Abstract
BackgroundMurine experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis, presents typically as ascending paralysis. However, in mice in which interferon-gamma (IFNγ) signaling is disrupted by genetic deletion, limb paralysis is accompanied by atypical deficits, including head tilt, postural imbalance, and circling, consistent with cerebellar/vestibular dysfunction. This was previously attributed to intense cerebellar and brainstem infiltration by peripheral immune cells and formation of neutrophil-rich foci within the CNS. However, the exact mechanism by which IFNγ signaling prohibits the development of vestibular deficits, and whether the distribution and composition of inflammatory foci within the CNS affects the course of atypical EAE remains elusive.MethodsWe induced EAE in IFNγ-/- mice and bone marrow chimeric mice in which IFNγR is not expressed in the CNS but is intact in the periphery (IFNγRCNSKO) and vice versa (IFNγRperiKO). Blood-brain barrier permeability was determined by Evans blue intravenous administration at disease onset. Populations of immune cell subsets in the periphery and the CNS were quantified by flow cytometry. CNS tissues isolated at various time points after EAE induction, were analyzed by immunohistochemistry for composition of inflammatory foci and patterns of axonal degeneration.ResultsIncidence and severity of atypical EAE were more pronounced in IFNγRCNSKO as compared to IFNγRperiKO mice. Contrary to what we anticipated, cerebella/brainstems of IFNγRCNSKO mice were only minimally infiltrated, while the same areas of IFNγRperiKO mice were extensively populated by peripheral immune cells. Furthermore, the CNS of IFNγRperiKO mice was characterized by persistent neutrophil-rich foci as compared to IFNγRCNSKO. Immunohistochemical analysis of the CNS of IFNγ-/- and IFNγR chimeric mice revealed that IFNγ protective actions are exerted through microglial STAT1.ConclusionsAlterations in distribution and composition of CNS inflammatory foci are not sufficient for the onset of atypical EAE. IFNγ dictates the course of neuroinflammatory disorders mainly through actions exerted within the CNS. This study provides strong evidence that link microglial STAT1 inactivation to vestibular dysfunction.
Highlights
Experimental autoimmune encephalomyelitis (EAE) is the most commonly used animal model for multiple sclerosis (MS)
Atypical neurological deficits initiate in the absence of IFNg signaling in the central nervous system (CNS) Clinical course in wild type and IFNg -/- mice Classic neurological deficits of EAE appeared both in IFNg-/- and wild-type (WT) controls on or around day 10 post-immunization
EAE induction in mice without IFNg signaling in the CNS (IFNgRCNSKO) resulted in the development of more severe and more frequent atypical disease, that had an earlier onset than mice without IFNg signaling in the periphery
Summary
Experimental autoimmune encephalomyelitis (EAE) is the most commonly used animal model for multiple sclerosis (MS). Mice in which IFNg signaling has been genetically disrupted (IFNg-/-, or IFNgR-/- mice), show evidences of cerebellar/ vestibular dysfunction, deficits that are regarded as atypical EAE features Such deficits in MS patients are associated with poor prognosis [3,4,5]. In mice in which interferon-gamma (IFNg) signaling is disrupted by genetic deletion, limb paralysis is accompanied by atypical deficits, including head tilt, postural imbalance, and circling, consistent with cerebellar/vestibular dysfunction. This was previously attributed to intense cerebellar and brainstem infiltration by peripheral immune cells and formation of neutrophil-rich foci within the CNS. The exact mechanism by which IFNg signaling prohibits the development of vestibular deficits, and whether the distribution and composition of inflammatory foci within the CNS affects the course of atypical EAE remains elusive
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
