Factsheet by Trevor Owens

Group name: Owens group/Neuroimmunology
Group leader: Trevor Owens, PhD
Group members:
1 assoc prof/ATAP
1 clinical assoc prof
2 postdocs
4 PhD students
1 masters students
2 technicians
3 project students (number varies)

Department & University/Hospital/Other: Neurobiology, IMM, SDU
Funding sources: Scleroseforeningen, Lundbeckfonden, FSS, NovoNordiskFonden, RegionSyddanmark, ECTRIMS


Description of research:
1. 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 location in the CNS and their migration to and interaction with elements of the immune response.

2. 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 (NMO). We have published adoptive transfer models for NMO using patient-derived IgG and we recently developed stereotactic models for focal white matter demyelination. Antibody+complement-mediated pathologies are dependent on Type I IFN, which is nevertheless 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 NMO-like pathology.

3. 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. Cells with a distinct phenotype corresponding to microglial precursors are located in the placenta and we study whether they may be responsible for pregnancy-associated remission from MS.


Key publications (last 10 years):
Remington, L.T., Babcock, A.A., Zehntner, S.P., and Owens, T. 2007. Microglial Recruitment, Activation and Proliferation in Response to Primary Demyelination. Am. J. Pathol. 170:1713-1724.

Millward, J. M., M. Caruso, I. L. Campbell, J. Gauldie, and T. Owens. 2007. IFN-{gamma}-Induced Chemokines Synergize with Pertussis Toxin to Promote T Cell Entry to the Central Nervous System. J Immunol 178:8175-8182.

Babcock, A.A., Toft-Hansen, H. and Owens, T. 2008. Signaling Through MyD88 Regulates Leu-kocyte Recruitment After Brain Injury. J. Immunol. 181: 6481-6490.

Füchtbauer, L, Toft-Hansen, H., Khorooshi, R., and Owens T. 2010. Expression of astrocytic type 2 angiotensin receptor in CNS inflammation correlates with blood-brain barrier breakdown. J. Mol. Neurosci. 42:89-98.

Khorooshi, R. and Owens, T. 2010. Injury-induced type I interferon signaling regulates inflamma-tory responses in the CNS. J. Immunol. 185: 1258-1264.

Millward, J.M., Løbner, M., Wheeler, R.D. and Owens, T. 2010. Inflammation in the central nerv-ous system and Th17 responses are inhibited by interferon-gamma-induced interleukin-18 binding protein. J. Immunol. 185:2458-2466.

Toft-Hansen, H., Füchtbauer, LM, and Owens, T. 2011. Inhibition of reactive astrocytosis in estab-lished experimental autoimmune encephalomyelitis favors infiltration by myeloid cells over T cells and enhances severity of disease. Glia 59:166-176.

Salem, M., J. T. Mony, M. Løbner, R. Khorooshi, and T. Owens. 2011. Interferon regulatory fac-tor-7 modulates inflammatory responses in experimental autoimmune encephalomyelitis in mice. J. Neuroinflamm. 8:181-189.

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, Eggen BJL and Owens T.. 2017. A novel microglial subset plays a key role in myelinogenesis in de-veloping brain. EMBO J (in press)

Cédile, O, Wlodarczyk, A, and Owens T. 2017. CCL2 recruits T cells into the brain in a CCR2-independent manner. APMIS: Doi 10.1111/apm.12740


Submitted papers:
Cédile, O, Østerby Jørgensen, L, Frank, I, Wlodarczyk, A and Owens, T. 2017. The chemokine receptor CCR2 maintains plasmacytoid dendritic cell homeostasis. In revision Immunol Letts.

Khorooshi, R, Wais, V, Dieu, RS, Kavan, S, Burton, M, Kruse TA Thomassen M, Webster, GA, and Owens, T. Myeloid cell phagocytosis in CNS induces EAE-suppressive Type I IFN re-sponse.

Khorooshi R, Tofte-Hansen EU, Hermansen C, Rosell RM, Limburg HL, Asgari N, Steckelings UM, and Owens T. Angiotensin II type 2 receptor stimulation induces IL-10 and plays a protec-tive role in neuromyelitis optica spectrum disorder.

Prajeeth, CK, Kronisch, J, Khorooshi, R, Knier, B, Toft-Hansen, H, Gudi, V, Floess, S, Huehn, J, Owens, T, Korn, T Stangel, M. Effectors of Th1 and Th17 cells act on astrocytes and augment their neuroinflammatory properties.


Key collaborations:
Danish:
Søren Paludan, Aarhus University (AU) – interferon induced genes in CNS
Lisbeth Laursen, AU – antibody+complement-mediated oligodendrocyte pathology and effects of IFN signaling
Ulrike Muscha Steckelings, SDU – Angiotensin II Type 2 receptor in regulation of neuroinflammation

International:
Bart Eggen, UMC Groningen, Netherlands – transcriptomic analysis of mouse microglia
Ari Waisman, Mainz, Germany – depletion and repopulation of microglial subsets in mouse brain
Gill Webster, Auckland, New Zealand – innate triggers for tolerogenic myeloid cells in CNS
Martin Krueger, Leipzig University, Germany – myelin pathology in developing brain