Oligodendrocyte degeneration and concomitant microglia activation directs peripheral immune cells into the forebrain

Abstract

Brain-intrinsic degenerative cascades are a proposed factor driving inflammatory lesion formation in multiple sclerosis (MS) patients. We recently showed that encephalitogenic lymphocytes are recruited to the sites of active demyelination induced by cuprizone. Here, we investigated whether cuprizoneinduced oligodendrocyte and myelin pathology is sufficient to trigger peripheral immune cell recruitment into the forebrain. We show that early cuprizone-induced white matter lesions display a striking similarity to early MS lesions, i.e., oligodendrocyte degeneration, microglia activation and absence of severe lymphocyte infiltration. Such early cuprizone lesions are sufficient to trigger peripheral immune cell recruitment secondary to subsequent EAE (experimental autoimmune encephalomyelitis) induction. The lesions are characterized by discontinuation of the perivascular glia limitans, focal axonal damage, and perivascular astrocyte pathology. Time course studies showed that the severity of cuprizone-induced lesions positively correlates with the extent of peripheral immune cell recruitment. Furthermore, results of genome-wide array analyses suggest that moesin is integral for early microglia activation in cuprizone and MS lesions. This study underpins the significance of brainintrinsic degenerative cascades for immune cell recruitment and, in consequence, MS lesion formation.

High-Resolution Transcriptomic and Proteomic Profiling of Heterogeneity of Brain-Derived Microglia in Multiple Sclerosis

“…Importantly, all above cell types are involved in (de)(re)myelination and immune signaling, which are the main processes that are altered in MS (Domingues et al, 2016;Molina-Gonzalez and Miron, 2019). In addition, recruitment of peripheral immune cells during MS pathogenesis is mediated by oligodendrocyte apoptosis and microglia immune activation (Chrzanowski et al, 2019). Therefore, high-resolution transcriptomic profiling of all cell types potentially involved in MS are relevant to understand MS pathology.…”

Oligodendrocyte Response to Pathophysiological Conditions Triggered by Episode of Perinatal Hypoxia-Ischemia: Role of IGF-1 Secretion by Glial Cells

“…Namely, this cell population (CD11c + ) exhibits unique properties during the early postnatal period, providing neurosupportive and myelinogenic signals [103,104]. Oligodendrocyte-microglia cross-talk has been shown to play an important role both under physiological conditions (during neurodevelopment and aging) and in different pathological disorders [105][106][107][108]. Moreover, there is a growing list of evidence that IGF-1 is involved in modulation of neuroimmunological processes [109][110][111][112].…”

Does Siponimod Exert Direct Effects in the Central Nervous System?

“…The axonal spheroid highlighted by the arrowhead is displayed on the right site at a higher magnification. ( C ) Shows the anti-glial fibrillary acidic protein-stained sections of a cuprizone-experimental autoimmune encephalomyelitis (EAE) mouse [ 41 ]. The image on the left shows moderate, and the image on the right shows severe, astrogliosis.…”