New potential ligand-receptor axis involved in tissue repair as therapeutic targets in progressive multiple sclerosis.

Progressive multiple sclerosis (PMS) represents the worsening phase of the disease by accumulative neurodegeneration and disability, mainly refractory to current treatments. The therapeutic options remain challenging based partially on the lack of understanding of the pathogenic mechanisms but also because the early dogma was centered on neuroinflammation, overshadowing the critical role of the tissue repair process. The tissue repair target should necessarily start early in disease development and PMS should combine anti-inflammatory and neuroprotective therapeutic strategies. Increasing preclinical evidence, together with the new era of omics applied on frozen human brain tissue, shed light on some ligand receptors axis, such as GAS6/TYRO3 and PROS1/AXL required to dampen inflammation, promote tissue repair and engage remyelination, at the early stages of multiple sclerosis (MS) as a critical step in preventing or stopping neurodegeneration. Here, we will discuss those receptor/ligand pairs that could be targetable for therapeutic intervention in progressive MS disease. Significance Statement The aim for PMS should be to combine anti-inflammatory and neuroprotective therapeutic strategies based on early intervention. The TYRO3, AXL, and MERTK (TAM) signaling axis, particularly GAS6/TYRO3 and PROS1/AXL, which are involved in tempering inflammation, promoting tissue repair, and engaging remyelination, could significantly benefit patients at the early PMS.