气候变化领域集成服务门户(CCPortal): The hedgehog pathway suppresses neuropathogenesis in CD4 T cell-driven inflammation

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DOI	10.1093/brain/awab083
	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
通讯作者	Alvarez, JI (通讯作者)，Univ Penn, Sch Vet Med, Dept Pathobiol, 380 South Univ Ave,412 Hill, Philadelphia, PA 19104 USA.
发表日期	2021
ISSN	0006-8950
EISSN	1460-2156
起始页码	1670
结束页码	1683
卷号	144
英文摘要	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	EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS BLOOD-BRAIN-BARRIER CYTOKINE GM-CSF NF-KAPPA-B MULTIPLE-SCLEROSIS CEREBROSPINAL-FLUID SIGNALING PATHWAY EFFECTOR PHASE T(H)17 CELLS EXPRESSION
英文关键词	sonic hedgehog; neuroinflammation; autoimmunity; experimental autoimmune encephalomyelitis; T cells
语种	英语
WOS研究方向	Neurosciences & Neurology
WOS类目	Clinical Neurology ; Neurosciences
WOS记录号	WOS:000710929200016
来源期刊	BRAIN
来源机构	中国科学院西北生态环境资源研究院
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/254825
作者单位	[Benallegue, Nail; Kebir, Hania; Kapoor, Richa; Crockett, Alexis; Li, Cen; Cheslow, Lara; Gesualdi, James; Miller, Miles C.; Church, Molly E.; Alvarez, Jorge, I] Univ Penn, Sch Vet Med, Dept Pathobiol, 380 South Univ Ave,412 Hill, Philadelphia, PA 19104 USA; [Benallegue, Nail] Univ Nantes, Ctr Rech Transplantat & Immunol, ITUN, CHU Nantes,UMR 1064,Inserm, F-44000 Nantes, France; [Li, Cen] Chinese Acad Sci, Northwest Inst Plateau Biol, Xining 810008, Peoples R China; [Abdel-Hakeem, Mohamed S.; Wherry, E. John] Univ Penn, Perelman Sch Med, Inst Immunol, Philadelphia, PA 19104 USA; [Abdel-Hakeem, Mohamed S.; Wherry, E. John] Univ Penn, Sch Med, Dept Syst Pharmacol & Translat Therapeut, Philadelphia, PA 19104 USA; [Abdel-Hakeem, Mohamed S.] Cairo Univ, Fac Pharm, Dept Microbiol & Immunol, Cairo 11562, Egypt; [Blanco, M. Andres] Univ Penn, Sch Vet Med, Dept Biomed Sci, Philadelphia, PA 19104 USA
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]. 中国科学院西北生态环境资源研究院,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).