Pleiotropic Protective Effects of Progranulin in the Treatment of Ischemic Stroke

  • Masato KanazawaEmail author
  • Kunio Kawamura
  • Tetsuya Takahashi
  • Takayoshi Shimohata


Stroke is one of the leading causes of morbidity and mortality in the world. The majority of strokes is ischemic. Unfortunately, there is still not well substantial treatment option to increase the survival and alleviate the outcome after ischemic stroke. In the central nervous system, progranulin (PGRN) is considered to play important roles in the maintenance of physiological functions. Mutations in the gene that encodes PGRN cause transactive response DNA-binding protein 43-positive frontotemporal lobar degeneration. Several studies have reported that PGRN exerts protective effects against ischemic brain injury. PGRN alleviates the impairments after acute focal cerebral ischemia by a variety of mechanisms, which we call “brain protection”. This includes neuroprotection, suppression of neuroinflammation, and attenuation of blood-brain barrier disruption, i.e., vascular protection. PGRN has pleiotropic protective effects and is, therefore, an ideal candidate molecule for the therapy of stroke. We will accelerate the research towards further development of PGRN-based treatments of stroke.


Cerebral ischemia Tissue plasminogen activator Brain protection Pleiotropic protective effects 


  1. Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C et al (2006) Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442:916–919CrossRefGoogle Scholar
  2. Chiba Y, Danno S, Suto R, Suto W, Yamane Y, Hanazaki M et al (2018) Intranasal administration of recombinant progranulin inhibits bronchial smooth muscle hyperresponsiveness in mouse allergic asthma. Am J Physiol Lung Cell Mol Physiol 314:L215–L223CrossRefGoogle Scholar
  3. Chitramuthu BP, Bennett HPJ, Bateman A (2017) Progranulin: a new avenue towards the understanding and treatment of neurodegenerative disease. Brain 140:3081–3104CrossRefGoogle Scholar
  4. Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, Pirici D et al (2006) Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442:920–924CrossRefGoogle Scholar
  5. Daniel R, He Z, Carmichael KP, Halper J, Bateman A (2000) Cellular localization of gene expression for progranulin. J Histochem Cytochem 48:999–1009CrossRefGoogle Scholar
  6. Egashira Y, Suzuki Y, Azuma Y, Takagi T, Mishiro K, Sugitani S et al (2013) The growth factor progranulin attenuates neuronal injury induced by cerebral ischemia-reperfusion through the suppression of neutrophil recruitment. J Neuroinflammation 10:105CrossRefGoogle Scholar
  7. Feigin VL, Lawes CM, Bennett DA, Barker-Collo SL, Parag V (2009) Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol 8:355–369CrossRefGoogle Scholar
  8. Gao X, Joselin AP, Wang L, Kar A, Ray P, Bateman A et al (2010) Progranulin promotes neurite outgrowth and neuronal differentiation by regulating GSK-3β. Protein Cell 1:552–562CrossRefGoogle Scholar
  9. Gass J, Lee WC, Cook C, Finch N, Stetler C, Jansen-West K et al (2012) Progranulin regulates neuronal outgrowth independent of sortilin. Mol Neurodegener 7:33CrossRefGoogle Scholar
  10. Goyal M, Menon BK, van Zwam WH, Dippel DW, Mitchell PJ, Demchuk AM et al (2016) Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet 387:1723–1731CrossRefGoogle Scholar
  11. Guo Z, Li Q, Han Y, Liang Y, Xu Z, Ren T (2012) Prevention of LPS-induced acute lung injury in mice by progranulin. Mediat Inflamm 2012:540794CrossRefGoogle Scholar
  12. He Z, Ong CH, Halper J, Bateman A (2003) Progranulin is a mediator of the wound response. Nat Med 9:225–229CrossRefGoogle Scholar
  13. Jackman K, Kahles T, Lane D, Garcia-Bonilla L, Abe T, Capone C et al (2013) Progranulin deficiency promotes post-ischemic blood–brain barrier disruption. J Neurosci 33:19579–19589CrossRefGoogle Scholar
  14. Kanazawa M, Kakita A, Igarashi H, Takahashi T, Kawamura K, Takahashi H et al (2011a) Biochemical and histopathological alterations in TAR DNA binding protein-43 after acute ischemic stroke in rats. J Neurochem 116:957–965CrossRefGoogle Scholar
