Mariane
Avila, Pricila
Vieira, Andriele
Borges, Heloisa
Carvalho Junior, Celso
Wendhausen, Diogo
Gasparotto, Juciano
Tiefensee Ribeiro, Camila
Moreira, José Cláudio Fonseca
Pens Gelain, Daniel
Dal‐Pizzol, Felipe
dc.subject.spa.fl_str_mv M1/M2
Microglia
Inflammation
Microglial polarization
Phenotypes
Sepsis
topic M1/M2
Microglia
Inflammation
Microglial polarization
Phenotypes
Sepsis
description We aim to characterize the kinetics of early and late microglial phenotypes after systemic inflammation in an animal model of severe sepsis and the effects of minocycline on these phenotypes. Rats were subjected to CLP, and some animals were treated with minocycline (10 ug/kg) by i.c.v. administration. Animals were killed 24 hours, 5, 10 and 30 days after sepsis induction, and serum and hippocampus were collected for subsequent analyses. Real‐time PCR was performed for M1 and M2 markers. TNF‐α, IL‐1β, IL‐6, IL‐10, CCL‐22 and nitrite/nitrate levels were measured. Immunofluorescence for IBA‐1, CD11b and arginase was also performed. We demonstrated that early after sepsis, there was a preponderant up‐regulation of M1 markers, and this was not switched to M2 phenotype markers later on. We found that up‐regulation of both M1 and M2 markers co‐existed up to 30 days after sepsis induction. In addition, minocycline induced a down‐regulation, predominantly, of M1 markers. Our results suggest early activation of M1 microglia that is followed by an overlap of both M1 and M2 phenotypes and that the beneficial effects of minocycline on sepsis‐associated brain dysfunction may be related to its effects predominantly on the M1 phenotype.
publishDate 2019
dc.date.accessioned.none.fl_str_mv 2019-11-13T15:19:40Z
dc.date.available.none.fl_str_mv 2019-11-13T15:19:40Z
dc.date.issued.none.fl_str_mv 2019-10-26
dc.type.spa.fl_str_mv Artículo de revista
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dc.identifier.issn.spa.fl_str_mv 1582-1838
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dc.identifier.uri.spa.fl_str_mv https://hdl.handle.net/11323/5646
dc.identifier.instname.spa.fl_str_mv Corporación Universidad de la Costa
dc.identifier.reponame.spa.fl_str_mv REDICUC - Repositorio CUC
dc.identifier.repourl.spa.fl_str_mv https://repositorio.cuc.edu.co/
identifier_str_mv 1582-1838
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Corporación Universidad de la Costa
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url https://hdl.handle.net/11323/5646
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dc.language.iso.none.fl_str_mv eng
language eng
dc.relation.ispartof.spa.fl_str_mv https://doi.org/10.1111/jcmm.14606
dc.relation.references.spa.fl_str_mv 1. Deng YY, Fang M, Zhu GF, et al. Role of microglia in the pathogen-esis of sepsis-associated encephalopathy. CNS Neurol Disord Drug Targets.2013;12:720‐725. 2. Michels M, Danielski LG, Dal-Pizzol F, et al. Neuroinflammation: microglial activation during sepsis. Curr Neurovasc Res. 2014;11:262-270. 3. Michels M, Vieira AS, Vuolo F, et al. The role of microglia activation in the development of sepsis-induced long-term cognitive impair-ment. Brain Behav Immun.2015;43:54‐59. 4. Michels M, Danieslki LG, Vieira A, et al. CD40-CD40 ligand path-way is a major component of acute neuroinflammation and con-tributes to long-term cognitive dysfunction after sepsis. Mol Med. 2015;26(21):219‐226. 5. Moraes CA, Santos G, Spohr TCLdSe, et al. Activated microglia‐in-duced deficits in excitatory synapses through IL- 1β: implications for cognitive impairment in sepsis. Mol Neurobiol. 