Advertisement

Translational Stroke Research

, Volume 10, Issue 4, pp 440–448 | Cite as

Preconditioning in the Rhesus Macaque Induces a Proteomic Signature Following Cerebral Ischemia that Is Associated with Neuroprotection

  • Susan L. Stevens
  • Tao Liu
  • Frances Rena Bahjat
  • Vladislav A. Petyuk
  • Athena A. Schepmoes
  • Ryan L. Sontag
  • Marina A. Gritsenko
  • Chaochao Wu
  • Sheng Wang
  • Anil K. Shukla
  • Jon M. Jacobs
  • Richard D. Smith
  • Karin D. Rodland
  • G. Alexander West
  • Steven G. Kohama
  • Christine Glynn
  • Mary P. Stenzel-PooreEmail author
Original Article

Abstract

Each year, thousands of patients are at risk of cerebral ischemic injury, due to iatrogenic responses to surgical procedures. Prophylactic treatment of these patients as standard care could minimize potential neurological complications. We have shown that protection of brain tissue, in a non-human primate model of cerebral ischemic injury, is possible through pharmacological preconditioning using the immune activator D192935. We postulate that preconditioning with D192935 results in neuroprotective reprogramming that is evident in the brain following experimentally induced cerebral ischemia. We performed quantitative proteomic analysis of cerebral spinal fluid (CSF) collected post-stroke from our previously published efficacy study to determine whether CSF protein profiles correlated with induced protection. Four groups of animals were examined: naïve animals (no treatment or stroke); animals treated with vehicle prior to stroke; D192935 treated and stroked animals, further delineated into two groups, ones that were protected (small infarcts) and those that were not protected (large infarcts). We found that distinct protein clusters defined the protected and non-protected animal groups, with a 16-member cluster of proteins induced exclusively in D192935 protected animals. Seventy percent of the proteins induced in the protected animals have functions that would enhance neuroprotection and tissue repair, including several members associated with M2 macrophages, a macrophage phenotype shown to contribute to neuroprotection and repair during ischemic injury. These studies highlight the translational importance of CSF biomarkers in defining mechanism and monitoring responses to treatment in development of stroke therapeutics.

Keywords

Neuroprotection Non-human primates Stroke Proteomics Cerebral spinal fluid 

Notes

Acknowledgements

The proteomics work described herein was performed in the Environmental Molecular Sciences Laboratory, a U.S. Department of Energy (DOE) national scientific user facility located at PNNL in Richland, Washington. PNNL is a multi-program national laboratory operated by Battelle Memorial Institute for the DOE under Contract DE-AC05-76RL01830.

Funding

This work was supported by National Institutes of Health grants NS064953 (MSP, SGK), OD011092 (SGK), and P41GM103493 (RDS).

Compliance with Ethical Standards

Conflict of Interest

All authors declare that they have no conflict of interest.

Ethical Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.

Supplementary material

12975_2018_670_MOESM1_ESM.pdf (899 kb)
Supplemental Fig. 1 (PDF 899 kb)
12975_2018_670_MOESM2_ESM.pdf (25 kb)
Supplemental Table 1 (PDF 24 kb)
12975_2018_670_MOESM3_ESM.xlsx (713 kb)
Supplemental Table 2 (XLSX 713 kb)
12975_2018_670_MOESM4_ESM.xlsx (940 kb)
Supplemental Table 3 (XLSX 939 kb)
12975_2018_670_MOESM5_ESM.xlsx (498 kb)
Supplemental Table 4 (XLSX 498 kb)
12975_2018_670_MOESM6_ESM.xlsx (127 kb)
Supplemental Table 5 (XLSX 127 kb)
12975_2018_670_MOESM7_ESM.xlsx (14 kb)
Supplemental Table 6 (XLSX 13 kb)

