The hedgehog pathway suppresses neuropathogenesis in CD4 T cell-driven inflammation

NWIPB OpenIR

	The hedgehog pathway suppresses neuropathogenesis in CD4 T cell-driven inflammation
	Benallegue, Nail; Kebir, Hania; Kapoor, Richa; Crockett, Alexis; Li, Cen; Cheslow, Lara; Abdel-Hakeem, Mohamed S.; Gesualdi, James; Miller, Miles C.; Wherry, E. John; Church, Molly E.; Blanco, M. Andres; Alvarez, Jorge, I
	2021
发表期刊	BRAIN
卷号	144
摘要	The concerted actions of the CNS and the immune system are essential to coordinating 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 signalling is compromised in CD4 T cells, we show that the hedgehog pathway acts on CD4 T cells to suppress the pathogenic hallmarks of autoimmune neuroinflammation, including demyelination and axonal damage, and thus mitigates the development of experimental autoimmune encephalomyelitis. Impairment of hedgehog signalling in CD4 T cells exacerbates brain-brainstem- cerebellum inflammation and leads to the development of atypical disease. Moreover, we present evidence that hedgehog signalling regulates the pathogenic profile of CD4 T cells by limiting their production of the inflammatory cytokines granulocyte-macrophage colony-stimulating factor and interferon-7 and by antagonizing their inflammatory program at the transcriptome level. Likewise, hedgehog signalling 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 and propose to exploit its ability to modulate this neuroimmune network as a strategy to limit the progression of ongoing neuroinflammation.
关键词	sonic hedgehog neuroinflammation autoimmunity experimental autoimmune encephalomyelitis T cells
文献类型	期刊论文
条目标识符	http://210.75.249.4/handle/363003/60793
专题	中国科学院西北高原生物研究所
推荐引用方式 GB/T 7714	Benallegue, Nail,Kebir, Hania,Kapoor, Richa,et al. The hedgehog pathway suppresses neuropathogenesis in CD4 T cell-driven inflammation[J]. BRAIN,2021,144.
APA	Benallegue, Nail.,Kebir, Hania.,Kapoor, Richa.,Crockett, Alexis.,Li, Cen.,...&Alvarez, Jorge, I.(2021).The hedgehog pathway suppresses neuropathogenesis in CD4 T cell-driven inflammation.BRAIN,144.
MLA	Benallegue, Nail,et al."The hedgehog pathway suppresses neuropathogenesis in CD4 T cell-driven inflammation".BRAIN 144(2021).