Our research team puts emphasis on understanding the basic signaling pathways involved in maintenance of central nervous system (CNS) homeostasis; important to prevent Neuroinflammation, Neurodegeneration and NeuroOncology. We aim to understand how immune genes are involved in the function of neurons in the CNS. During last 10 years, we have identified several nominal findings including a central role for immunoregulatory genes not only in regulation of immune system but also as indispensable regulatory mechanisms for the central nervous system including the essential brain functions, and for the cross-talk between these two systems. Our aim is to identify shared molecules central for stability, integrity and functionality of these two organs with goal to find new therapeutic targets.
Our research team is aiming to understand how immune genes are involved in the function of neurons in the CNS. In particular our team have identified several nominal immunoregulatory genes central for cross-talk between these immune systems & brain. For example when immunoregulatory cytokine, interferon (IFN)-β and/or its receptor IFN-A receptor are knocked out, mice develop spontaneous neurodegeneration, motor-coordination and cognitive deficits resembling Parkinson’s disease dementia and Dementia with Lewy Bodies (Cell 2015). We reported that IFN-β is regulating CNS-inflammation by regulating a transcription factor called FoxA1, and by generating a previously unknown type of immune cells, we called FoxA1+Tregulatory cells (Nature Medicine 2014). Nevertheless we identified that Ifnb gene in neurons is essential for them to fight CNS cancer namely glioblastoma (J. Neurosci 2013). This is because IFN-β regulates autophagy, a protein degradation pathway important for cell survival (Autophagy 2013). We are currently investigating the basic molecular mechanisms of function of several other immune-related leads that are also regulating neuronal functions, lack or malfunctioning of which leads to different neurologic or neuro-oncologic diseases.
Figure 1. a-synuclein, a PD dementia-causing protein-aggregate accumulates in nerve cells when Ifnb gene is lacking. A) Light microscopy image of a Lewy body (red) inside the brain of a mouse lacking the Ifnb gene. A similar protein aggregate shown by electron microscopy (arrowhead) (B). Based on our publication Ejlerskov et. al. Cell 2015.
Figure 2. Neurons regulate CNS inflammation
by inducing T lymphocytes plasticity via FoxA1 & FoxP3.
A) Neurons via expression of IFN-β regulate pathogenic T lymphocytes in the brain
to become anti-inflammatory cells called FoxA1+Tregulatory cells in MS.
Summary of our research published in Nature Medicine 2014, Liu et al.
Adapted from News & Views written by Delgoffe & Vingali (Nature Medicine 2014)
to highlight our paper.
|B) Neurons via expression of TGF-β & B7 regulate pathogenic T lymphocytes in the brain to become anti-inflammatory cells called FoxP3+Tregulatory cells, which prevent MS-like disease (EAE). Summary of our research published in Nature Medicine 2006, Liu et al. & highlighted as News & Views by Fujinami RS. (Nature Medicine 2006)|
Scientific goals and projects
Neuroinflammation has received more recognition as a central pathologic process involved not only in classic neuroinflammatory diseases like multiple sclerosis (MS), but also being detrimental for classic neurodegenerative diseases such as Alzheimer’s and Parkinson’s Diseases (AD and PD) and also precede neurooncological diseases like glioblastoma (GBM).
We have identified several pioneering mechanisms by which immunoregulatory factors control function of neurons. We have identified the factors, which are central for neuronal circuit, survival, apoptosis, waste-protein handling and hence neuronal homeostasis. Function of these molecules also prevents neuroinflammatory conditions as primary or secondary phenomenon proceeding neurodegeneration and also preventing tumor growth. We have shown that these factors have similar functions in regulation of T-lymphocytes in and outside of the CNS. We will investigate the function of the identified molecules, in particular;
1. The function of novel transcription factor/s in plasticity of immune cells, important for regulation of neuroinflammation in MS.
2. Role of selective immunoregulatory genes in A) controlling neuronal hemostasis via regulating autophagy and mitochondrial, functions central for preventing pathology in PD, AD & other dementias, B) in regulating gliosis (pathogenic activation, proliferation & proinflammatory function of micorglia and astrocytic), the local neuroinflammation.
