Skip to main content

Advertisement

Log in

A New Role Discovered for IGTP: The Protective Effect of IGTP in ICH-Induced Neuronal Apoptosis

  • Original Research
  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Interferon gamma-induced GTPase (IGTP), which is also named Irgm3, has been widely described in regulating host resistance against intracellular pathogens. Previous researches have demonstrated that IGTP exerts beneficial function during coxsackievirus B3 (CVB3) infection. However, little information is available regarding the role of IGTP in central nervous system. Here, our study revealed that IGTP may have an essential role during ICH-induced neuronal apoptosis. We found the expression level of IGTP adjacent to hematoma was strongly increased after ICH, accompanied with the up-regulation of proliferating cell nuclear antigen (PCNA), active-caspase-3, p-GSK-3β, and Bax. IGTP was also observed to be co-localized with PCNA in astrocytes and active-caspase-3 in neurons, indicating its association with astrocyte proliferation and neuronal apoptosis after ICH. Finally, in vitro study, knocking down IGTP with IGTP-specific siRNA promoted active-caspase-3, p-GSK-3β, and Bax expression, and led to more severe neuronal apoptosis after ICH. All these results above suggested that IGTP might play a critical role in protecting neurons from apoptosis after ICH.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Al-Zeer MA, Al-Younes HM, Braun PR, Zerrahn J, Meyer TF (2009) IFN-gamma-inducible Irga6 mediates host resistance against Chlamydia trachomatis via autophagy. PLoS ONE 4:e4588

    Article  PubMed  PubMed Central  Google Scholar 

  • Billiau A (1996) Interferon-gamma: biology and role in pathogenesis. Adv Immunol 62:61–130

    Article  CAS  PubMed  Google Scholar 

  • Boehm U, Klamp T, Groot M, Howard JC (1997) Cellular responses to interferon-gamma. Annu Rev Immunol 15:749–795

    Article  CAS  PubMed  Google Scholar 

  • Carlow DA, Teh SJ, Teh HS (1998) Specific antiviral activity demonstrated by TGTP, a member of a new family of interferon-induced GTPases. Eur J Immunol 161:2348–2355

    CAS  Google Scholar 

  • Carthy CM, Granville DJ, Watson KA, Anderson DR, Wilson JE, Yang D, Hunt DW, McManus BM (1998) Caspase activation and specific cleavage of substrates after coxsackievirus B3-induced cytopathic effect in HeLa cells. J Virol 72:7669–7675

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chen X, Du X, Zhang M, Zhang D, Ji M, Wu G (2010) IFN-inducible p47 GTPases display differential responses to Schistosoma japonicum acute infection. Cell Mol Immunol 7:69–76

    Article  CAS  PubMed  Google Scholar 

  • Chuang CL, Lu YN, Wang HC, Chang HY (2014) Genetic dissection reveals that Akt is the critical kinase downstream of LRRK2 to phosphorylate and inhibit FOXO1, and promotes neuron survival. Hum Mol Genet 23:5649–5658

    Article  PubMed  Google Scholar 

  • Collazo CM, Yap GS, Sempowski GD, Lusby KC, Tessarollo L, Vande Woude GF, Sher A, Taylor GA (2001) Inactivation of LRG-47 and IRG-47 reveals a family of interferon gamma-inducible genes with essential, pathogen-specific roles in resistance to infection. J Exp Med 194:181–188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Collazo CM, Yap GS, Hieny S, Caspar P, Feng CG, Taylor GA, Sher A (2002) The function of gamma interferon-inducible GTP-binding protein IGTP in host resistance to Toxoplasma gondii is Stat1 dependent and requires expression in both hematopoietic and nonhematopoietic cellular compartments. Infect Immun 70:6933–6939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dalton DK, Pitts-Meek S, Keshav S, Figari IS, Bradley A, Stewart TA (1993) Multiple defects of immune cell function in mice with disrupted interferon-gamma genes. Science 259:1739–1742

    Article  CAS  PubMed  Google Scholar 

  • 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 8:355–369

    Article  PubMed  Google Scholar 

  • Friedlander RM (2003) Apoptosis and caspases in neurodegenerative diseases. N Engl J Med 348:1365–1375

    Article  CAS  PubMed  Google Scholar 

  • Gao L, Lu Q, Huang L, Ruan L, Yang J, Huang W, ZhuGe W, Zhang Y, Fu B, Jin K, ZhuGe Q (2014) Transplanted neural stem cells modulate regulatory T, gammadelta T cells and corresponding cytokines after intracerebral hemorrhage in rats. Int J Mol Sci 15:4431–4441

