Amelioration of Japanese encephalitis by blockage of 4-1BB signaling is coupled to divergent enhancement of type I-II IFN responses and Ly-6Chi monocyte differentiationReportar como inadecuado




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Journal of Neuroinflammation

, 12:216

First Online: 24 November 2015Received: 02 October 2015Accepted: 16 November 2015

Abstract

BackgroundJapanese encephalitis JE, a neuroinflammation caused by zoonotic JE virus, is the major cause of viral encephalitis worldwide and poses an increasing threat to global health and welfare. To date, however, there has been no report describing the regulation of JE progression using immunomodulatory tools for developing therapeutic strategies. We tested whether blocking the 4-1BB signaling pathway would regulate JE progression using murine JE model.

MethodsInfected wild-type and 4-1BB-knockout KO mice were examined daily for mortality and clinical signs, and neuroinflammation in the CNS was evaluated by infiltration of inflammatory leukocytes and cytokine expression. In addition, viral burden, JEV-specific T cell, and type I-II IFN IFN-I-II innate responses were analyzed.

ResultsBlocking the 4-1BB signaling pathway significantly increased resistance to JE and reduced viral burden in extraneural tissues and the CNS, rather than causing a detrimental effect. In addition, treatment with 4-1BB agonistic antibody exacerbated JE. Furthermore, JE amelioration and reduction of viral burden by blocking the 4-1BB signaling pathway were associated with an increased frequency of IFN-II-producing NK and CD4 Th1 cells as well as increased infiltration of mature Ly-6C monocytes in the inflamed CNS. More interestingly, DCs and macrophages derived from 4-1BB KO mice showed potent and rapid IFN-I innate immune responses upon JEV infection, which was coupled to strong induction of PRRs RIG-I, MDA5, transcription factors IRF7, and antiviral ISG genes ISG49, ISG54, ISG56. Further, the ablation of 4-1BB signaling enhanced IFN-I innate responses in neuron cells, which likely regulated viral spread in the CNS. Finally, we confirmed that blocking the 4-1BB signaling pathway in myeloid cells derived from hematopoietic stem cells HSCs played a dominant role in ameliorating JE. In support of this finding, HSC-derived leukocytes played a dominant role in generating the IFN-I innate responses in the host.

ConclusionsBlocking the 4-1BB signaling pathway ameliorates JE via divergent enhancement of IFN-II-producing NK and CD4 Th1 cells and mature Ly-6C monocyte infiltration, as well as an IFN-I innate response of myeloid-derived cells. Therefore, regulation of the 4-1BB signaling pathway with antibodies or inhibitors could be a valuable therapeutic strategy for the treatment of JE.

Keywords4-1BB signal Japanese encephalitis Type I-II IFN Ly-6C monocytes Zoonotic diseases Neurologic disorder AbbreviationsBBBblood–brain barrier

BMbone marrow

BMDCbone marrow-derived dendritic cell

BMDMbone marrow-derived macrophage

dpidays post-infection

HSChematopoietic stem cell

IFN-I-IItype I-II interferon

JEJapanese encephalitis

KOknockout

TLRToll-like receptor

TNFRtumor necrosis factor receptor

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Autor: Seong Bum Kim - Jin Young Choi - Jin Hyoung Kim - Erdenebelig Uyangaa - Ajit Mahadev Patil - Sang-Youel Park - John Hwa

Fuente: https://link.springer.com/







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