Molecular interventions that limit pathogenic CNS inflammation are used to treat autoimmune conditions such as multiple sclerosis (MS). Remarkably, IL-1β-knockout mice are highly resistant to experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Here, we show that interfering with the IL-1β/IL-1R1 axis severely impairs the transmigration of myeloid cells across central nervous system (CNS) endothelial cells (ECs). Notably, we report that IL-1β expression by inflammatory CCR2hi monocytes favors their entry into the spinal cord before EAE onset. Following activation with IL-1β, CNS ECs release GM-CSF, which in turn converts monocytes into antigen-presenting cells (APCs). Accordingly, spinal cord-infiltrated monocyte-derived APCs are associated with dividing CD4+ T cells. Factors released from the interaction between IL-1β-competent myeloid cells and CD4+ T cells are highly toxic to neurons. Together, our results suggest that IL-1β signaling is an entry point for targeting both the initiation and exacerbation of neuroinflammation.
Keywords: autoimmunity; blood–brain barrier; experimental autoimmune encephalomyelitis; interleukin-1β; multiple sclerosis.