2015;52(1):653‐663. 6. Hoogland ICM, Houbolt C, van Westerloo DJ, van Gool WA, van de Beek D. Systemic inflammation and microglial activation: systematic review of animal experiments. J. Neuroinflammation. 2015;12:114. 7. Sandiego CM, Gallezot JD, Pittman B, et al. Imaging robust microg-lial activation after lipopolysaccharide administration in humans with PET. Proc Natl Acad Sci U S A. 2015;112(40):12468‐12473. 8. Hanisch UK. Proteins in microglial activation: inputs and outputs by subsets. Curr Protein Pep Sci. 2013;14:3‐15. 9. Kettenmann H, Hanisch U-K, Noda M, Verkhratsky A. Physiology of microglia. Physiol Rev. 2011;91:461‐553. 10. Ransohoff RM. A polarizing question: do M1 and M2 microglia exist Nat Neurosci. 2016;19:987-991. 11. Ekdahl CT, Claasen JH, Bonde S, et al. Inflammation is detri-mental for neurogenesis in adult brain. Proc Natl Acad Sci U S A. 2003;100(23):13632-13637. 12. Butovsky O, Ziv Y, Schwartz A, et al. Microglia activated by IL-4 or IFN-γ differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol Cell Neurosci. 2006;31:149-160. 13. Roughton K, Andreasson U, Blomgren K, Kalm M. Lipopolysaccharide-induced inflammation aggravates irradiation-induced injury to the young mouse brain. Dev Neurosci. 2013;35:406‐415. 14. Nikolakopoulou AM, Dutta R, Chen Z, et al. Activated microglia en-hance neurogenesis via trypsinogen secretion. Proc Natl Acad Sci U S A. 2013;110:8714-8719. 15. Pang T, Wang J, Benicky J, et al. Minocycline ameliorates LPS‐in-duced inflammation in human monocytes by novel mechanisms in-cluding LOX-1, Nur77 and LITAF inhibition. Biochim Biophys Acta. 2012;1820:503‐510. 16. Fink MP, Heard SO. Laboratory models of sepsis and septic shock. J Surg Res. 1990;49:186-196. 17. Schwalm MT, Pasquali M, Miguel SP, et al. Acute brain inflamma-tion and oxidative damage are related to long-term cognitive defi-cits and markers of neurodegeneration in sepsis-survivor rats. Mol Neurobiol. 2014;49(1):380‐385. 18. Biff D, Petronilho F, Constantino L, et al. Correlation of acute phase inflammatory and oxidative markers with long-term cognitive im-pairment in sepsis survivors rats. Shock. 2013;40:45‐48. 19. Comim CM, Cassol-Jr OJ, Constantino LS, et al. Alterations in in-flammatory mediators, oxidative stress parameters and energetic metabolism in the brain of sepsis survivor rats. Neurochem Res. 2011;36(2):304-311. 20. Miranda KM, Espey MG, Wink DA. A rapid, simple spectrophoto-metric method for simultaneous detection of nitrate and nitrite. Nitric Oxide. 2001;5:62‐71. 21. d’Avila JC, Siqueira LD, Mazeraud A, et al. Age-related cognitive im-pairment is associated with long-term neuroinflammation and oxi-dative stress in a mouse model of episodic systemic inflammation. J Neuroinflammation. 2018;15(1):28. 22. Michels M, Ávila P, Pescador B, et al. Microglial cells depletion increases inflammation and modifies microglial phenotypes in an animal model of severe sepsis. Mol Neurobiol. 2019. https://doi.org/10.1007/s12035‐019‐1606‐2 23. Zrzavy T, Höftberger R, Berger T, et al. Pro-inflammatory activation of microglia in the brain of patients with sepsis. Neuropathol Appl Neurobiol. 2019;45(3):278‐290. 24. Martinez FO, Sica A, Mantovani A, et al. Macrophage activation and polarization. Front Biosci. 2018;13:453‐461. 25. Munder M, Eichmann K, Moran JM, et al. Th1/Th2‐regulated ex-pression of arginase isoforms in murine macrophages and dendritic cells. J Immunol. 1999;163:3771-3777. 26. Zhang W, Narayanan M, Friedlander RM. Additive neuroprotective effects of minocycline with creatine in a mouse model of ALS. Ann Neurol. 