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Complement Component C3 Promotes Cerebral Ischemia/Reperfusion Injury Mediated by TLR2/NFκB Activation in Diabetic Mice

  • Zheng Lin
  • Haoran Lin
  • Wenlu Li
  • Yuwen Huang
  • Haibin Dai
Original Paper
  • 13 Downloads

Abstract

Complement component C3 (C3), a key factor in the complement system, is heavily involved in various inflammation-associated diseases. However, it remains obscure for its role in the pathogenesis of cerebral ischemia/reperfusion (I/R) injury in diabetes. A transient middle cerebral artery occlusion (tMCAO) model was used for cerebral I/R injury in streptozotocin-induced diabetic mice. Cerebral infarct volume and neurological function were measured at different times of reperfusion. Complement C3 was measured by ELISA and western blotting. It was observed that complement C3 expression was increased in cerebral I/R injury of diabetic mice, whereas complement C3 deficiency abrogated the activation and injury. Furthermore, activating complement C3 promotes TLR2/NFκB activation after I/R injury in diabetic mice, which is inhibited by of the silencing of TLR2. Taken together, our data demonstrate that complement C3 promotes cerebral I/R injury via the TLR2/NFκB pathway in diabetic mice, and regulating the complement C3/TLR2/NFκB pathway may be a novel target for therapeutic intervention in diabetic stroke.

Keywords

Complement C3 Cerebral ischemia/reperfusion injury TLR2 NFκB Diabetes 

Notes

Acknowledgements

The authors wish to thank Xiuyang Li (Department of Epidemiology & Biostatistics, Zhejiang University School of Medicine) for assistance in the statistical analysis.

Funding

This study was supported by the Grants from the National Natural Science Foundation of China (81373391, 81471395, 81573402, 81703479, 81703498 and 81773700), the foundation from the Zhejiang Provincial Natural Science Foundation of China (LY15H310006, LY16H310002 and LY16H310001), the Foundation from Science and Technology Department of Zhejiang Province (2014C33185, 2016C33G2010098), the Health Bureau of Zhejiang Province (2014KYB104, 2014RCA008, and 2016ZDA009). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Compliance with Ethical Standards

Conflict of interest

The authors have declared that no competing interests exist.

