Abstract
Multiple sclerosis (MS) is the most common causes of non-traumatic disability in young adults worldwide. MS pathophysiologies include the formation of inflammatory lesions, axonal damage and demyelination, and blood brain barrier (BBB) disruption. Coagulation proteins, including factor (F)XII, can serve as important mediators of the adaptive immune response during neuroinflammation. Indeed, plasma FXII levels are increased during relapse in relapsing-remitting MS patients, and previous studies showed that reducing FXII levels was protective in a murine model of MS, experimental autoimmune encephalomyelitis (EAE). Our objective was to determine if pharmacological targeting of FXI, a major substrate of activated FXII (FXIIa), improves neurological function and attenuates CNS damage in the setting of EAE. EAE was induced in male mice using murine myelin oligodendrocyte glycoprotein peptides combined with heat-inactivated Mycobacterium tuberculosis and pertussis toxin. Upon onset of symptoms, mice were treated every other day intravenously with anti-FXI antibody, 14E11, or saline. Disease scores were recorded daily until euthanasia for ex vivo analyses of inflammation. Compared to the vehicle control, 14E11 treatment reduced the clinical severity of EAE and total mononuclear cells, including CD11b+CD45high macrophage/microglia and CD4+ T cell numbers in brain. Following pharmacological targeting of FXI, BBB disruption was reduced, as measured by decreased axonal damage and fibrin(ogen) accumulation in the spinal cord. These data demonstrate that pharmacological inhibition of FXI reduces disease severity, immune cell migration, axonal damage, and BBB disruption in mice with EAE. Thus, therapeutic agents targeting FXI and FXII may provide a useful approach for treating autoimmune and neurologic disorders.
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The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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Funding
This study was supported by the National Multiple Sclerosis Society (PP1900), the National Institutes of Health (R01HL101972, 1F31HL162467-01A1), the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development Merit Review Award 2I01 BX000226 (AAV), BLR&D Merit Review for Pre-IND studies of Drugs and Biologics Award 5I01 BX005112 (AAV), Senior Research Career Scientist Award 1IK6BX004209 (AAV), the National Institute of Allergy and Infectious Diseases Award R21 AI148490 (HO) and 2R42AI122574 (AAV; HO).
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O.J.T. McCarty, H. Offner, and N.G. Verbout were responsible for study conception and design. N. Verbout and L.D. Healy contributed to data collection and analysis. T.C.L. Kohs and M.E. Fallon analyzed data and created figures. T.C.L. Kohs, M.E. Fallon, E.C. Oseas, and N.G. Verbout drafted and edited the manuscript. E.I. Tucker, O.J.T. McCarty, D. Gailani, A.A. Vandenbark, and H. Offner critically reviewed the manuscript.
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The animal care and procedures in this study were performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and the regulations of the Oregon Health & Science University Institutional Animal Care and Use Committee (National Research Council Committee for the Update of the Guide for the C and Use of Laboratory A 2011). The male C57BL/6 mice used in this study were housed at the Portland Veterans Affairs Medical Center in the Animal Resource Facility (Portland, OR, US) according to guidelines set by the National Research Council and the Committee on Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources.
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E.I. Tucker and N.G. Verbout are employees of Aronora, Inc., a company that may have financial interest in the study results. The Oregon Health & Science University Conflict of Interest in Research Committee has reviewed and managed this potential conflict of interest. The remaining authors declare no competing interests.
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Kohs, T.C.L., Fallon, M.E., Oseas, E.C. et al. Pharmacological targeting of coagulation factor XI attenuates experimental autoimmune encephalomyelitis in mice. Metab Brain Dis 38, 2383–2391 (2023). https://doi.org/10.1007/s11011-023-01251-1
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DOI: https://doi.org/10.1007/s11011-023-01251-1