References

  1. 1.
    Bonati LH, Jongen LM, Haller S, Flach HZ, Dobson J, Nederkoorn PJ, et al. New ischaemic brain lesions on MRI after stenting or endarterectomy for symptomatic carotid stenosis: a substudy of the International Carotid Stenting Study (ICSS). Lancet Neurol. 2010;9:353–62.CrossRefGoogle Scholar
  2. 2.
    Sun X, Lindsay J, Monsein LH, Hill PC, Corso PJ. Silent brain injury after cardiac surgery: a review: cognitive dysfunction and magnetic resonance imaging diffusion-weighted imaging findings. J Am Coll Cardiol. 2012;60:791–7.CrossRefGoogle Scholar
  3. 3.
    Bendszus M, Stoll G. Silent cerebral ischaemia: hidden fingerprints of invasive medical procedures. Lancet Neurol. 2006;5:364–72.CrossRefGoogle Scholar
  4. 4.
    Kahlert P, Al-Rashid F, Dottger P, Mori K, Plicht B, Wendt D, et al. Cerebral embolization during transcatheter aortic valve implantation: a transcranial Doppler study. Circulation. 2012;126:1245–55.CrossRefGoogle Scholar
  5. 5.
    Rosenkranz M, Gerloff C. New ischemic brain lesions after carotid artery stenting. J Cardiovasc Surg. 2013;54:93–9.Google Scholar
  6. 6.
    Shibazaki K, Iguchi Y, Kimura K, Ueno Y, Inoue T. New asymptomatic ischemic lesions on diffusion-weighted imaging after cerebral angiography. J Neurol Sci. 2008;266:150–5.CrossRefGoogle Scholar
  7. 7.
    Sun S, Zhang X, Tough DF, Sprent J. Type I interferon-mediated stimulation of T cells by CpG DNA. J Exp Med. 1998;188:2335–42.CrossRefGoogle Scholar
  8. 8.
    Dirnagl U, Simon RP, Hallenbeck JM. Ischemic tolerance and endogenous neuroprotection. Trends in Neuroscience. 2003;26:248–54.CrossRefGoogle Scholar
  9. 9.
    Bahjat FR, Williams-Karnesky RL, Kohama SG, West GA, Doyle KP, Spector MD, et al. Proof of concept: pharmacological preconditioning with a Toll-like receptor agonist protects against cerebrovascular injury in a primate model of stroke. J Cereb Blood Flow Metab. 2011;31:1229–42.CrossRefGoogle Scholar
  10. 10.
    Brown JM, Grosso MA, Terada LS, Whitman GJ, Banerjee A, White CW, et al. Endotoxin pretreatment increases endogenous myocardial catalase activity and decreases ischemia-reperfusion injury of isolated rat hearts. Proc Natl Acad Sci U S A. 1989;86:2516–20.CrossRefGoogle Scholar
  11. 11.
    Dave KR, Saul I, Prado R, Busto R, Perez-Pinzon MA. Remote organ ischemic preconditioning protect brain from ischemic damage following asphyxial cardiac arrest. Neurosci Lett. 2006;404:170–5.CrossRefGoogle Scholar
  12. 12.
    Packard AE, Hedges JC, Bahjat FR, Stevens SL, Conlin MJ, Salazar AM, et al. Poly-IC preconditioning protects against cerebral and renal ischemia-reperfusion injury. J Cereb Blood Flow Metab. 2012;32:242–7.CrossRefGoogle Scholar
  13. 13.
    Hausenloy DJ, Mwamure PK, Venugopal V, Harris J, Barnard M, Grundy E, et al. Effect of remote ischaemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery: a randomised controlled trial. Lancet. 2007;370:575–9.CrossRefGoogle Scholar
  14. 14.
    Hausenloy DJ, Kharbanda R, Rahbek Schmidt M, Møller UK, Ravkilde J, Okkels Jensen L, et al. Effect of remote ischaemic conditioning on clinical outcomes in patients presenting with an ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Eur Heart J. 2015;36:1846–8.Google Scholar
  15. 15.
    Meybohm P, Bein B, Brosteanu O, Cremer J, Gruenewald M, Stoppe C, et al. A multicenter trial of remote ischemic preconditioning for heart surgery. N Engl J Med. 2015;373:1397–407.CrossRefGoogle Scholar
  16. 16.
    Bahjat FR, West GA, Kohama SG, Glynn C, Urbanski HF, Hobbs TR, et al. Preclinical development of a prophylactic neuroprotective therapy for the preventive treatment of anticipated ischemia-reperfusion injury. Transl Stroke Res. 2017;8:322–33.CrossRefGoogle Scholar