2003;53:267‐270. 27. Barichello T, Machado RA, Constantino L, et al. Antioxidant treat-ment prevented late memory impairment in an animal model of sep-sis. Crit Care Med. 2007;35(9):2186‐2190. 28. Mantovani A, Germano G, Marchesi F, et al. Cancer-promoting tumor-associated macrophages: new vistas and open questions. Eur J Immunol.2011;41:2522‐2525. 29. Zhao Q, Xie X, Fan Y, et al. Phenotypic dysregulation of microglial activation in young offspring rats with maternal sleep deprivation-induced cognitive impairment. Sci Rep. 2015;5:9513. 30. Hoeger S, Bergstraesser C, Selhorst J, et al. Modulation of brain dead induced inflammation by vagus nerve stimulation. Am J Transplant. 2010;10(3):477-489. 31. Schweighöfer H, Rummel C, Roth J, et al. Modulatory effects of vagal stimulation on neurophysiological parameters and the cellu-lar immune response in the rat brain during systemic inflammation. Intensive Care Med Exp. 2016;4(1):19. 32. Hunter CL, Quintero EM, Gilstrap L, Bhat NR, Granholm A-C. Minocycline protects basal forebrain cholinergic neurons from mu p75‐saporin immunotoxic lesioning. Eur J Neurosci. 2004;19(12):3305‐3316. 33. Jeremias IC, Victorino VJ, Barbeiro HV, et al. The role of ace-tylcholine in the inflammatory response in animals surviving sepsis induced by cecal ligation and puncture. Mol Neurobiol. 2016;53(10):6635‐6643. 34. Adembri C, Selmi V, Vitali L, et al. Minocycline but not tigecycline is neuroprotective and reduces the neuroinflammatory response in-duced by the superimposition of sepsis upon traumatic brain injury. Crit Care Med. 2014;42(8):e570‐e582. 35. Hoshino K, Hayakawa M, Morimoto Y. Minocycline prevents the impairment of hippocampal long-term potentiation in the septic mouse. Shock. 2017;48(2):209-214. 36. Michels M, Steckert AV, Quevedo J, Barichello T, Dal-Pizzol F. Mechanisms of long-term cognitive dysfunction of sepsis: from blood-borne leukocytes to glial cells. Intensive Care Med Exp. 2015c;3(1):30.
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spelling Michels, MoniqueRocha Abatti, MarianeAvila, PricilaVieira, AndrieleBorges, HeloisaCarvalho Junior, CelsoWendhausen, DiogoGasparotto, JucianoTiefensee Ribeiro, CamilaMoreira, José Cláudio FonsecaPens Gelain, DanielDal‐Pizzol, Felipe2019-11-13T15:19:40Z2019-11-13T15:19:40Z2019-10-261582-18381582-4934https://hdl.handle.net/11323/5646Corporación Universidad de la CostaREDICUC - Repositorio CUChttps://repositorio.cuc.edu.co/We aim to characterize the kinetics of early and late microglial phenotypes after systemic inflammation in an animal model of severe sepsis and the effects of minocycline on these phenotypes. Rats were subjected to CLP, and some animals were treated with minocycline (10 ug/kg) by i.c.v. administration. Animals were killed 24 hours, 5, 10 and 30 days after sepsis induction, and serum and hippocampus were collected for subsequent analyses. Real‐time PCR was performed for M1 and M2 markers. TNF‐α, IL‐1β, IL‐6, IL‐10, CCL‐22 and nitrite/nitrate levels were measured. Immunofluorescence for IBA‐1, CD11b and arginase was also performed. We demonstrated that early after sepsis, there was a preponderant up‐regulation of M1 markers, and this was not switched to M2 phenotype markers later on. We found that up‐regulation of both M1 and M2 markers co‐existed up to 30 days after sepsis induction. In addition, minocycline induced a down‐regulation, predominantly, of M1 markers. Our results suggest early activation of M1 microglia that is followed by an overlap of both M1 and M2 phenotypes and that the