  15. Kanazawa M, Igarashi H, Kawamura K, Takahashi T, Kakita A, Takahashi H et al (2011b) Inhibition of VEGF signaling pathway attenuates hemorrhage after t-PA treatment. J Cereb Blood Flow Metab 31:1461–1474CrossRefGoogle Scholar
  16. Kanazawa M, Kawamura K, Takahashi T, Miura M, Tanaka Y, Koyama M et al (2015) Multiple therapeutic effects of progranulin on experimental acute ischaemic stroke. Brain 138:1932–1948CrossRefGoogle Scholar
  17. Kanazawa M, Ninomiya I, Hatakeyama M, Takahashi T, Shimohata T (2017a) Microglia and monocytes/macrophages polarization reveal novel therapeutic mechanism against stroke. Int J Mol Sci 18:E2135CrossRefGoogle Scholar
  18. Kanazawa M, Miura M, Toriyabe M, Koyama M, Hatakeyama M, Ishikawa M et al (2017b) Microglia preconditioned by oxygen-glucose deprivation promote functional recovery in ischemic rats. Sci Rep 7:42582CrossRefGoogle Scholar
  19. Kao AW, McKay A, Singh PP, Brunet A, Huang EJ (2017) Progranulin, lysosomal regulation and neurodegenerative disease. Nat Rev Neurosci 18:325–333CrossRefGoogle Scholar
  20. Kawamura K, Takahashi T, Kanazawa M, Igarashi H, Nakada T, Nishizawa M et al (2014) Effects of angiopoietin-1 on hemorrhagic transformation and cerebral edema after tissue plasminogen activator treatment for ischemic stroke in rats. PLoS One 9:e98639CrossRefGoogle Scholar
  21. Kleinberger G, Wils H, Ponsaerts P, Joris G, Timmermans JP, Van Broeckhoven C et al (2010) Increased caspase activation and decreased TDP-43 solubility in progranulin knockout cortical cultures. J Neurochem 115:735–747CrossRefGoogle Scholar
  22. Laird AS, Van Hoecke A, De Muynck L, Timmers M, Van den Bosch L, Van Damme P et al (2010) Progranulin is neurotrophic in vivo and protects against a mutant TDP-43 induced axonopathy. PLoS One 5:e13368CrossRefGoogle Scholar
  23. Lees KR, Bluhmki E, von Kummer R, Brott TG, Toni D, Grotta JC et al (2010) Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet 375:1695–1703CrossRefGoogle Scholar
  24. Li B, He Y, Xu L, Hu Q, Tang J, Chen Y, Tang J, Feng H, Zhang JH (2015) Progranulin reduced neuronal cell death by activation of sortilin 1 signaling pathways after subarachnoid hemorrhage in rats. Crit Care Med 43:e304–e301CrossRefGoogle Scholar
  25. Liu CJ (2011) Progranulin: a promising therapeutic target for rheumatoid arthritis. FEBS Lett 585:3675–3680CrossRefGoogle Scholar
  26. Ma Y, Wang J, Wang Y, Yang GY (2017) The biphasic function of microglia in ischemic stroke. Prog Neurobiol 157:247–272CrossRefGoogle Scholar
  27. Mabuchi T, Kitagawa K, Ohtsuki T, Kuwabara K, Yagita Y, Yanagihara T et al (2000) Contribution of microglia/macrophages to expansion of infarction and response of oligodendrocytes after focal cerebral ischemia in rats. Stroke 31:1735–1743CrossRefGoogle Scholar
  28. Menzel L, Kleber L, Friedrich C, Hummel R, Dangel L, Winter J et al (2017) Progranulin protects against exaggerated axonal injury and astrogliosis following traumatic brain injury. Glia 65:278–292CrossRefGoogle Scholar
  29. Moskowitz MA, Lo EH, Iadecola C (2010) The science of stroke: mechanisms in search of treatments. Neuron 67:181–198CrossRefGoogle Scholar
  30. Naphade SB, Kigerl KA, Jakeman LB, Kostyk SK, Popovich PG, Kuret J (2010) Progranulin expression is upregulated after spinal contusion in mice. Acta Neuropathol 119:123–133CrossRefGoogle Scholar
  31. Okubo S, Igarashi H, Kanamatsu T, Hasegawa D, Orima H, Katayama Y (2007) FK-506 extended the therapeutic time window for thrombolysis without increasing the risk of hemorrhagic transformation in an embolic rat stroke model. Brain Res 1143:221–227CrossRefGoogle Scholar
  32. Palfree RG, Bennett HP, Bateman A (2015) The evolution of the secreted regulatory protein progranulin. PLoS One 10:e0133749CrossRefGoogle Scholar
  33. Shu Q, Fan H, Li SJ, Zhou D, Ma W, Zhao XY et al (2018) Protective effects of Progranulin against focal cerebral ischemia-reperfusion injury in rats by suppressing endoplasmic reticulum stress and NF-κB activation in reactive astrocytes. J Cell Biochem 119:6584–6597CrossRefGoogle Scholar
