Inflammasome activation negatively regulates MyD88-IRF7 type I IFN signaling and anti-malaria immunity

Xiao Yu, Yang Du, Chunmei Cai, Baowei Cai, Motao Zhu, Changsheng Xing, Peng Tan, Meng Lin, Jian Wu, Jian Li, Mingjun Wang, Helen Y. Wang, Xin-zhuan Su () and Rong-Fu Wang ()
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Xiao Yu: Houston Methodist Research Institute
Yang Du: Houston Methodist Research Institute
Chunmei Cai: Houston Methodist Research Institute
Baowei Cai: Houston Methodist Research Institute
Motao Zhu: Houston Methodist Research Institute
Changsheng Xing: Houston Methodist Research Institute
Peng Tan: Houston Methodist Research Institute
Meng Lin: Houston Methodist Research Institute
Jian Wu: National Institutes of Health
Jian Li: Xiamen University
Mingjun Wang: Houston Methodist Research Institute
Helen Y. Wang: Houston Methodist Research Institute
Xin-zhuan Su: National Institutes of Health
Rong-Fu Wang: Houston Methodist Research Institute

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: Abstract The inflammasome plays a critical role in inflammation and immune responses against pathogens. However, whether or how inflammasome activation regulates type I interferon (IFN-I) signaling in the context of malaria infection remain unknown. Here we show mice deficient in inflammasome sensors AIM2, NLRP3 or adaptor Caspase-1 produce high levels of IFN-I cytokines and are resistant to lethal Plasmodium yoelii YM infection. Inactivation of inflammasome signaling reduces interleukin (IL)-1β production, but increases IFN-I production. Mechanistically, we show inflammsome activation enhances IL-1β-mediated MyD88-TRAF3-IRF3 signaling and SOCS1 upregulation. However, SOCS1 inhibits MyD88-IRF7-mediated-IFN-I signaling and cytokine production in plasmacytoid dendritic cells. By contrast, ablation of inflammsome components reduces SOCS1 induction, and relieves its inhibition on MyD88-IRF7-dependent-IFN-I signaling, leading to high levels of IFN-α/β production and host survival. Our study identifies a previously unrecognized role of inflammasome activation in the negative regulation of IFN-I signaling pathways and provides potential targets for developing effective malaria vaccines.

Date: 2018
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DOI: 10.1038/s41467-018-07384-7

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