    Article  PubMed  PubMed Central  Google Scholar 

  • Guo J, McQuillan JA, Yau B, Tullo GS, Long CA, Bertolino P, Roediger B, Weninger W, Taylor GA, Hunt NH et al (2015) IRGM3 contributes to immunopathology and is required for differentiation of antigen-specific effector CD8+T cells in experimental cerebral malaria. Infect Immun 83:1406–1417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Halonen SK, Taylor GA, Weiss LM (2001) Gamma interferon-induced inhibition of Toxoplasma gondii in astrocytes is mediated by IGTP. Infect Immun 69:5573–5576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hua Y, Schallert T, Keep RF, Wu J, Hoff JT, Xi G (2002) Behavioral tests after intracerebral hemorrhage in the rat. Stroke 33:2478–2484

    Article  PubMed  Google Scholar 

  • Huang S, Hendriks W, Althage A, Hemmi S, Bluethmann H, Kamijo R, Vilcek J, Zinkernagel RM, Aguet M (1993) Immune response in mice that lack the interferon-gamma receptor. Science 259:1742–1745

    Article  CAS  PubMed  Google Scholar 

  • Janzen C, Kochs G, Haller O (2000) A monomeric GTPase-negative MxA mutant with antiviral activity. J Virol 74:8202–8206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaplan DH, Shankaran V, Dighe AS, Stockert E, Aguet M, Old LJ, Schreiber RD (1998) Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proc Natl Acad Sci USA 95:7556–7561

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ke K, Li L, Rui Y, Zheng H, Tan X, Xu W, Cao J, Xu J, Cui G, Xu G, Cao M (2013) Increased expression of small heat shock protein alphaB-crystallin after intracerebral hemorrhage in adult rats. J Mol Neurosci 51:159–169

    Article  CAS  PubMed  Google Scholar 

  • Krafft PR, Altay O, Rolland WB, Duris K, Lekic T, Tang J, Zhang JH (2011) α7 nicotinic acetylcholine receptor agonism confers neuroprotection through GSK-3 inhibition in a mouse model of intracerebral hemorrhage. Stroke 43:844–850

    Article  PubMed  PubMed Central  Google Scholar 

  • Laird MD, Vender JR, Dhandapani KM (2008) Opposing roles for reactive astrocytes following traumatic brain injury. Neurosignals 16:154–164

    Article  CAS  PubMed  Google Scholar 

  • Lapaque N, Takeuchi O, Corrales F, Akira S, Moriyon I, Howard JC, Gorvel JP (2006) Differential inductions of TNF-alpha and IGTP, IIGP by structurally diverse classic and non-classic lipopolysaccharides. Cell Microbiol 8:401–413

    Article  CAS  PubMed  Google Scholar 

  • Lapaque N, Muller A, Alexopoulou L, Howard JC, Gorvel JP (2009) Brucella abortus induces Irgm3 and Irga6 expression via type-I IFN by a MyD88-dependent pathway, without the requirement of TLR2, TLR4, TLR5 and TLR9. Microb Pathog 47:299–304

    Article  CAS  PubMed  Google Scholar 

  • Liu Z, Zhang HM, Yuan J, Lim T, Sall A, Taylor GA, Yang D (2008) Focal adhesion kinase mediates the interferon-gamma-inducible GTPase-induced phosphatidylinositol 3-kinase/Akt survival pathway and further initiates a positive feedback loop of NF-kappaB activation. Cell Microbiol 10:1787–1800

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu Z, Zhang HM, Yuan J, Ye X, Taylor GA, Yang D (2012) The immunity-related GTPase Irgm3 relieves endoplasmic reticulum stress response during coxsackievirus B3 infection via a PI3K/Akt dependent pathway. Cell Microbiol 14:133–146

    Article  CAS  PubMed  Google Scholar 

  • MacMicking JD (2004) IFN-inducible GTPases and immunity to intracellular pathogens. Trends Immunol 25:601–609

    Article  CAS  PubMed  Google Scholar 

  • Melzer T, Duffy A, Weiss LM, Halonen SK (2008) The gamma interferon (IFN-gamma)-inducible GTP-binding protein IGTP is necessary for toxoplasma vacuolar disruption and induces parasite egression in IFN-gamma-stimulated astrocytes. Infect Immun 76:4883–4894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ohnishi M, Katsuki H, Fukutomi C, Takahashi M, Motomura M, Fukunaga M, Matsuoka Y, Isohama Y, Izumi Y, Kume T et al (2011) HMGB1 inhibitor glycyrrhizin attenuates intracerebral hemorrhage-induced injury in rats. Neuropharmacology 61:975–980

    Article  CAS  PubMed  Google Scholar 

  • Okauchi M, Hua Y, Keep RF, Morgenstern LB, Schallert T, Xi G (2010) Deferoxamine treatment for intracerebral hemorrhage in aged rats: therapeutic time window and optimal duration. Stroke 41:375–382

