Pro-inflammatory activation following demyelination is required for myelin clearance and oligodendrogenesis

Abstract

Remyelination requires innate immune system function, but how exactly microglia and macrophages clear myelin debris after injury and tailor a specific regenerative response is unclear. Here, we asked whether pro-inflammatory microglial/macrophage activation is required for this process. We established a novel toxin-based spinal cord model of de- and remyelination in zebrafish and showed that pro-inflammatory NF-κB–dependent activation in phagocytes occurs rapidly after myelin injury. We found that the pro-inflammatory response depends on myeloid differentiation primary response 88 (MyD88). MyD88-deficient mice and zebrafish were not only impaired in the degradation of myelin debris, but also in initiating the generation of new oligodendrocytes for myelin repair. We identified reduced generation of TNF-α in lesions of MyD88-deficient animals, a pro-inflammatory molecule that was able to induce the generation of new premyelinating oligodendrocytes. Our study shows that pro-inflammatory phagocytic signaling is required for myelin debris degradation, for inflammation resolution, and for initiating the generation of new oligodendrocytes.

TNF Production and Release from Microglia via Extracellular Vesicles: Impact on Brain Functions

“…A very recent paper showed that TNF released by microglial cells, besides being fundamental for efficient clearance and degradation of myelin debris by phagocytes, it is also required for the generation of new myelinating cells within demyelinated areas, suggesting direct effects of this cytokine on OPCs [ 159 ]. This is in line with previous findings showing that TNF is able to finely regulate oligodendroglial functions, albeit its specific role still remains controversial.…”

Re-Examining the Role of TNF in MS Pathogenesis and Therapy

“…The toxic role of TNF on oligodendrocyte lineage is also highlighted by the evidence of spontaneous demyelination in transgenic mice overexpressing TNF [ 96 ]. However, in pathological states microglia-derived TNF has been reported to exert homeostatic effects in tissue regeneration, favoring neuronal remyelination, as shown in a recently established toxic model of demyelination in zebrafish [ 97 ], suggesting that TNF can exert a dual role also in pathological states. Interestingly, the development of a transgenic mouse line with the selective ablation of TNF2 in oligodendrocytes has shown that signaling through TNFR2 is not necessary for physiological development of oligodendrocytes but it promotes remyelination in pathological conditions [ 98 ].…”

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

“…First, a proinflammatory state is initiated to clear myelin debris and to stimulate oligodendrogenesis in newly formed lesions. When lesions expand, phagocytes acquire a more anti-inflammatory state and produce factors (IL-4, IL13, and IL-10) required for OPC differentiation (Butovsky et al, 2006;Miron et al, 2013;Cunha et al, 2020). This results in the de-and remyelinated regions that are often detected in/around active lesions.…”