Toll-like receptor signaling directly increases functional IL-17RA expression in neuroglial cells

IL-17, the hallmark cytokine of Th17 cells, plays a pivotal role in the pathogenesis of autoimmune diseases, including encephalomyelitis. In the central nervous system, neuroglial cells are the main residents that express IL-17R and respond to IL-17 by producing chemokines/cytokines and boosting local inflammation. Factors that influence the IL-17R expression in neuroglial cells can also exert their impacts on the outbreak, progression and outcome of encephalomyelitis. Here, we reported that Toll-like receptor signaling has its bias for promoting the IL-17RA, but not the IL-17RC, expression in mouse neuroglial cells in a T cell infiltration independent manner. Elevated IL-17R functionally responded to IL-17 by secreting more chemokines and accelerating CD4 cell migration. First, real-time PCR confirmed that the expression of Il-17ra, but not Il-17rc, was significantly increased in the brain and spinal cord of EAE-induced mice. This effect was elicited by something in complete Freundʹs adjuvant (CFA), because markedly increased IL-17R was detected in mice immunized with CFA only, even though no evidence of EAE was found. Furthermore, in Rag1−/− mice, it was confirmed that CFA could augment the IL-17RA expression in the CNS in the absence of T cell infiltration. In vivo immunization with TLR ligands and in vitro treatment of purified neuroglial cells demonstrated that TLR ligands directly and effectively evoke the IL-17RA expression in the CNS and in cultured astrocytes, microglia and oligodendrocytes. LPS was the most effective inducer of the IL-17RA expression in astrocytes, and polyIC was superior to LPS for microglia and oligodendrocytes. Activated CD4 cells can also promote the secretion of chemokines by LPS pre-treated astrocytes, and hence accelerate the migration of CD4 cells, which was blocked by the neutralization of IL-17RA on the surface of the astrocyte. Taken together, we concluded that TLR signaling can directly stimulate the expression of IL-17RA, but not IL-17RC, in neuroglial cells, which functionally respond to IL-17A by secreting chemokines, accelerating CD4 cell migration, and contributing to the pathogenesis of encephalomyelitis.