  17. 17.
    Stevens SL, Ciesielski TM, Marsh BJ, Yang T, Homen DS, Boule JL, et al. Toll-like receptor 9: a new target of ischemic preconditioning in the brain. J Cereb Blood Flow Metab. 2008;28:1040–7.CrossRefGoogle Scholar
  18. 18.
    Stevens SL, Leung PY, Vartanian KB, Gopalan B, Yang T, Simon RP, et al. Multiple preconditioning paradigms converge on interferon regulatory factor-dependent signaling to promote tolerance to ischemic brain injury. J Neurosci. 2011;31:8456–63.CrossRefGoogle Scholar
  19. 19.
    Aluise CD, Sowell RA, Butterfield DA. Peptides and proteins in plasma and cerebrospinal fluid as biomarkers for the prediction, diagnosis, and monitoring of therapeutic efficacy of Alzheimer’s disease. Biochim Biophys Acta. 1782;2008:549–58.Google Scholar
  20. 20.
    Novakova L, Axelsson M, Khademi M, Zetterberg H, Blennow K, Malmeström C, et al. Cerebrospinal fluid biomarkers as a measure of disease activity and treatment efficacy in relapsing-remitting multiple sclerosis. J Neurochem. 2017;141:296–304.CrossRefGoogle Scholar
  21. 21.
    Jung CS, Lange B, Zimmermann M, Seifert V. CSF and serum biomarkers focusing on cerebral vasospasm and ischemia after subarachnoid hemorrhage. Stroke Res Treat. 2013;2013:560305.Google Scholar
  22. 22.
    Mertens JC, Leenaerts D, Brouns R, Engelborghs S, Ieven M, De Deyn PP, et al. Procarboxypeptidase U (proCPU, TAFI, proCPB2) in cerebrospinal fluid during ischemic stroke is associated with stroke progression, outcome and blood-brain barrier dysfunction. J Thromb Haemost. 2018;16:342–8.CrossRefGoogle Scholar
  23. 23.
    Zhang Y, Fan F, Zeng G, Zhou L, Zhang Y, Zhang J, et al. Temporal analysis of blood-brain barrier disruption and cerebrospinal fluid matrix metalloproteinases in rhesus monkeys subjected to transient ischemic stroke. J Cereb Blood Flow Metab. 2017;37:2963–74.CrossRefGoogle Scholar
  24. 24.
    Thompson A, Schäfer J, Kuhn K, Kienle S, Schwarz J, Schmidt G, et al. Tandem mass tags: a novel quantification strategy for comparative analysis of complex protein mixtures by MS/MS. Anal Chem. 2003;75:1895–904.CrossRefGoogle Scholar
  25. 25.
    Wang Y, Yang F, Gritsenko MA, Wang Y, Clauss T, Liu T, et al. Reversed-phase chromatography with multiple fraction concatenation strategy for proteome profiling of human MCF10A cells. Proteomics. 2011;11:2019–26.CrossRefGoogle Scholar
  26. 26.
    Kim S, Pevzner PA. MS-GF+ makes progress towards a universal database search tool for proteomics. Nat Commun. 2014;5:5277.CrossRefGoogle Scholar
  27. 27.
    Monroe ME, Shaw JL, Daly DS, Adkins JN, Smith RD. MASIC: a software program for fast quantitation and flexible visualization of chromatographic profiles from detected LC-MS(/MS) features. Comput Biol Chem. 2008;32:215–7.CrossRefGoogle Scholar
  28. 28.
    Mertins P, Mani DR, Ruggles KV, Gillette MA, Clauser KR, Wang P, et al. Proteogenomics connects somatic mutations to signalling in breast cancer. Nature. 2016;534:55–62.CrossRefGoogle Scholar
  29. 29.
    Zhang H, Liu T, Zhang Z, Payne SH, Zhang B, McDermott JE, et al. Integrated proteogenomic characterization of human high-grade serous ovarian cancer. Cell. 2016;166:755–65.CrossRefGoogle Scholar
  30. 30.
    Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43:e47.CrossRefGoogle Scholar
  31. 31.
    Storey JD, Tibshirani R. Statistical significance for genomewide studies. Proc Natl Acad Sci U S A. 2003;100:9440–5.CrossRefGoogle Scholar
  32. 32.
    Sonnhammer EL, Östlund G. InParanoid 8: orthology analysis between 273 proteomes, mostly eukaryotic. Nucleic Acids Res. 2015;43:D234–9.CrossRefGoogle Scholar
