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

Progressive multiple sclerosis (MS) represents the worsening phase of the disease, characterized by increasing neurodegeneration and disability and mainly refractory to current treatments. Finding therapeutic options remains challenging partially not only because of the lack of understanding of 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 start early in disease development, and therapeutic strategies for progressive MS should combine anti-inflammatory and neuroprotective aspects. Increasing preclinical evidence, together with the new era of omics applied on frozen human brain tissue, has shed light on some ligand receptor pairs, such as growth-arrest-specific 6 (GAS6)/protein tyrosine kinase receptor (TYRO3) and protein S (PROS1)/AXL receptor tyrosine kinase (AXL), required to dampen inflammation, promote tissue repair, and engage remyelination. Understanding the role of these proteins in the early stages of MS is a critical step toward preventing or stopping neurodegeneration. Herein, we will discuss the receptor/ligand pairs that might be targetable for therapeutic intervention in progressive MS. SIGNIFICANCE STATEMENT: The aim for progressive multiple sclerosis treatment should be to combine anti-inflammatory and neuroprotective therapeutic strategies based on early intervention. Targeting the TYRO3, AXL, and MER tyrosine kinase receptor (TAM) signaling axis, particularly as growth-arrest-specific 6/TYRO3 and protein S/AXL, which are involved in tempering inflammation, promoting tissue repair, and engaging remyelination, could significantly benefit patients in the early stages of progressive multiple sclerosis.