Anti- and pro-inflammatory milieu differentially regulate differentiation and immune functions of oligodendrocyte progenitor cells

Oligodendrocyte progenitor cells (OPCs) were regarded for years solely for their regenerative role; however, their immune-modulatory roles have gained much attention recently, particularly in the context of multiple sclerosis (MS). Despite extensive studies on OPCs, there are limited data elucidating the interactions between their intrinsic regenerative and immune functions, as well as their relationship with the inflamed central nervous system (CNS) environment, a key factor in MS pathology. We examined the effects of pro-inflammatory cytokines, represented by interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha, as well as anti-inflammatory cytokines, represented by interleukin (IL)-4 and IL-10, on OPC differentiation and immune characteristics. Using primary cultures, enzyme-linked immunosorbent assay and immunofluorescence stainings, we assessed differentiation capacity, phagocytic activity, major histocompatibility complex (MHC)-II expression, and cytokine secretion. We observed that the anti-inflammatory milieu (IL4 and IL10) reduced both OPC differentiation and immune functions. Conversely, exposure to TNF-alpha led to intact differentiation, increased phagocytic activity, high levels of MHC-II expression, and cytokines secretion. Those effects were attributed to signalling via TNF-receptor-2 and counteracted the detrimental effects of IFN-gamma on OPC differentiation. Our findings suggest that a pro-regenerative, permissive inflammatory environment is needed for OPCs to execute both regenerative and immune-modulatory functions. Anti-inflammatory milieu (IL4 and IL10) reduced both OPC differentiation and immune functions. Conversely, exposure to TNF-alpha led to intact differentiation, increased phagocytic activity, high levels of MHC-II expression, cytokines secretion, and lower levels of morphological complexity. Those effects were attributed to signalling via TNFR2 and counteracted the detrimental effects of IFN gamma on OPC differentiation. Our findings point towards the essentiality of a pro-regenerative inflammatory environment, emphasising the pivotal role of TNF alpha and TNFR2 in harmonising the balance between the regenerative and immunological tasks of OPCs in the inflamed CNS.image