References

  1. 1.
    Zhang ZG, Chopp M (2015) Promoting brain remodeling to aid in stroke recovery. Trends Mol Med 21:543–548CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Luitse MJ, Biessels GJ, Rutten GE, Kappelle LJ (2012) Diabetes, hyperglycaemia, and acute ischaemic stroke. Lancet Neurol 11:261–271CrossRefPubMedGoogle Scholar
  3. 3.
    Duan J, Yin Y, Cui J, Yan J, Zhu Y, Guan Y, Wei G, Weng Y, Wu X, Guo C, Wang Y, Xi M, Wen A (2016) Chikusetsu saponin IVa ameliorates cerebral ischemia reperfusion injury in diabetic mice via adiponectin-mediated AMPK/GSK-3beta pathway in vivo and in vitro. Mol Neurobiol 53:728–743CrossRefPubMedGoogle Scholar
  4. 4.
    Yu X, Xu X, Jackson A, Sun J, Huang P, Mao Y, Chen Z, Lou M, Jiang Q, Zhang M (2016) Blood brain barrier disruption in diabetic stroke related to unfavorable outcome. Cerebrovasc Dis 42:49–56CrossRefPubMedGoogle Scholar
  5. 5.
    Song FY, Wu MH, Zhu LH, Zhang ZQ, Qi QD, Lou CL (2015) Elevated serum mannose-binding lectin levels are associated with poor outcome after acute ischemic stroke in patients with type 2 diabetes. Mol Neurobiol 52:1330–1340CrossRefPubMedGoogle Scholar
  6. 6.
    Mandava P, Martini SR, Munoz M, Dalmeida W, Sarma AK, Anderson JA, Fabian RH, Kent TA (2014) Hyperglycemia worsens outcome after rt-PA primarily in the large-vessel occlusive stroke subtype. Transl Stroke Res 5:519–525CrossRefPubMedGoogle Scholar
  7. 7.
    Kratzer I, Chip S, Vexler ZS (2014) Barrier mechanisms in neonatal stroke. Front Neurosci 8:359CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Fu Y, Liu Q, Anrather J, Shi FD (2015) Immune interventions in stroke. Nat Rev Neurol 11:524–535CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Nakata M, Nakagomi T, Maeda M, Nakano-Doi A, Momota Y, Matsuyama T (2017) Induction of perivascular neural stem cells and possible contribution to neurogenesis following transient brain ischemia/reperfusion injury. Transl Stroke Res 8:131–143CrossRefPubMedGoogle Scholar
  10. 10.
    Alawieh A, Elvington A, Tomlinson S (2015) Complement in the homeostatic and ischemic brain. Front Immunol 6:417CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Guo F, Jiang T, Song W, Wei H, Wang F, Liu L, Ma L, Yin H, Wang Q, Xiong L (2015) Electroacupuncture attenuates cerebral ischemia-reperfusion injury in diabetic mice through adiponectin receptor 1-mediated phosphorylation of GSK-3beta. Mol Neurobiol 51:685–695CrossRefPubMedGoogle Scholar
  12. 12.
    Suzuki Y, Nagai N, Umemura K (2016) A review of the mechanisms of blood-brain barrier permeability by tissue-type plasminogen activator treatment for cerebral ischemia. Front Cell Neurosci 10:2PubMedPubMedCentralGoogle Scholar
  13. 13.
    Kotimaa J, van der Pol P, Leijtens S, Klar-Mohammad N, Schilders G, Daha MR, Rutjes H, van Kooten C (2014) Functional assessment of rat complement pathway activities and quantification of soluble C5b-9 in an experimental model of renal ischemia/reperfusion injury. J Immunol Methods 412:14–23CrossRefPubMedGoogle Scholar
  14. 14.
    Pedersen ED, Waje-Andreassen U, Vedeler CA, Aamodt G, Mollnes TE (2004) Systemic complement activation following human acute ischaemic stroke. Clin Exp Immunol 137:117–122CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    De Simoni MG, Storini C, Barba M, Catapano L, Arabia AM, Rossi E, Bergamaschini L (2003) Neuroprotection by complement (C1) inhibitor in mouse transient brain ischemia. J Cereb Blood Flow Metab 23:232–239CrossRefPubMedGoogle Scholar
  16. 16.
    Alcorlo M, Lopez-Perrote A, Delgado S, Yebenes H, Subias M, Rodriguez-Gallego C, Rodriguez de Cordoba S, Llorca O (2015) Structural insights on complement activation. FEBS J 282:3883–3891CrossRefPubMedGoogle Scholar
  17. 17.
    Alawieh A, Elvington A, Zhu H, Yu J, Kindy MS, Atkinson C, Tomlinson S (2015) Modulation of post-stroke degenerative and regenerative processes and subacute protection by site-targeted inhibition of the alternative pathway of complement. J Neuroinflammation 12:247CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Di Napoli M (2001) Systemic complement activation in ischemic stroke. Stroke 32:1443–1448CrossRefPubMedGoogle Scholar
  19. 19.
    Mellbin LG, Bjerre M, Thiel S, Hansen TK (2012) Complement activation and prognosis in patients with type 2 diabetes and myocardial infarction: a report from the DIGAMI 2 trial. Diabetes Care 35:911–917CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Fan YY, Hu WW, Dai HB, Zhang JX, Zhang LY, He P, Shen Y, Ohtsu H, Wei EQ, Chen Z (2011) Activation of the central histaminergic system is involved in hypoxia-induced stroke tolerance in adult mice. J Cereb Blood Flow Metab 31:305–314CrossRefPubMedGoogle Scholar
  21. 21.
    Bjerre M, Hansen TK, Flyvbjerg A (2008) Complement activation and cardiovascular disease. Hormon Metab Res 40:626–634CrossRefGoogle Scholar
  22. 22.
    Speidl WS, Kastl SP, Huber K, Wojta J (2011) Complement in atherosclerosis: friend or foe? J Thromb Haemost 9:428–440CrossRefPubMedGoogle Scholar
  23. 23.
    Ricklin D, Hajishengallis G, Yang K, Lambris JD (2010) Complement: a key system for immune surveillance and homeostasis. Nat Immunol 11:785–797CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Moghaddam HK, Baluchnejadmojarad T, Roghani M, Khaksari M, Norouzi P, Ahooie M, Mahboobi F (2014) Berberine ameliorate oxidative stress and astrogliosis in the hippocampus of STZ-induced diabetic rats. Mol Neurobiol 49:820–826CrossRefPubMedGoogle Scholar
  25. 25.
    Ergul A, Hafez S, Fouda A, Fagan SC (2016) Impact of comorbidities on acute injury and recovery in preclinical stroke research: focus on hypertension and diabetes. Transl Stroke Res 7:248–260CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Chamorro A, Meisel A, Planas AM, Urra X, van de Beek D, Veltkamp R (2012) The immunology of acute stroke. Nat Rev Neurol 8:401–410CrossRefPubMedGoogle Scholar
  27. 27.
    Singhrao SK, Neal JW, Rushmere NK, Morgan BP, Gasque P (2000) Spontaneous classical pathway activation and deficiency of membrane regulators render human neurons susceptible to complement lysis. Am J Pathol 157:905–918CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Elgebaly MM, Ogbi S, Li W, Mezzetti EM, Prakash R, Johnson MH, Bruno A, Fagan SC, Ergul A (2011) Neurovascular injury in acute hyperglycemia and diabetes: A comparative analysis in experimental stroke. Transl Stroke Res 2:391–398CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Fourgeaud L, Boulanger LM (2007) Synapse remodeling, compliments of the complement system. Cell 131:1034–1036CrossRefPubMedGoogle Scholar
  30. 30.
    Oliveira AL, Thams S, Lidman O, Piehl F, Hokfelt T, Karre K, Linda H, Cullheim S (2004) A role for MHC class I molecules in synaptic plasticity and regeneration of neurons after axotomy. Proc Natl Acad Sci USA 101:17843–17848CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Anttila JE, Whitaker KW, Wires ES, Harvey BK, Airavaara M (2017) Role of microglia in ischemic focal stroke and recovery: focus on Toll-like receptors. Prog Neuropsychopharmacol Biol Psychiatry 79:3–14CrossRefPubMedGoogle Scholar
  32. 32.
    Jack CS, Arbour N, Manusow J, Montgrain V, Blain M, McCrea E, Shapiro A, Antel JP (2005) TLR signaling tailors innate immune responses in human microglia and astrocytes. J Immunol 175:4320–4330CrossRefPubMedGoogle Scholar
  33. 33.
    Tang SC, Arumugam TV, Xu X, Cheng A, Mughal MR, Jo DG, Lathia JD, Siler DA, Chigurupati S, Ouyang X, Magnus T, Camandola S, Mattson MP (2007) Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits. Proc Natl Acad Sci USA 104:13798–13803CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Hayward JH, Lee SJ (2014) A decade of research on TLR2 discovering its pivotal role in glial activation and neuroinflammation in neurodegenerative diseases. Exp Neurobiol 23:138–147CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Verstrepen L, Bekaert T, Chau TL, Tavernier J, Chariot A, Beyaert R (2008) TLR-4, IL-1R and TNF-R signaling to NF-kappaB: variations on a common theme. Cell Mol Life Sci 65:2964–2978CrossRefPubMedGoogle Scholar
  36. 36.
    Zhu L, Ye T, Tang Q, Wang Y, Wu X, Li H, Jiang Y (2016) Exercise preconditioning regulates the toll-like receptor 4/nuclear factor-kappaB signaling pathway and reduces cerebral ischemia/reperfusion inflammatory injury: a study in rats. J Stroke Cerebrovasc Dis 25:2770–2779CrossRefPubMedGoogle Scholar
  37. 37.
    Kim BS, Lim SW, Li C, Kim JS, Sun BK, Ahn KO, Han SW, Kim J, Yang CW (2005) Ischemia-reperfusion injury activates innate immunity in rat kidneys. Transplantation 79:1370–1377CrossRefPubMedGoogle Scholar
  38. 38.
    Dybdahl B, Wahba A, Lien E, Flo TH, Waage A, Qureshi N, Sellevold OF, Espevik T, Sundan A (2002) Inflammatory response after open heart surgery: release of heat-shock protein 70 and signaling through toll-like receptor-4. Circulation 105:685–690CrossRefPubMedGoogle Scholar

Copyright information

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

Authors and Affiliations

  1. 1.Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina

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