Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Inserm, Université de Nantes, CHU Nantes, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, F-44000 Nantes, France.
Brain. 2021 Jul 28;144(6):1670-1683. doi: 10.1093/brain/awab083.
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-γ 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.
中枢神经系统（CNS）与免疫系统的协同作用对于协调神经炎症反应的结果至关重要。然而，这种串扰中涉及的确切机制及其对神经炎症性疾病的病理生理学的贡献在很大程度上仍未被我们所了解。在这里，我们表明，CNS 内源性的 hedgehog 信号通路是宿主在多发性硬化症和实验性自身免疫性脑脊髓炎的炎症阶段反应的一部分，通过调节其促炎细胞因子的产生，从而减弱人类和小鼠效应性 CD4 T 细胞的致病性。利用 hedgehog 信号在 CD4 T 细胞中受到损害的小鼠遗传模型，我们表明 hedgehog 通路作用于 CD4 T 细胞，以抑制自身免疫性神经炎症的发病特征，包括脱髓鞘和轴突损伤，从而减轻实验性自身免疫性脑脊髓炎的发展。CD4 T 细胞中 hedgehog 信号的损伤会加剧脑-脑干-小脑炎症，并导致非典型疾病的发生。此外，我们提供的证据表明，hedgehog 信号通过限制促炎细胞因子粒细胞-巨噬细胞集落刺激因子和干扰素-γ的产生，并通过在转录组水平拮抗其炎症程序，来调节 CD4 T 细胞的致病性特征。同样，hedgehog 信号也会减弱人类 CD4 记忆 T 细胞的炎症表型。从治疗的角度来看，我们的研究强调了利用 hedgehog 通路来对抗持续的中枢神经系统过度炎症的潜力，因为疾病发作后系统性给予 hedgehog 激动剂可有效阻止疾病进展，并显著减少神经炎症和潜在的神经病理学。因此，我们揭示了 hedgehog 通路在调节中枢神经系统内致病性炎症中的一个先前未被认识的作用，并提出利用其调节这种神经免疫网络的能力作为限制持续神经炎症进展的策略。