    Article  CAS  PubMed  Google Scholar 

  • Ridet JL, Malhotra SK, Privat A, Gage FH (1997) Reactive astrocytes: cellular and molecular cues to biological function. Trends Neurosci 20:570–577

    Article  CAS  PubMed  Google Scholar 

  • Singh SB, Davis AS, Taylor GA, Deretic V (2006) Human IRGM induces autophagy to eliminate intracellular mycobacteria. Science 313:1438–1441

    Article  CAS  PubMed  Google Scholar 

  • Sofroniew MV (2005) Reactive astrocytes in neural repair andprotection. Neuroscientist 11:400–407

    Article  CAS  PubMed  Google Scholar 

  • Spath GF, Beverley SM (2001) A lipophosphoglycan-independent method for isolation of infective Leishmania metacyclic promastigotes by density gradient centrifugation. Exp Parasitol 99:97–103

    Article  CAS  PubMed  Google Scholar 

  • Stark GR, Kerr IM, Williams BR, Silverman RH, Schreiber RD (1998) How cells respond to interferons. Annu Rev Biochem 67:227–264

    Article  CAS  PubMed  Google Scholar 

  • Sun H, Li L, Zhou F, Zhu L, Ke K, Tan X, Xu W, Rui Y, Zheng H, Zhou Z et al (2013) The member of high temperature requirement family HtrA2 participates in neuronal apoptosis after intracerebral hemorrhage in adult rats. J Mol Histol 44:369–379

    Article  CAS  PubMed  Google Scholar 

  • Taylor GA, Jeffers M, Largaespada DA, Jenkins NA, Copeland NG, Vande Woude GF (1996) Identification of a novel GTPase, the inducibly expressed GTPase, that accumulates in response to interferon gamma. J Biol Chem 271:20399–20405

    Article  CAS  PubMed  Google Scholar 

  • Taylor GA, Stauber R, Rulong S, Hudson E, Pei V, Pavlakis GN, Resau JH, Vande Woude GF (1997) The inducibly expressed GTPase localizes to the endoplasmic reticulum, independently of GTP binding. J Biol Chem 272:10639–10645

    Article  CAS  PubMed  Google Scholar 

  • Taylor GA, Collazo CM, Yap GS, Nguyen K, Gregorio TA, Taylor LS, Eagleson B, Secrest L, Southon EA, Reid SW et al (2000) Pathogen-specific loss of host resistance in mice lacking the IFN-gamma-inducible gene IGTP. Proc Natl Acad Sci USA 97:751–755

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Taylor GA, Feng CG, Sher A (2004) p47 GTPases: regulators of immunity to intracellular pathogens. Nat Rev Immunol 4:100–109

    Article  CAS  PubMed  Google Scholar 

  • van Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A, Klijn CJ (2010) Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol 9:167–176

    Article  PubMed  Google Scholar 

  • Varnero S, Susco G, Martinengo E (1987) Aortic insufficiency associated with mitral prolapse. Minerva Cardioangiol 35:483–490

    CAS  PubMed  Google Scholar 

  • Wilson D, Charidimou A, Werring DJ (2014) Advances in understanding spontaneous intracerebral hemorrhage: insights from neuroimaging. Expert Rev Neurother 14:661–678

    Article  CAS  PubMed  Google Scholar 

  • Xi G, Keep RF, Hoff JT (2006) Mechanisms of brain injury after intracerebral haemorrhage. Lancet Neurol 5:53–63

    Article  PubMed  Google Scholar 

  • Xue M, Del Bigio MR (2000) Intracerebral injection of autologous whole blood in rats: time course of inflammation and cell death. Neurosci Lett 283:230–232

    Article  CAS  PubMed  Google Scholar 

  • Zhang HM, Yuan J, Cheung P, Luo H, Yanagawa B, Chau D, Stephan-Tozy N, Wong BW, Zhang J, Wilson JE et al (2003) Overexpression of interferon-gamma-inducible GTPase inhibits coxsackievirus B3-induced apoptosis through the activation of the phosphatidylinositol 3-kinase/Akt pathway and inhibition of viral replication. J Biol Chem 278:33011–33019

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kaifu Ke.

Additional information

Lijian Han and Yaohui Ni contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Han, L., Ni, Y., Cao, M. et al. A New Role Discovered for IGTP: The Protective Effect of IGTP in ICH-Induced Neuronal Apoptosis. Cell Mol Neurobiol 36, 713–724 (2016). https://doi.org/10.1007/s10571-015-0251-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-015-0251-1

Keywords

Navigation