Inflammasome activation negatively regulates MyD88-IRF7 type I IFN signaling and anti-malaria immunity
Authors: Jian Wu
Motao Zhu
Meng Lin
Xiao Yu
Peng Tan
Changsheng Xing
Jian Li
Rong-Fu Wang
Mingjun Wang
Xin-Zhuan Su
Chunmei Cai
Yang Du
Baowei Cai
Helen Y Wang
Journal: Nature Communications (2018)
Discipline: Multidisciplinary
Keywords: inflammasome; IFN-I signaling; malaria infection; cytokines; Plasmodium yoelii YM
Affiliations: Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX, 77030, USA., Department of Immunology, School of Basic Medical Sciences, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China., Zhongshan School of Medicine, Sun Yat-sen University, 510275, Guangzhou, Guangdong, People's Republic of China., Institute of Biosciences and Technology, College of Medicine, Texas A & M University, Houston, TX, 77030, USA., School of Life Sciences, Sun Yat-sen University, 510275, Guangzhou, Guangdong, People's Republic of China., Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA., State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, 361005, Xiamen, Fujian, People's Republic of China., Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA. ., Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX, 77030, USA. ., Institute of Biosciences and Technology, College of Medicine, Texas A & M University, Houston, TX, 77030, USA. ., Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, 10065, USA. .

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. 

Retracted: No

PubPeer comments:
 The western immunoblots in this article are supported with raw data presented as uncut blots in the supplementary figure. The problem is that the raw data does not support anything. The blots appear to be randomly put together. There is no proof that the blots are generated from the same experiment, with identical experimental setup. The uncut blots should actually show that they areretrieved from the same gel and membrane (pieces put together, where MW markers are cleary shown. Examples are shown from Figure 1 and 2. ![file] ![file] ![file] , 
 Because pro-IL1b and IL-1b are 31 and 17 kDa, and they were blotted with different antibodies (12507S for pro and 63124S for cleaved isoform). Meanwhile, the antibody of caspase-1 had multiple unspecific bands as shown on the raw data. To get better imaging, we used cell lysis samples from the same experiment and run on different gels or cut the membrane to blot with different antibodies. Each membrane was blotted with b-actin after blotted with target antibodies to check whether the input is identical and one of the representative bands was showed. Besides detecting the activation of inflammasome in WT and CASP KO mice after YM infection, we also tested whether inflammasome is activated after different malaria strains infection or in other KO mice at the same time. That is why we have other samples on the same membrane without labeling, those are unpublished raw data for the related projects. ,