Altered Expression of Oligodendrocyte and Neuronal Marker Genes Predicts the Clinical Onset of Autoimmune Encephalomyelitis and Indicates the Effectiveness of Multiple Sclerosis–Directed Therapeutics

Abstract

Experimental autoimmune encephalomyelitis (EAE) is a valuable model for studying immunopathology in multiple sclerosis (MS) and for exploring the interface between autoimmune responses and CNS tissue that ultimately leads to lesion development. In this study, we measured gene expression in mouse spinal cord during myelin oligodendrocyte gp35–55 peptide–induced EAE, using quantitative RT-PCR, to identify gene markers that monitor individual hallmark pathological processes. We defined a small panel of genes whose longitudinal expression patterns provided insight into the timing, interrelationships, and mechanisms of individual disease processes and the efficacy of therapeutics for the treatment of MS. Earliest transcriptional changes were upregulation of Il17a and sharp downregulation of neuronal and oligodendrocyte marker genes preceding clinical disease onset, whereas neuroinflammatory markers progressively increased as symptoms and tissue lesions developed. EAE-induced gene-expression changes were not altered in mice deficient in IKKβ in cells of the myeloid lineage compared with controls, but the administration of a selective inhibitor of soluble TNF to mice from the day of immunization delayed changes in the expression of innate inflammation, myelin, and neuron markers from the presymptomatic phase. Proof of principle that the gene panel shows drug screening potential was obtained using a well-established MS therapeutic, glatiramer acetate. Prophylactic treatment of mice with glatiramer acetate normalized gene marker expression, and this correlated with the level of therapeutic success. These results show that neurons and oligodendrocytes are highly sensitive to CNS-directed autoimmunity before the development of clinical symptoms and immunopathology and reveal a role for soluble TNF in mediating the earliest changes in gene expression.

Therapeutic inhibition of soluble brain TNF promotes remyelination by increasing myelin phagocytosis by microglia

“…Interestingly, XPro1595-treated naive mice showed increased brain expression of Chil3, which encodes a protein associated with host defense (37) and is used as a marker for beneficial alternatively activated macrophages. Previous work also shows that XPro1595 treatment induces a transient activation of immune genes in the spinal cord at the onset of EAE, in parallel to having protective effects on OLG and neuronal gene expression (50). Here, although XPro1595 treatment did not alter the numbers of Mac3-positive macrophages in early demyelinating lesions, it increased the numbers and size of macrophages containing myelin degradation products and facilitated the clearance of myelin debris and remyelination in corpus callosum lesions.…”

TNFR2 Deficiency Acts in Concert with Gut Microbiota To Precipitate Spontaneous Sex-Biased Central Nervous System Demyelinating Autoimmune Disease

“…Consistent with this hypothesis, TNF plays dual roles during autoimmune demyelination, namely exacerbation of inflammation at the onset of disease and facilitation of the resolution of inflammation and myelin repair during ongoing disease (18,22). In agreement, selective pharmacological inhibition of soluble TNF prevents transcriptional changes associated with the onset of CNS inflammatory demyelination and protects against MOG-induced EAE (23). Therefore, it is conceivable that selective blockade of TNFR1 may minimize undesirable side effects from anti-TNF therapy.…”

Essential protective role of tumor necrosis factor receptor 2 in neurodegeneration

“…In support of this finding, we here provide compelling evidence in an in vivo model of NMDAinduced acute neuronal lesions that abrogation of complete TNF signaling by blocking both TNFRs is not protective, because mounting of a neuroprotective TNFR2-dependent response is prevented. However, preclinical studies in the experimental autoimmune encephalomyelitis (EAE) model (36)(37)(38) or a mouse model of spinal cord injury (39) revealed that selective neutralization of sTNF/TNFR1 signaling is neuroprotective. Of note, in the EAE model, systemic application of TNFR1-blocking antibodies proved to be therapeutically effective (40).…”