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Protective role of cellular prion protein against TNF?-mediated inflammation through TACE ?-secretase.

ABSTRACT: Although cellular prion protein PrPC is well known for its implication in Transmissible Spongiform Encephalopathies, its functions remain elusive. Combining in vitro and in vivo approaches, we here show that PrPC displays the intrinsic capacity to protect neuronal cells from a pro-inflammatory TNF? noxious insult. Mechanistically, PrPC coupling to the NADPH oxidase-TACE ?-secretase signaling pathway promotes TACE-mediated cleavage of transmembrane TNF? receptors (TNFRs) and the release of soluble TNFR, which limits the sensitivity of recipient cells to TNF?. We further show that PrPC expression is necessary for TACE ?-secretase to stay at the plasma membrane in an active state for TNFR shedding. Such PrPC control of TACE localization depends on PrPC modulation of ?1 integrin signaling and downstream activation of ROCK-I and PDK1 kinases. Loss of PrPC provokes TACE internalization, which in turn cancels TACE-mediated cleavage of TNFR and renders PrPC-depleted neuronal cells as well as PrPC knockout mice highly vulnerable to pro-inflammatory TNF? insult. Our work provides the prime evidence that in an inflammatory context PrPC adjusts the response of neuronal cells targeted by TNF? through TACE ?-secretase. Our data also support the view that abnormal TACE trafficking and activity in prion diseases originate from a-loss-of-PrPC cytoprotective function.

SUBMITTER: Ezpeleta J

PROVIDER: S-EPMC5550509 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Protective role of cellular prion protein against TNFα-mediated inflammation through TACE α-secretase.

Ezpeleta Juliette J Boudet-Devaud François F Pietri Mathéa M Baudry Anne A Baudouin Vincent V Alleaume-Butaux Aurélie A Dagoneau Nathalie N Kellermann Odile O Launay Jean-Marie JM Schneider Benoit B

Scientific reports 20170809 1

Although cellular prion protein PrPC is well known for its implication in Transmissible Spongiform Encephalopathies, its functions remain elusive. Combining in vitro and in vivo approaches, we here show that PrPC displays the intrinsic capacity to protect neuronal cells from a pro-inflammatory TNFα noxious insult. Mechanistically, PrPC coupling to the NADPH oxidase-TACE α-secretase signaling pathway promotes TACE-mediated cleavage of transmembrane TNFα receptors ...[more]

PMID: 28794434

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Project description:UnlabelledMorphological switch is tightly coupled with the pathogenesis of many dimorphic fungal pathogens. Cryptococcus neoformans, the major causative agent of cryptococcal meningitis, mostly presents as the yeast form but is capable of switching to the hyphal form. The filamentous form has long been associated with attenuated virulence, yet the underlying mechanism remains elusive. We previously identified the master regulator Znf2 that controls the yeast-to-hypha transition in Cryptococcus. Activation of Znf2 promotes hyphal formation and abolishes fungal virulence in vivo. Here we demonstrated that the cryptococcal strain overexpressing ZNF2 elicited strong and yet temporally confined proinflammatory responses in the early stage of infection. In contrast, exacerbated inflammation in mice infected with the wild-type (WT) strain showed that they were unable to control the infection. Animals inoculated with this filamentous Cryptococcus strain had fewer pulmonary eosinophils and CD11c(+) CD11b(+) cells than animals inoculated with WT yeast. Moreover, mice infected with this strain developed protective Th1- or Th17-type T cell responses. These findings suggest that the virulence attenuation of the filamentous form is likely due to its elicitation of protective host responses. The antivirulence effect of Znf2 was independent of two previously identified factors downstream of Znf2. Interestingly, mucosal immunizations with high doses of ZNF2-overexpressing cells, either in the live or heat-killed form, offered 100% protection to the host from a subsequent challenge with the otherwise lethal clinical strain H99. Our results demonstrate that heat-resistant cellular components presented in cryptococcal cells with activated ZNF2 elicit protective host immune responses. These findings could facilitate future research on novel immunological therapies.ImportanceCryptococcal meningitis is one of the leading causes of death among AIDS patients. This disease presents a severe threat to public health. The current antifungal regimens are unsatisfactory in controlling or clearing the pathogen Cryptococcus neoformans. Immunotherapies and/or vaccines could be a promising approach to prevent or manage this deadly disease. However, the lack of understanding of host-pathogen interactions during cryptococcal infection greatly hampers the development of effective immunotherapies. In this study, we discovered that inoculation of cryptococcal cells with activated Znf2, a morphogenesis regulator and an antivirulence factor, could shift the host pathological Th2 responses to the protective Th1 or Th17 responses. Importantly, we discovered that vaccination with either the viable or heat-killed form of ZNF2-overexpressing cells protected animals from the otherwise lethal infection by the highly virulent clinical strain. Our study suggests that the fungal cellular component(s) of the ZNF2-overexpressing strain may provide potential vaccine candidate(s) for controlling the fatal disease.

Dataset Information

Protective role of cellular prion protein against TNF?-mediated inflammation through TACE ?-secretase.

Publications

Protective role of cellular prion protein against TNFα-mediated inflammation through TACE α-secretase.

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