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Neural precursor cell–secreted TGF-β2 redirects inflammatory monocyte-derived cells in CNS autoimmunity
The Journal of Clinical Investigation ( IF 13.3 ) Pub Date : 2017-09-25 , DOI: 10.1172/jci92387
Donatella De Feo , Arianna Merlini , Elena Brambilla , Linda Ottoboni , Cecilia Laterza , Ramesh Menon , Sundararajan Srinivasan , Cinthia Farina , Jose Manuel Garcia Manteiga , Erica Butti , Marco Bacigaluppi , Giancarlo Comi , Melanie Greter , Gianvito Martino

In multiple sclerosis, the pathological interaction between autoreactive Th cells and mononuclear phagocytes in the CNS drives initiation and maintenance of chronic neuroinflammation. Here, we found that intrathecal transplantation of neural stem/precursor cells (NPCs) in mice with experimental autoimmune encephalomyelitis (EAE) impairs the accumulation of inflammatory monocyte-derived cells (MCs) in the CNS, leading to improved clinical outcome. Secretion of IL-23, IL-1, and TNF-α, the cytokines required for terminal differentiation of Th cells, decreased in the CNS of NPC-treated mice, consequently inhibiting the induction of GM-CSF–producing pathogenic Th cells. In vivo and in vitro transcriptome analyses showed that NPC-secreted factors inhibit MC differentiation and activation, favoring the switch toward an antiinflammatory phenotype. Tgfb2–/– NPCs transplanted into EAE mice were ineffective in impairing MC accumulation within the CNS and failed to drive clinical improvement. Moreover, intrathecal delivery of TGF-β2 during the effector phase of EAE ameliorated disease severity. Taken together, these observations identify TGF-β2 as the crucial mediator of NPC immunomodulation. This study provides evidence that intrathecally transplanted NPCs interfere with the CNS-restricted inflammation of EAE by reprogramming infiltrating MCs into antiinflammatory myeloid cells via secretion of TGF-β2.

中文翻译:

神经前体细胞分泌的TGF- β2在中枢神经系统自身免疫中重定向炎性单核细胞衍生的细胞

在多发性硬化症中,中枢神经系统中自身反应性Th细胞与单核吞噬细胞之间的病理相互作用驱动慢性神经炎症的发生和维持。在这里,我们发现在患有实验性自身免疫性脑脊髓炎(EAE)的小鼠中鞘内移植神经干/前体细胞(NPC)会损害中枢神经系统中炎性单核细胞衍生细胞(MC)的积累,从而改善临床结果。NPC处理的小鼠的中枢神经系统分泌的IL-23,IL-1和TNF-α是Th细胞终末分化所需的细胞因子,其分泌减少了,因此抑制了产生GM-CSF的致病Th细胞的诱导。体内和体外转录组分析表明,NPC分泌的因子抑制MC分化和激活,有利于转为抗炎表型。移植到EAE小鼠中的Tgfb2 – / – NPC在削弱CNS内MC蓄积方面无效,并且无法推动临床改善。此外,在EAE的效应期鞘内递送TGF-β2改善了疾病的严重性。综上所述,这些观察结果确定TGF-β2是NPC免疫调节的关键介质。这项研究提供了证据,证明通过鞘内移植的NPC通过TGF-β2的分泌将浸润的MCs重编程为抗炎性髓样细胞,从而干扰了CNS限制的EAE炎症。
更新日期:2017-11-02
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