beneficial effects of minocycline on sepsis‐associated brain dysfunction may be related to its effects predominantly on the M1 phenotype.Michels, Monique-will be generated-orcid-0000-0001-8440-1976-600Rocha Abatti, MarianeAvila, Pricila-will be generated-orcid-0000-0001-9490-1448-600Vieira, AndrieleBorges, Heloisa-will be generated-orcid-0000-0003-0316-2382-600Carvalho Junior, CelsoWendhausen, DiogoGasparotto, Juciano-will be generated-orcid-0000-0003-2545-7288-600Tiefensee Ribeiro, CamilaMoreira, José Cláudio Fonseca-will be generated-orcid-0000-0002-0619-4913-600Pens Gelain, DanielDal‐Pizzol, FelipeengJournal of Cellular and Molecular Medicinehttps://doi.org/10.1111/jcmm.146061. Deng YY, Fang M, Zhu GF, et al. Role of microglia in the pathogen-esis of sepsis-associated encephalopathy. CNS Neurol Disord Drug Targets.2013;12:720‐725. 2. Michels M, Danielski LG, Dal-Pizzol F, et al. Neuroinflammation: microglial activation during sepsis. Curr Neurovasc Res. 2014;11:262-270. 3. Michels M, Vieira AS, Vuolo F, et al. The role of microglia activation in the development of sepsis-induced long-term cognitive impair-ment. Brain Behav Immun.2015;43:54‐59. 4. Michels M, Danieslki LG, Vieira A, et al. CD40-CD40 ligand path-way is a major component of acute neuroinflammation and con-tributes to long-term cognitive dysfunction after sepsis. Mol Med. 2015;26(21):219‐226. 5. Moraes CA, Santos G, Spohr TCLdSe, et al. Activated microglia‐in-duced deficits in excitatory synapses through IL- 1β: implications for cognitive impairment in sepsis. Mol Neurobiol. 2015;52(1):653‐663. 6. Hoogland ICM, Houbolt C, van Westerloo DJ, van Gool WA, van de Beek D. Systemic inflammation and microglial activation: systematic review of animal experiments. J. Neuroinflammation. 2015;12:114. 7. Sandiego CM, Gallezot JD, Pittman B, et al. Imaging robust microg-lial activation after lipopolysaccharide administration in humans with PET. Proc Natl Acad Sci U S A. 2015;112(40):12468‐12473. 8. Hanisch UK. Proteins in microglial activation: inputs and outputs by subsets. Curr Protein Pep Sci. 2013;14:3‐15. 9. Kettenmann H, Hanisch U-K, Noda M, Verkhratsky A. Physiology of microglia. Physiol Rev. 2011;91:461‐553. 10. Ransohoff RM. A polarizing question: do M1 and M2 microglia exist Nat Neurosci. 2016;19:987-991. 11. Ekdahl CT, Claasen JH, Bonde S, et al. Inflammation is detri-mental for neurogenesis in adult brain. Proc Natl Acad Sci U S A. 2003;100(23):13632-13637. 12. Butovsky O, Ziv Y, Schwartz A, et al. Microglia activated by IL-4 or IFN-γ differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol Cell Neurosci. 2006;31:149-160. 13. Roughton K, Andreasson U, Blomgren K, Kalm M. Lipopolysaccharide-induced inflammation aggravates irradiation-induced injury to the young mouse brain. Dev Neurosci. 2013;35:406‐415. 14. Nikolakopoulou AM, Dutta R, Chen Z, et al. Activated microglia en-hance neurogenesis via trypsinogen secretion. Proc Natl Acad Sci U S A. 2013;110:8714-8719. 15. Pang T, Wang J, Benicky J, et al. Minocycline ameliorates LPS‐in-duced inflammation in human monocytes by novel mechanisms in-cluding LOX-1, Nur77 and LITAF inhibition. Biochim Biophys Acta. 2012;1820:503‐510. 16. Fink MP, Heard SO. Laboratory models of sepsis and septic shock. J Surg Res. 1990;49:186-196. 17. Schwalm MT, Pasquali M, Miguel SP, et al. Acute brain inflamma-tion and oxidative damage are related to long-term cognitive defi-cits and markers of neurodegeneration in sepsis-survivor rats. Mol Neurobiol. 2014;49(1):380‐385. 