TY - JOUR TI - The hedgehog pathway suppresses neuropathogenesis in CD4 T cell-driven inflammation AU - Benallegue, Nail AU - Kebir, Hania AU - Kapoor, Richa AU - Crockett, Alexis AU - Li, Cen AU - Cheslow, Lara AU - Abdel-Hakeem, Mohamed S AU - Gesualdi, James AU - Miller, Miles C AU - Wherry, E John AU - Church, Molly E AU - Blanco, M Andres AU - Alvarez, Jorge I T2 - Brain AB - The concerted actions of the CNS and the immune system are essential to coordinate the outcome of neuroinflammatory responses. Yet, the precise mechanisms involved in this crosstalk and their contribution to the pathophysiology of neuroinflammatory diseases largely elude us. Here, we show that the CNS-endogenous hedgehog pathway, a signal triggered as part of the host response during the inflammatory phase of multiple sclerosis and experimental autoimmune encephalomyelitis, attenuates the pathogenicity of human and mouse effector CD4 T cells by regulating their production of inflammatory cytokines. Using a murine genetic model in which the hedgehog signaling is compromised in CD4 T cells, we show that the hedgehog pathway acts on CD4 T cells to suppress pathogenic hallmarks of autoimmune neuroinflammation, including demyelination and axonal damage, and thus mitigates the development of experimental autoimmune encephalomyelitis. Impairment of hedgehog signaling in CD4 T cells exacerbates brain-brainstem-cerebellum inflammation and leads to the development of atypical disease. Moreover, we present evidence that hedgehog signaling regulates the pathogenic profile of CD4 T cells by limiting their production of inflammatory cytokines GM-CSF and IFN-γ and by antagonizing their inflammatory program at the transcriptome level. Likewise, hedgehog signaling attenuates the inflammatory phenotype of human CD4 memory T cells. From a therapeutic point of view, our study underlines the potential of harnessing the hedgehog pathway to counteract ongoing excessive CNS inflammation as systemic administration of a hedgehog agonist after disease onset effectively halts disease progression and significantly reduces neuroinflammation and the underlying neuropathology. We thus unveil a previously unrecognized role for the hedgehog pathway in regulating pathogenic inflammation within the CNS, but also propose to exploit its ability to modulate this neuroimmune network as a strategy to limit the progression of ongoing neuroinflammation. DA - 2021/03/16/ PY - 2021 DO - 10.1093/brain/awab083 DP - Silverchair IS - awab083 J2 - Brain SN - 0006-8950 UR - https://doi.org/10.1093/brain/awab083 Y2 - 2021/03/19/06:44:13 ER -