Journal of Molecular Medicine

, Volume 88, Issue 11, pp 1133–1141 | Cite as

In vivo and in vitro genetic evidence of involvement of neuregulin 1 in immune system dysregulation

  • Ketan Marballi
  • Marlon P. Quinones
  • Fabio Jimenez
  • Michael A. Escamilla
  • Henriette Raventós
  • Maria Clara Soto-Bernardini
  • Seema S. Ahuja
  • Consuelo Walss-BassEmail author
Original Article


Neuregulin 1 (NRG1) has been implicated in several disorders including breast cancer, multiple sclerosis, and schizophrenia. Also, recent evidence suggests that NRG1 may play a role in regulation of inflammation and immune system response. We therefore hypothesized that a schizophrenia-associated missense mutation (valine to leucine) we identified within the transmembrane region of NRG1 would also be linked to immune dysregulation. We used plasma samples from families carrying the mutation to measure levels of antibodies to 41 autoimmune markers and six cytokines (IL-1b, IL-6, IL-10, IL-8, IL-12p70, and TNF-α) and used these levels as quantitative traits to evaluate association with the NRG1 mutation, using FBAT. Next, we used Epstein–Barr virus-transformed B cells from heterozygous mutation carriers and wild-type individuals to evaluate protein and mRNA cytokine expression in vitro using quantitative PCR and ELISA assays. In vivo, increased levels of 25 autoimmune markers as well as elevated levels of cytokines were significantly associated with the NRG1 mutation. In vitro, we observed a significant increase in protein secretion levels of IL-6, TNF-α, and IL-8 in mutation carriers compared with controls. At the mRNA level, we observed a significant increase in IL-6 expression, while IL-4 levels appeared to be down-regulated in heterozygous individuals compared with wild-type controls. This is the first report of association of a NRG1 mutation with immune dysregulation. This study could contribute towards understanding the role of NRG1 in the pathogenesis of schizophrenia and other disorders in which inflammation plays an important role.


Neuregulin-1 Immune system Inflammation Cytokines Autoantibodies Lymphoblastoid cell lines 



This work was supported by grants from the National Institutes of Health (K01MH077777), the Stanley Medical Research Institute, and NARSAD, the mental health research association to CWB. We thank the personnel of the CIBCM at the University of Costa Rica for their assistance in collecting the samples.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary material

109_2010_653_MOESM1_ESM.pdf (11 kb)
Supplemental Table 1 Mean values of autoantibodies and cytokine levels observed in plasma of 14 families informative for the NRG1 Val (G) > Leu (T) mutation (PDF 10 kb)