18. Biff D, Petronilho F, Constantino L, et al. Correlation of acute phase inflammatory and oxidative markers with long-term cognitive im-pairment in sepsis survivors rats. Shock. 2013;40:45‐48. 19. Comim CM, Cassol-Jr OJ, Constantino LS, et al. Alterations in in-flammatory mediators, oxidative stress parameters and energetic metabolism in the brain of sepsis survivor rats. Neurochem Res. 2011;36(2):304-311. 20. Miranda KM, Espey MG, Wink DA. A rapid, simple spectrophoto-metric method for simultaneous detection of nitrate and nitrite. Nitric Oxide. 2001;5:62‐71. 21. d’Avila JC, Siqueira LD, Mazeraud A, et al. Age-related cognitive im-pairment is associated with long-term neuroinflammation and oxi-dative stress in a mouse model of episodic systemic inflammation. J Neuroinflammation. 2018;15(1):28. 22. Michels M, Ávila P, Pescador B, et al. Microglial cells depletion increases inflammation and modifies microglial phenotypes in an animal model of severe sepsis. Mol Neurobiol. 2019. https://doi.org/10.1007/s12035‐019‐1606‐2 23. Zrzavy T, Höftberger R, Berger T, et al. Pro-inflammatory activation of microglia in the brain of patients with sepsis. Neuropathol Appl Neurobiol. 2019;45(3):278‐290. 24. Martinez FO, Sica A, Mantovani A, et al. Macrophage activation and polarization. Front Biosci. 2018;13:453‐461. 25. Munder M, Eichmann K, Moran JM, et al. Th1/Th2‐regulated ex-pression of arginase isoforms in murine macrophages and dendritic cells. J Immunol. 1999;163:3771-3777. 26. Zhang W, Narayanan M, Friedlander RM. Additive neuroprotective effects of minocycline with creatine in a mouse model of ALS. Ann Neurol. 2003;53:267‐270. 27. Barichello T, Machado RA, Constantino L, et al. Antioxidant treat-ment prevented late memory impairment in an animal model of sep-sis. Crit Care Med. 2007;35(9):2186‐2190. 28. Mantovani A, Germano G, Marchesi F, et al. Cancer-promoting tumor-associated macrophages: new vistas and open questions. Eur J Immunol.2011;41:2522‐2525. 29. Zhao Q, Xie X, Fan Y, et al. Phenotypic dysregulation of microglial activation in young offspring rats with maternal sleep deprivation-induced cognitive impairment. Sci Rep. 2015;5:9513. 30. Hoeger S, Bergstraesser C, Selhorst J, et al. Modulation of brain dead induced inflammation by vagus nerve stimulation. Am J Transplant. 2010;10(3):477-489. 31. Schweighöfer H, Rummel C, Roth J, et al. Modulatory effects of vagal stimulation on neurophysiological parameters and the cellu-lar immune response in the rat brain during systemic inflammation. Intensive Care Med Exp. 2016;4(1):19. 32. Hunter CL, Quintero EM, Gilstrap L, Bhat NR, Granholm A-C. Minocycline protects basal forebrain cholinergic neurons from mu p75‐saporin immunotoxic lesioning. Eur J Neurosci. 2004;19(12):3305‐3316. 33. Jeremias IC, Victorino VJ, Barbeiro HV, et al. The role of ace-tylcholine in the inflammatory response in animals surviving sepsis induced by cecal ligation and puncture. Mol Neurobiol. 2016;53(10):6635‐6643. 34. Adembri C, Selmi V, Vitali L, et al. Minocycline but not tigecycline is neuroprotective and reduces the neuroinflammatory response in-duced by the superimposition of sepsis upon traumatic brain injury. Crit Care Med. 2014;42(8):e570‐e582. 35. Hoshino K, Hayakawa M, Morimoto Y. Minocycline prevents the impairment of hippocampal long-term potentiation in the septic mouse. Shock. 2017;48(2):209-214. 36. Michels M, Steckert AV, Quevedo J, Barichello T, Dal-Pizzol F. Mechanisms of long-term cognitive dysfunction of sepsis: from blood-borne leukocytes to glial cells. 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