Microglial PD-1/PD-L1 axis in CNS demyelinating diseases: a dual immunoregulatory perspective

Multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) stand as archetypal autoimmune-mediated demyelinating diseases of the central nervous system (CNS). Emerging evidence highlights the dual immunomodulatory functions of microglia in these diseases: on the one hand, they can secrete neurotoxic molecules that exacerbate neural damage; on the other hand, they are capable of releasing neuroprotective factors that promote tissue repair and enhance neuronal survival. This review dissects the programmed cell death ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) immune checkpoint axis, expressed on activated microglia, T cells, and other immune cells, as a pivotal rheostat of neuroinflammation. The binding of PD-1 to PD-L1 dampens immune cell activation and proliferation, curtails pro-inflammatory cytokine output, and is instrumental in preserving immune tolerance. In the context of chronic inflammation, persistent PD-1/PD-L1 signaling has been closely associated with the induction of T cell exhaustion than with direct apoptosis, though context-dependent effects on cell survival have been reported in certain experimental paradigms. Both microglia and the PD-1/PD-L1 axis are critically intertwined in the initiation and perpetuation of CNS demyelinating diseases. A more granular comprehension of their interplay will not only illuminate the molecular underpinnings of neuroinflammation and immune regulation in MS and NMOSD but also pave the way for crafting precision immunotherapies aimed at modulating microglial polarization. Here, we systematically review the dual immunomodulatory functions of the microglial PD-1/PD-L1 axis in these diseases and deliberate on the therapeutic prospects of targeting this pathway, thereby furnishing a conceptual framework for novel immune intervention strategies.