  34. Suzuki M, Lee HC, Kayasuga Y, Chiba S, Nedachi T, Matsuwaki T et al (2009) Roles of progranulin in sexual differentiation of the developing brain and adult neurogenesis. J Reprod Dev 55:351–355CrossRefGoogle Scholar
  35. Tanaka Y, Matsuwaki T, Yamanouchi K, Nishihara M (2013) Exacerbated inflammatory responses related to activated microglia after traumatic brain injury in progranulin-deficient mice. Neuroscience 250:8–19CrossRefGoogle Scholar
  36. Tang W, Lu Y, Tian QY, Zhang Y, Guo FJ, Liu GY et al (2011) The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice. Science 332:478–484CrossRefGoogle Scholar
  37. Tao J, Ji F, Wang F, Liu B, Zhu Y (2012) Neuroprotective effects of progranulin in ischemic mice. Brain Res 1436:130–136CrossRefGoogle Scholar
  38. Van Damme P, Van Hoecke A, Lambrechts D et al (2008) Progranulin functions as a neurotrophic factor to regulate neurite outgrowth and enhance neuronal survival. J Cell Biol 181:37–41CrossRefGoogle Scholar
  39. Wei F, Zhang Y, Jian J, Mundra JJ, Tian Q, Lin J et al (2014) PGRN protects against colitis progression in mice in an IL-10 and TNFR2 dependent manner. Sci Rep 4:7023CrossRefGoogle Scholar
  40. Writing Group Members, Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M et al (2016) American Heart Association Statistics Committee; stroke statistics subcommittee. Executive summary: heart disease and stroke Statistics-2016 update: a report from the American Heart Association. Circulation 133:447–454CrossRefGoogle Scholar
  41. Xie S, Lu L, Liu L, Bi G, Zheng L (2016) Progranulin and short-term outcome in patients with acute ischaemic stroke. Eur J Neurol 23:648–655CrossRefGoogle Scholar
  42. Yenari MA, Kauppinen TM, Swanson RA (2010) Microglial activation in stroke: therapeutic targets. Neurotherapeutics 7:378–391CrossRefGoogle Scholar
  43. Yin F, Banerjee R, Thomas B, Zhou P, Qian L, Jia T et al (2010) Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice. J Exp Med 207:117–128CrossRefGoogle Scholar
  44. Yoshida A, Yoshida S, Khalil AK, Ishibashi T, Inomata H (1998) Role of NF-kappa B-mediated interleukin-8 expression in intraocular neovascularization. Invest Ophthalmol Vis Sci 39:1097–1106PubMedGoogle Scholar
  45. Yu Y, Xu X, Liu L, Mao S, Feng T, Lu Y et al (2016) Progranulin deficiency leads to severe inflammation, lung injury and cell death in a mouse model of endotoxic shock. J Cell Mol Med 20:506–517CrossRefGoogle Scholar
  46. Zhang YJ, Xu YF, Dickey CA, Buratti E, Baralle F, Bailey R et al (2007) Progranulin mediates caspase-dependent cleavage of TAR DNA binding protein-43. J Neurosci 27:10530–10534CrossRefGoogle Scholar
  47. Zhang YJ, Xu YF, Cook C, Gendron TF, Roettges P, Link CD et al (2009) Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity. Proc Natl Acad Sci U S A 106:7607–7612CrossRefGoogle Scholar
  48. Zhao C, Bateman A (2015) Progranulin protects against the tissue damage of acute ischaemic stroke. Brain 138:1770–1773CrossRefGoogle Scholar
  49. Zhou C, Xie G, Wang C, Zhang Z, Chen Q, Zhang L et al (2015a) Decreased progranulin levels in patients and rats with subarachnoid hemorrhage: a potential role in inhibiting inflammation by suppressing neutrophil recruitment. J Neuroinflammation 12:200CrossRefGoogle Scholar
  50. Zhou M, Tang W, Fu Y, Xu X, Wang Z, Lu Y et al (2015b) Progranulin protects against renal ischemia/reperfusion injury in mice. Kidney Int 87:918–929CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Masato Kanazawa
    • 1
    Email author
  • Kunio Kawamura
    • 2
  • Tetsuya Takahashi
    • 3
  • Takayoshi Shimohata
    • 4
  1. 1.Department of Neurology, Brain Research InstituteNiigata UniversityNiigataJapan
  2. 2.Midori HospitalNiigataJapan
  3. 3.Department of NeurologyNishi-Niigata Chuo HospitalNiigataJapan
  4. 4.Department of NeurologyGifu University Graduate School of MedicineGifuJapan

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