Group name: Owens group/Neuroimmunology
Group leader: Trevor Owens, PhD
Group members:
1 clinical Prof
1 assistant Prof + their group members attend shared lab meetings
1 assoc prof/ATAP
1 postdoc (co-supervised)
1 PhD student
1 masters student
2 technicians
1 project student (number varies)
Department & University/Hospital/Other:
Neurobiology, IMM, SDU
Neurology, Slagelse Hospital
Funding sources:
Scleroseforeningen, Lundbeckfonden, DFF, NovoNordiskFonden, RegionSyddanmark, EU MSCA
Description of research:
Innate regulation of neuroinflammation
We study CNS-endogenous mechanisms for regulation of inflammation, using EAE in mice as an MS-relevant model. We find that innate signaling receptors normally considered to operate in context of infection or tissue damage, induce production of anti-inflammatory cytokines, particularly Type I interferons and interleukin-10. Experimental ligation of these receptors can suppress EAE. Our research leads to questions about the myeloid cells that initiate these responses, including microglia, their source and location in the CNS and their migration to and interaction with elements of the immune response.
Cortical brain lesions
Demylinating lesions in the subpial cortex are characteristic of progressive MS (PMS) but are not a common feature in EAE. We have developed mouse models for PMS-like cortical lesions based on cuprizone inflammation with subarachnoid and intrathecal cytokines and microglial activating stimuli. We are studying the involvement of B cells in this pathology as well as the influence of Type I IFN and aging (collaboration with Nasrin Asgari, IMAGINE project).
Antibody-mediated pathology in CNS
Autoantibodies are speculated to contribute to demyelinating pathology in MS and are known to mediate astrocytopathology in the related disease Neuromyelitis Optica Spectrum Disorders (NMOSD). We have published adoptive transfer models for NMOSD using patient-derived IgG and we have developed stereotactic models for focal white matter demyelination. Antibody+complement-mediated pathologies are dependent on Type I IFN, although this is beneficial for MS. We are investigating the differential effect of IFN signaling (both Type I and II) on antibody+complement versus cellular cytotoxic mechanisms of demyelination, as well as the role of innately-triggered IL-10 in alleviating NMOSD-like pathology.
Microglial subsets in developing and adult CNS
Microglia are CNS-resident myeloid cells, equivalent to tissue macrophages. We study their heterogeneity and their role in regulation of inflammation as well as in development. Transcriptomic analysis shows that neonatal microglia are distinct from adult, and a subset that express the integrin complement receptor CD11c are particularly important for primary myelination as well as regulation of EAE.
Key publications (last 10 years):
Holm, TH, D. Draeby, and T. Owens. 2012. Microglia are required for astroglial Toll-like receptor 4 response, and for optimal Toll-like receptor 2 and 3 response. Glia 60:630-638.
Reinert, L. S., Harder, L., C.K., H., Iversen, M. B., Horan, K. A., Dagnæs-Hansen, F., Ulhøi, B. P., Holm, T. H., Mogensen, T. H., Owens, T., Nyengaard, J. R., Thomsen, A. R. & Palu-dan, S. R. 2012. TLR3-deficiency renders astrocytes permissive to HSV infection and fa-cilitates establishment of CNS infection in mice. Journal of Clinical Investigation 122:1368-76.
Asgari, N., R. Khorooshi, S. Lillevang, & T. Owens. 2013. Complement-dependent pathogenicity of brain-specific antibodies in cerebrospinal fluid. J. Neuroimmunol. 254:76-82. Epub 2012/10/04.
Khorooshi, R., A. Wlodarczyk, N. Asgari, & T. Owens. 2013. Neuromyelitis optica-like pathology is dependent on type I interferon response. Exp Neurol 247: 744-747.
Mony JT, Khorooshi R, Owens T. 2014. Chemokine receptor expression by inflammatory T cells in EAE. Front Cell Neurosci. 8:187. IF 4,18
Cédile, O, Løbner, M, Toft-Hansen, H, Frank, I, Wlodarczyk, A, Irla, M, & Owens, T. 2014 Thymic CCL2 influences induction of T-cell tolerance. J Autoimmun 55:73-85. IF 7,02
Khorooshi, R., Mørch, M, Berg, CT, Holm, TH, Dieu, RT, Dræby, D, Issazadeh-Navikas, S, Weiss, S, Lienenklaus, S and Owens, T. 2015. Induction of endogenous Type I interferon within the central nervous system plays a protective role in experimental autoimmune en-cephalomyelitis. Acta Neuropathologica, 130:107-118.
Wlodarczyk, A, Cédile, O, Jensen, KN, Jasson, A, Mony, JT, Khorooshi, R, and Owens, T. 2015. Pathologic and protective roles for microglial subsets and bone marrow- and blood-derived myeloid cells in central nervous system inflammation. Frontiers in Immunology 6:463 doi: 10.3389/fimmu.2015.00463
Berg, CT, Khorooshi R, Asgari N, Owens, T. 2017. Influence of Type I IFN signalling on anti-MOG-mediated demyelination. J Neuroinflammation 14: 127 Doi 10.1186/s12974-017-0899-1
Wlodarczyk A, Holtman IR, Krueger M, Yogev N, Bruttger J, Khorooshi, R, Benmamar-Badel, A, de Boer-Bergsma JJ, Martin,NA, Karram K, Kramer, I, Boddeke EWGM, Waisman A, Eg-gen BJL and Owens T. 2017. A novel microglial subset plays a key role in myelinogenesis in developing brain. EMBO J. doi: 10.15252/embj.201696056.