3. Identification of tumor-specific immune receptor/s to regulate GBM & anti-tumor immune activation.
Interested postdoctoral scientists, students and lab technicians are always welcomed to contact us regarding possibility to join the group.
1. Ejlerskov P, Göransdotter Hultberg J, JY. W, Carlsson R, Ambjørn M, Kuss M, Y. L, Porcu G, Kolkova K, Friis Rundsten C, Karsten Ruscher, Pakkenberg B, Goldmann, T, Prinz M, Rubinsztein, D C & Issazadeh-Navikas, S Lack of neuronal IFN-β–IFNAR signaling causes Lewy body and Parkinson’s disease-like dementia in mice. Cell. 163, 1–16 October 8, 2015. http://dx.doi.org/10.1016/j.cell.2015.08.069.
2. Yawei Liu, Robert Carlsson, Manuel Comabella, JunYang Wang, Michael Kosicki, Belinda Carrion, Maruf Hasan, Xudong Wu, Xavier Montalban, Morten Hanefeld Dziegiel, Finn Sellebjerg, Per Soelberg Sørensen, Kristian Helin & Shohreh Issazadeh-Navikas. FoxA1 directs the lineage and immunosuppressive properties of a novel regulatory T cell population in EAE and MS. (2014) Nature Medicine, doi:10.1038/nm.3485.
• Highlighted by Yvone Bordon; Regulatory T cells: Mind control. Yvonne Bordon. Nature Reviews Immunology. (2014). doi:10.1038/nri3643. Published online 28 February 2014.
3. Yawei Liu, Robert Carlsson, Malene Ambjørn, Maruf Hasan, Wiaam Badn, Anna Darabi, Peter Siesjö & Shohreh Issazadeh-Navikas. PD-L1 expression by neurons nearby tumors indicates better prognosis in glioblastoma patients. (2013). The Journal of Neuroscience. 28;33(35):14231-45. doi: 10.1523/JNEUROSCI.5812-12.2013.
• Reviewed in Nature Review Neurology by Kate Kingwell, 09/2013; DOI:10.1038/nrneurol.2013.197. Impact factor: 15.518
4. Ambjørn, M., Ejlerskov, P., Liu, Y., Lees, M., Jäättelä, M., Issazadeh-Navikas, S. IFNB1/interferon-β-induced autophagy in MCF-7 breast cancer cells counteracts its proapoptotic function. Autophagy. (2013) 9(3):287-302.
5. Liu Y, Teige A, Mondoc E, Ibrahim S, Holmdahl R, Issazadeh-Navikas S. Endogenous collagen peptide activation of CD1d-restricted NKT cells ameliorates tissue-specific inflammation in mice. J Clin Invest. 2011;121(1):249-64.
6. Liu Y, Teige I, Birnir B, Issazadeh-Navikas S. Neuron-mediated generation of regulatory T cells from encephalitogenic T cells suppresses EAE. Nature Medicine. 2006;12(5):518-25.
7. Treschow AP, Teige I, Nandakumar KS, Holmdahl R, Issazadeh-Navikas S. Stromal cells and osteoclasts are responsible for exacerbated collagen-induced arthritis in interferon-beta-deficient mice. Arthritis Rheum. 2005;52(12):3739-48.
8. Matheu V, Back O, Mondoc E, Issazadeh-Navikas S. Dual effects of vitamin D-induced alteration of TH1/TH2 cytokine expression: enhancing IgE production and decreasing airway eosinophilia in murine allergic airway disease. J Allergy Clin Immunol. 2003;112(3):585-92.
9. Weiner HL, Lemere CA, Maron R, Spooner ET, Grenfell TJ, Mori C, Issazadeh S, Hancock WW, Selkoe DJ. Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer's disease. Ann Neurol. 2000;48(4):567-79.
10. Issazadeh S, Abdallah K, Chitnis T, Chandraker A, Wells AD, Turka LA, Sayegh MH, Khoury SJ. Role of passive T-cell death in chronic experimental autoimmune encephalomyelitis. J Clin Invest. 2000;105(8):1109-16.