  1. 1.
    Falls DL (2003) Neuregulins: functions, forms, and signaling strategies. Exp Cell Res 284:14–30CrossRefPubMedGoogle Scholar
  2. 2.
    Dimayuga FO, Ding Q, Keller JN, Marchionni MA, Seroogy KB, Bruce-Keller AJ (2003) The neuregulin GGF2 attenuates free radical release from activated microglial cells. J Neuroimmunol 136:67–74CrossRefPubMedGoogle Scholar
  3. 3.
    Li Y, Xu Z, Ford GD, Croslan DR, Cairobe T, Li Z, Ford BD (2007) Neuroprotection by neuregulin-1 in a rat model of permanent focal cerebral ischemia. Brain Res 1184:277–283CrossRefPubMedGoogle Scholar
  4. 4.
    Hintsanen M, Elovainio M, Puttonen S, Kivimaki M, Raitakari OT, Lehtimaki T, Rontu R, Juonala M, Kahonen M, Viikari J et al (2007) Neuregulin-1 genotype moderates the association between job strain and early atherosclerosis in young men. Ann Behav Med 33:148–155CrossRefPubMedGoogle Scholar
  5. 5.
    Kanakry CG, Li Z, Nakai Y, Sei Y, Weinberger DR (2007) Neuregulin-1 regulates cell adhesion via an ErbB2/phosphoinositide-3 kinase/Akt-dependent pathway: potential implications for schizophrenia and cancer. PLoS ONE 2:e1369CrossRefPubMedGoogle Scholar
  6. 6.
    Asp L, Beraki S, Kristensson K, Ogren SO, Karlsson H (2009) Neonatal infection with neurotropic influenza A virus affects working memory and expression of type III Nrg1 in adult mice. Brain Behav Immun 23:733–741CrossRefPubMedGoogle Scholar
  7. 7.
    Potvin S, Stip E, Sepehry AA, Gendron A, Bah R, Kouassi E (2008) Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review. Biol Psychiatry 63:801–808CrossRefPubMedGoogle Scholar
  8. 8.
    Strous RD, Shoenfeld Y (2006) Schizophrenia, autoimmunity and immune system dysregulation: a comprehensive model updated and revisited. J Autoimmun 27:71–80CrossRefPubMedGoogle Scholar
  9. 9.
    Eaton WW, Byrne M, Ewald H, Mors O, Chen CY, Agerbo E, Mortensen PB (2006) Association of schizophrenia and autoimmune diseases: linkage of Danish national registers. Am J Psychiatry 163:521–528CrossRefPubMedGoogle Scholar
  10. 10.
    Walss-Bass C, Liu W, Lew DF, Villegas R, Montero P, Dassori A, Leach RJ, Almasy L, Escamilla M, Raventos H (2006) A novel missense mutation in the transmembrane domain of neuregulin 1 is associated with schizophrenia. Biol Psychiatry 60:548–553CrossRefPubMedGoogle Scholar
  11. 11.
    Dejaegere T, Serneels L, Schafer MK, Van Biervliet J, Horre K, Depboylu C, Alvarez-Fischer D, Herreman A, Willem M, Haass C et al (2008) Deficiency of Aph1B/C-gamma-secretase disturbs Nrg1 cleavage and sensorimotor gating that can be reversed with antipsychotic treatment. Proc Natl Acad Sci USA 105:9775–9780CrossRefPubMedGoogle Scholar
  12. 12.
    Bao J, Wolpowitz D, Role LW, Talmage DA (2003) Back signaling by the Nrg-1 intracellular domain. J Cell Biol 161:1133–1141. doi: 10.1083/jcb.200212085jcb.200212085 CrossRefPubMedGoogle Scholar
  13. 13.
    Camargo JF, Quinones MP, Mummidi S, Srinivas S, Gaitan AA, Begum K, Jimenez F, Van Compernolle S, Unutmaz D, Ahuja SS et al (2009) CCR5 expression levels influence NFAT translocation, IL-2 production, and subsequent signaling events during T lymphocyte activation. J Immunol 182:171–182PubMedGoogle Scholar
  14. 14.
    Morgan E, Varro R, Sepulveda H, Ember JA, Apgar J, Wilson J, Lowe L, Chen R, Shivraj L, Agadir A et al (2004) Cytometric bead array: a multiplexed assay platform with applications in various areas of biology. Clin Immunol 110:252–266CrossRefPubMedGoogle Scholar
  15. 15.
    Lange C, DeMeo DL, Laird NM (2002) Power and design considerations for a general class of family-based association tests: quantitative traits. Am J Hum Genet 71:1330–1341CrossRefPubMedGoogle Scholar
  16. 16.
    Abecasis GR, Cardon LR, Cookson WO (2000) A general test of association for quantitative traits in nuclear families. Am J Hum Genet 66:279–292CrossRefPubMedGoogle Scholar
  17. 17.
    Yu Y, Rabinowitz R, Steinitz M, Schlesinger M (2002) Correlation between the expression of CD4 and the level of CD4 mRNA in human B-cell lines. Cell Immunol 215:78–86CrossRefPubMedGoogle Scholar
  18. 18.
    Monks SA, Leonardson A, Zhu H, Cundiff P, Pietrusiak P, Edwards S, Phillips JW, Sachs A, Schadt EE (2004) Genetic inheritance of gene expression in human cell lines. Am J Hum Genet 75:1094–1105CrossRefPubMedGoogle Scholar
  19. 19.
    Hayes NV, Gullick WJ (2008) The neuregulin family of genes and their multiple splice variants in breast cancer. J Mammary Gland Biol Neoplasia 13:205–214CrossRefPubMedGoogle Scholar
  20. 20.
    Georgieva L, Dimitrova A, Ivanov D, Nikolov I, Williams NM, Grozeva D, Zaharieva I, Toncheva D, Owen MJ, Kirov G, O'Donovan MC (2008) Support for neuregulin 1 as a susceptibility gene for bipolar disorder and schizophrenia. Biol Psychiatry 64:419–427CrossRefPubMedGoogle Scholar
  21. 21.
