IL-1? enables CNS access to CCR2hi monocytes and the generation of pathogenic cells through GM-CSF released by CNS endothelial cells.

ABSTRACT: Molecular interventions that limit pathogenic CNS inflammation are used to treat autoimmune conditions such as multiple sclerosis (MS). Remarkably, IL-1?-knockout mice are highly resistant to experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Here, we show that interfering with the IL-1?/IL-1R1 axis severely impairs the transmigration of myeloid cells across central nervous system (CNS) endothelial cells (ECs). Notably, we report that IL-1? expression by inflammatory CCR2hi monocytes favors their entry into the spinal cord before EAE onset. Following activation with IL-1?, 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-1?-competent myeloid cells and CD4+ T cells are highly toxic to neurons. Together, our results suggest that IL-1? signaling is an entry point for targeting both the initiation and exacerbation of neuroinflammation.

SUBMITTER: Pare A 

PROVIDER: S-EPMC5819409 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature