In vivo and in vitro genetic evidence of involvement of neuregulin 1 in immune system dysregulation
- 532 Downloads
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.
KeywordsNeuregulin-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.
- 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
- 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
- 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
- 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.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
- 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