    Clement CM, Thomas LK, Mou Y, Croslan DR, Gibbons GH, Ford BD (2007) Neuregulin-1 attenuates neointimal formation following vascular injury and inhibits the proliferation of vascular smooth muscle cells. J Vasc Res 44:303–312CrossRefPubMedGoogle Scholar
  22. 22.
    Freedman NJ, Ginsburg GS (2006) Novel- and “neu”-therapeutic possibilities for heart failure. J Am Coll Cardiol 48:1448–1450CrossRefPubMedGoogle Scholar
  23. 23.
    Marchionni MA, Cannella B, Hoban C, Gao YL, Garcia-Arenas R, Lawson D, Happel E, Noel F, Tofilon P, Gwynne D, Raine CS (1999) Neuregulin in neuron/glial interactions in the central nervous system. GGF2 diminishes autoimmune demyelination, promotes oligodendrocyte progenitor expansion, and enhances remyelination. Adv Exp Med Biol 468:283–295PubMedGoogle Scholar
  24. 24.
    Hojilla CV, Wood GA, Khokha R (2008) Inflammation and breast cancer: metalloproteinases as common effectors of inflammation and extracellular matrix breakdown in breast cancer. Breast Cancer Res 10:205CrossRefPubMedGoogle Scholar
  25. 25.
    Bodi V, Sanchis J, Nunez J, Mainar L, Minana G, Benet I, Solano C, Chorro FJ, Llacer A (2008) Uncontrolled immune response in acute myocardial infarction: unraveling the thread. Am Heart J 156:1065–1073CrossRefPubMedGoogle Scholar
  26. 26.
    Brinkmann BG, Agarwal A, Sereda MW, Garratt AN, Muller T, Wende H, Stassart RM, Nawaz S, Humml C, Velanac V, Radyushkin K, Goebbels S, Fischer TM, Franklin RJ, Lai C, Ehrenreich H, Birchmeier C, Schwab MH, Nave KA (2008) Neuregulin-1/ErbB signaling serves distinct functions in myelination of the peripheral and central nervous system. Neuron 59:581–595. doi: 10.1016/j.neuron.2008.06.028 CrossRefPubMedGoogle Scholar
  27. 27.
    O'Tuathaigh CM, O'Connor AM, O'Sullivan GJ, Lai D, Harvey R, Croke DT, Waddington JL (2008) Disruption to social dyadic interactions but not emotional/anxiety-related behaviour in mice with heterozygous ‘knockout’ of the schizophrenia risk gene neuregulin-1. Prog Neuropsychopharmacol Biol Psychiatry 32:462–466. doi: 10.1016/j.pnpbp.2007.09.018 CrossRefPubMedGoogle Scholar
  28. 28.
    Paul-Samojedny M, Kowalczyk M, Suchanek R, Owczarek A, Fila-Danilow A, Szczygiel A, Kowalski J (2010) Functional polymorphism in the interleukin-6 and interleukin-10 genes in patients with paranoid schizophrenia—a case–control study. J Mol Neurosci. doi: 10.1007/s12031-010-9365-6 Google Scholar
  29. 29.
    Hanninen K, Katila H, Saarela M, Rontu R, Mattila KM, Fan M, Hurme M, Lehtimaki T (2008) Interleukin-1 beta gene polymorphism and its interactions with neuregulin-1 gene polymorphism are associated with schizophrenia. Eur Arch Psychiatry Clin Neurosci 258:10–15CrossRefPubMedGoogle Scholar
  30. 30.
    Na KS, Kim YK (2007) Monocytic, Th1 and th2 cytokine alterations in the pathophysiology of schizophrenia. Neuropsychobiology 56:55–63CrossRefPubMedGoogle Scholar
  31. 31.
    Mei L, Xiong WC (2008) Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat Rev Neurosci 9:437–452CrossRefPubMedGoogle Scholar
  32. 32.
    Wu T, Qin X, Kurepa Z, Kumar KR, Liu K, Kanta H, Zhou XJ, Satterthwaite AB, Davis LS, Mohan C (2007) Shared signaling networks active in B cells isolated from genetically distinct mouse models of lupus. J Clin Invest 117:2186–2196CrossRefPubMedGoogle Scholar
  33. 33.
    Ohnishi H, Takeda K, Domenico J, Lucas JJ, Miyahara N, Swasey CH, Dakhama A, Gelfand EW (2009) Mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2-dependent pathways are essential for CD8+ T cell-mediated airway hyperresponsiveness and inflammation. J Allergy Clin Immunol 123:249–257CrossRefPubMedGoogle Scholar
  34. 34.
    Deming PB, Rathmell JC (2006) Mitochondria, cell death, and B cell tolerance. Curr Dir Autoimmun 9:95–119PubMedGoogle Scholar
  35. 35.
    Kalinowski A, Plowes NJ, Huang Q, Berdejo-Izquierdo C, Russell RR, Russell KS (2010) Metalloproteinase-dependent cleavage of neuregulin and autocrine stimulation of vascular endothelial cells. FASEB J 24:000–000CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Ketan Marballi
    • 1
  • Marlon P. Quinones
    • 2
  • Fabio Jimenez
    • 3
  • Michael A. Escamilla
    • 4
  • Henriette Raventós
    • 5
  • Maria Clara Soto-Bernardini
    • 5
  • Seema S. Ahuja
    • 3
  • Consuelo Walss-Bass
    • 2
    Email author
  1. 1.Department of Cellular and Structural Biology and PsychiatryUniversity of Texas Health Sciences Center at San AntonioSan AntonioUSA
  2. 2.Department of PsychiatryUniversity of Texas Health Sciences Center at San AntonioSan AntonioUSA
  3. 3.Department of MedicineUniversity of Texas Health Sciences Center at San AntonioSan AntonioUSA
  4. 4.Texas Tech University Health Sciences CenterPaul L. Foster School of Medicine, Center of Excellence for NeuroscienceEl PasoUSA
  5. 5.Cellular and Molecular Biology Research Center, CIBCMUniversity of Costa RicaCiudad de la InvestigaciónCosta Rica

Personalised recommendations