Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) in which areas of demyelination are the main histopathological hallmark. Some of these areas are spontaneously remyelinated by oligodendrocyte precursor cells (OPCs), a process in which regulatory immune cells are important promoting factors. Myeloid-derived suppressor cells (MDSCs) are regulatory immune cells that promote OPC proliferation, survival and differentiation. Previous work of our group in the murine model of MS, Experimental Autoimmune Encephalomyelitis (EAE), showed that the peripheral load of MDSCs at the onset of symptoms is inversely correlated with the severity of the clinical course and the degree of demyelination, and directly correlated with the density of infiltrated MDSCs and OPCs in the demyelinated plaque and the adjacent periplaque of the spinal cord lesions, respectively.
Due to the fact that the mobilization of OPCs towards the inflammatory lesion area is crucial for myelin repair after a demyelinating insult, in the present work we interrogate whether the increase in OPC densities in EAE mice that have suffered a mild disease course could also be the consequence of greater proliferative activity during the inflammatory phase. Further, we will study whether MDSC peripheral load in the blood is a good bioindicator of this proliferative capacity as well as to a higher mature oligodendrocyte (OL) density associated to EAE demyelinated areas.
MDSCs were analyzed in the peripheral blood of each EAE mouse at onset of disease course. BrdU was i.p. injected since onset during three consecutive days. Animals were followed up till the day of maximal affectation and spinal cords were dissected out for the histopathology analysis of proliferating MDSCs and OPCs, and for OL distribution in association to areas of demyelination. A correlation analysis was carried out between blood MDSCs, the future disease severity, and the different histopathological parameters.
We show that the higher MDSC content in the peripheral blood at the onset of the disease is associated to the higher density of proliferating MDSCs in the demyelinated plaque together with a higher density of proliferating OPCs in the adjacent periplaque at the peak of the disease. In contrast, MDSCs at onset of EAE is independent of the abundance of OLs in areas of demyelination. Interestingly, the presence of MDSCs in the inflamed tissue directly correlated with a higher OPC proliferation and OL preservation in the adjacent areas. Finally, the more aggressive clinical course in each animal is related to a dramatic decrease in both OPCs and OLs in the inflamed CNS.
Our data indicate that the predictive capacity of peripheral MDSC-based association to a milder disease course can be considered as a good bioindicator of a CNS prone to succeed in spontaneous remyelination.