  33. 33.
    Leifer CA, Verthelyi D, Klinman DM. Heterogeneity in the human response to immunostimulatory CpG oligodeoxynucleotides. J Immunother. 2003;26:313–9.CrossRefGoogle Scholar
  34. 34.
    Hartmann G, Weeratna RD, Ballas ZK, Payette P, Blackwell S, Suparto I, et al. Delineation of a CpG phosphorothioate oligodeoxynucleotide for activating primate immune responses in vitro and in vivo. J Immunol. 2000;164:1617–24.CrossRefGoogle Scholar
  35. 35.
    Bohle B, Orel L, Kraft D, Ebner C. Oligodeoxynucleotides containing CpG motifs induce low levels of TNF-alpha in human B lymphocytes: possible adjuvants for Th1 responses. J Immunol. 2001;166:3743–8.CrossRefGoogle Scholar
  36. 36.
    Kanazawa, M., Ninomiya, I., Hatakeyama, M., Takahashi, T., and Shimohata, T. Microglia and monocytes/macrophages polarization reveal novel therapeutic mechanism against stroke. Int J Mol Sci 2017;18.Google Scholar
  37. 37.
    Amantea D, Certo M, Petrelli F, Tassorelli C, Micieli G, Corasaniti MT, et al. Azithromycin protects mice against ischemic stroke injury by promoting macrophage transition towards M2 phenotype. Exp Neurol. 2016;275(Pt 1):116–25.CrossRefGoogle Scholar
  38. 38.
    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 Transplant. 2016;25:1461–71.CrossRefGoogle Scholar
  39. 39.
    Soendergaard C, Kvist PH, Seidelin JB, Pelzer H, Nielsen OH. Systemic and intestinal levels of factor XIII-A: the impact of inflammation on expression in macrophage subtypes. J Gastroenterol. 2016;51:796–807.CrossRefGoogle Scholar
  40. 40.
    Palani S, Maksimow M, Miiluniemi M, Auvinen K, Jalkanen S, Salmi M. Stabilin-1/CLEVER-1, a type 2 macrophage marker, is an adhesion and scavenging molecule on human placental macrophages. Eur J Immunol. 2011;41:2052–63.CrossRefGoogle Scholar
  41. 41.
    Komori H, Watanabe H, Shuto T, Kodama A, Maeda H, Watanabe K, et al. α(1)-Acid glycoprotein up-regulates CD163 via TLR4/CD14 protein pathway: possible protection against hemolysis-induced oxidative stress. J Biol Chem. 2012;287:30688–700.CrossRefGoogle Scholar
  42. 42.
    Lovren F, Pan Y, Quan A, Szmitko PE, Singh KK, Shukla PC, et al. Adiponectin primes human monocytes into alternative anti-inflammatory M2 macrophages. Am J Physiol Heart Circ Physiol. 2010;299:H656–63.CrossRefGoogle Scholar
  43. 43.
    Fraser DA, Bohlson SS, Jasinskiene N, Rawal N, Palmarini G, Ruiz S, et al. C1q and MBL, components of the innate immune system, influence monocyte cytokine expression. J Leukoc Biol. 2006;80:107–16.CrossRefGoogle Scholar
  44. 44.
    Ogden CA, de Cathelineau A, Hoffmann PR, Bratton D, Ghebrehiwet B, Fadok VA, et al. C1q and mannose binding lectin engagement of cell surface calreticulin and CD91 initiates macropinocytosis and uptake of apoptotic cells. J Exp Med. 2001;194:781–95.CrossRefGoogle Scholar
  45. 45.
    Rőszer T. Understanding the mysterious M2 macrophage through activation markers and effector mechanisms. Mediat Inflamm. 2015;2015:816460.Google Scholar
  46. 46.
    de Bilbao F, Arsenijevic D, Moll T, Garcia-Gabay I, Vallet P, Langhans W, et al. In vivo over-expression of interleukin-10 increases resistance to focal brain ischemia in mice. J Neurochem. 2009;110:12–22.CrossRefGoogle Scholar
  47. 47.
    Pinteaux E, Rothwell NJ, Boutin H. Neuroprotective actions of endogenous interleukin-1 receptor antagonist (IL-1ra) are mediated by glia. Glia. 2006;53:551–6.CrossRefGoogle Scholar
  48. 48.
    Nishimura M, Izumiya Y, Higuchi A, Shibata R, Qiu J, Kudo C, et al. Adiponectin prevents cerebral ischemic injury through endothelial nitric oxide synthase dependent mechanisms. Circulation. 2008;117:216–23.CrossRefGoogle Scholar