Cédile, O, Østerby Jørgensen, L, Frank, I, Wlodarczyk, A and Owens, T. 2017. The chemokine receptor CCR2 maintains plasmacytoid dendritic cell homeostasis. Immun Letts. https://doi.org/10.1016/j.imlet.2017.10.012
Mørch, M, Forsberg Sørensen, S, Khorooshi, R, Asgari, N, Owens, T. 2018. Selective localization of IgG from cerebrospinal fluid to brain parenchyma. J Neuroinflammation 15:110. doi:10.1186/s12974-018-1159-8
Wlodarczyk A, Benmamar-Badel A, Cédile O, Jensen KN, Kramer I, Elsborg NB and Owens T. 2018. CSF1R stimulation promotes increased neuroprotection by CD11c+ microglia in EAE. Frontiers Cell. Neurosci. 12: doi: 10.3389/fncel.2018.00523.
Khorooshi R, Tofte-Hansen EU, Tygesen C, Montañana-Rosell R, Limburg HL, Marczynska, J, Asgari N, Steckelings UM, and Owens T. 2020. Angiotensin AT2-receptor induced inter-leukin-10 attenuates neuromyelitis optica spectrum disorder-like pathology. Mult Scler 26: 1187-1196 doi: 10.1177/1352458519860327.
Khorooshi, R., J. Marczynska, R.S. Dieu, V. Wais, C.R. Hansen, S. Kavan, M. Thomassen, M. Burton, T. Kruse, G.A. Webster, and T. Owens. 2020. Innate signaling within the central nervous system re-cruits protective neutrophils. Acta Neuropathologica Communications 8:2 doi: 10.1186/s40478-019-0876-2.
Benmamar-Badel, A., T. Owens, and A. Wlodarczyk. 2020. Protective microglial subset in development, aging and disease: lessons from transcriptomic studies. Frontiers in Immunology 11:43. Doi 10.3389/fimmu.2020.00430.
Wlodarczyk A, Khorooshi R, Marczynska J, Holtman IR, Burton M, Jensen KN, Blaabjerg M, Meyer M, Thomassen M, Eggen BJL, Asgari N, Owens T. 2020. Type I interferon-activated microglia are critical for neuromyelitis optica pathology. Glia. Doi 10.1002/glia.23938
Khorooshi, R., J. Marczynska, M. Dubik, R.S. Dieu, S.F. Sorensen, R. Montanana-Rosell, H.L. Limburg, C. Tygesen, N. Asgari, U.M. Steckelings, and T. Owens. 2021. The protective effect of Angioten-sin AT2-receptor stimulation in Neuromyelitis optica spectrum disorder is independent of astrocyte-derived BDNF. Mult Scler Relat Disord 53:103033. Doi 10.1016/j.msard.2021.103033
Dubik, M., J. Marczynska, M.T. Mørch, G. Webster, K.N. Jensen, A. Wlodarczyk, R. Khorooshi, and T. Owens. 2021. Innate Signaling in the CNS Prevents Demyelination in a Focal EAE Model. Fron-tiers in Neuroscience 15: Doi 10.3389/fnins.2021.682451
Dieu, R.S., V. Wais, M.Z. Sørensen, J. Marczynska, M. Dubik, S. Kavan, M. Thomassen, M. Burton, T. Kruse, R. Khorooshi, and T. Owens. 2021. Central Nervous System-Endogenous TLR7 and TLR9 Induce Different Immune Responses and Effects on Experimental Autoimmune Encephalomyelitis. Frontiers in Neuroscience 15: doi 10.3389/fnins.2021.685645
Soerensen, S.F., M. Wirenfeldt, A. Wlodarczyk, M.T. Moerch, R. Khorooshi, D.S. Arengoth, S.T. Lillevang, T. Owens, and N. Asgari. 2021. An Experimental Model of Neuromyelitis Optica Spec-trum Disorder-Optic Neuritis: Insights Into Disease Mechanisms. Front Neurol 12:703249. doi 10.3389/fneur.2021.703249
Morch, M.T., R. Khorooshi, J. Marczynska, M. Dubik, S. Nielsen, J.D. Nieland, N. Asgari, and T. Ow-ens. 2021. Mitochondria–A target for attenuation of astrocyte pathology. Journal of Neuroim-munology 577657. doi.org/10.1016/j.jneuroim.2021.577657
Key collaborations:
Danish:
Søren Paludan, Aarhus University (AU) – interferon induced genes in CNS
Ulrike Muscha Steckelings, SDU – Angiotensin II Type 2 receptor in regulation of neuroinflammation
Nasrin Asgari, SDU IMM and Slagelse Hospital – impact of comorbidity in MS and NMOSD
Agnieszka Wlodarczyk, SDU IMM – Immunoregulation by microglial precursors and subsets
International:
Bart Eggen, UMC Groningen, Netherlands – transcriptomic analysis of mouse microglia
Tanja Kuhlmann, Münster, Germany – microglia/macrophage involvement in PMS lesions
Gill Webster, Auckland, New Zealand – innate triggers for tolerogenic myeloid cells in CNS
Una Fitzgerald, NUI Galway, Ireland – immunoregulation in mouse models of PMS