  49. 49.
    Song W, Huo T, Guo F, Wang H, Wei H, Yang Q, et al. Globular adiponectin elicits neuroprotection by inhibiting NADPH oxidase-mediated oxidative damage in ischemic stroke. Neuroscience. 2013;248:136–44.CrossRefGoogle Scholar
  50. 50.
    Birkeland KI, Hanssen KF, Torjesen PA, Vaaler S. Level of sex hormone-binding globulin is positively correlated with insulin sensitivity in men with type 2 diabetes. J Clin Endocrinol Metab. 1993;76:275–8.Google Scholar
  51. 51.
    Tao C, Sifuentes A, Holland WL. Regulation of glucose and lipid homeostasis by adiponectin: effects on hepatocytes, pancreatic β cells and adipocytes. Best Pract Res Clin Endocrinol Metab. 2014;28:43–58.CrossRefGoogle Scholar
  52. 52.
    Schwenk RW, Dirkx E, Coumans WA, Bonen A, Klip A, Glatz JF, et al. Requirement for distinct vesicle-associated membrane proteins in insulin- and AMP-activated protein kinase (AMPK)-induced translocation of GLUT4 and CD36 in cultured cardiomyocytes. Diabetologia. 2010;53:2209–19.CrossRefGoogle Scholar
  53. 53.
    Simó R, Saez-Lopez C, Lecube A, Hernandez C, Fort JM, Selva DM. Adiponectin upregulates SHBG production: molecular mechanisms and potential implications. Endocrinology. 2014;155:2820–30.CrossRefGoogle Scholar
  54. 54.
    Glotov, A.S., Tiys, E.S., Vashukova, E.S., Pakin, V.S., Demenkov, P.S., Saik, O.V. et al. Molecular association of pathogenetic contributors to pre-eclampsia (pre-eclampsia associome). BMC Syst Biol. 2015;9 Suppl 2:S4.Google Scholar
  55. 55.
    Kzhyshkowska J, Workman G, Cardó-Vila M, Arap W, Pasqualini R, Gratchev A, et al. Novel function of alternatively activated macrophages: stabilin-1-mediated clearance of SPARC. J Immunol. 2006;176:5825–32.CrossRefGoogle Scholar
  56. 56.
    Noy PJ, Lodhia P, Khan K, Zhuang X, Ward DG, Verissimo AR, et al. Blocking CLEC14A-MMRN2 binding inhibits sprouting angiogenesis and tumour growth. Oncogene. 2015;34:5821–31.CrossRefGoogle Scholar
  57. 57.
    Conway CD, Howe KM, Nettleton NK, Price DJ, Mason JO, Pratt T. Heparan sulfate sugar modifications mediate the functions of slits and other factors needed for mouse forebrain commissure development. J Neurosci. 2011;31:1955–70.CrossRefGoogle Scholar
  58. 58.
    Guo L, Wang L, Li H, Yang X, Yang B, Li M, et al. Down regulation of GALNT3 contributes to endothelial cell injury via activation of p38 MAPK signaling pathway. Atherosclerosis. 2016;245:94–100.CrossRefGoogle Scholar
  59. 59.
    Remus EW, O’Donnell RE, Rafferty K, Weiss D, Joseph G, Csiszar K, et al. The role of lysyl oxidase family members in the stabilization of abdominal aortic aneurysms. Am J Physiol Heart Circ Physiol. 2012;303:H1067–75.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Susan L. Stevens
    • 1
  • Tao Liu
    • 2
  • Frances Rena Bahjat
    • 1
  • Vladislav A. Petyuk
    • 2
  • Athena A. Schepmoes
    • 2
  • Ryan L. Sontag
    • 2
  • Marina A. Gritsenko
    • 2
  • Chaochao Wu
    • 2
  • Sheng Wang
    • 2
  • Anil K. Shukla
    • 2
  • Jon M. Jacobs
    • 2
  • Richard D. Smith
    • 2
  • Karin D. Rodland
    • 2
  • G. Alexander West
    • 3
  • Steven G. Kohama
    • 4
  • Christine Glynn
    • 1
  • Mary P. Stenzel-Poore
    • 1
    Email author
  1. 1.Department of Molecular Microbiology and ImmunologyOregon Health & Science UniversityPortlandUSA
  2. 2.Biological Sciences DivisionPacific Northwest National LaboratoryRichlandUSA
  3. 3.Houston Methodist NeurosurgeryHoustonUSA
  4. 4.Division of NeuroscienceOregon National Primate Research CenterBeavertonUSA

Personalised recommendations