Cross-Regulation of Two Type I Interferon Signaling Pathways in Plasmacytoid Dendritic Cells Controls Anti-malaria Immunity and Host Mortality
Authors: Jian Wu
Xilai Ding
Changsheng Xing
Peng Tan
Xiao Yu
Jian Li
Pinghua Liu
Mingjun Wang
Xin-Zhuan Su
Helen Y Wang
Qingtian Li
Baowei Cai
Rong-Fu Wang
Journal: Immunity (2016)
Discipline: IMMUNOLOGY
Keywords: Innate immune response; Malaria infection; Plasmacytoid dendritic cells; Type I IFN signaling.
Affiliations: School of Life Sciences, Sun Yat-Sen University, 510275 Guangzhou, P.R. China; Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA., Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA; State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, 361005 Fujian, P.R. China., Zhongshan School of Medicine, Sun Yat-Sen University, 510275 Guangzhou, P.R. China; Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, 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., Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA., 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, Xiamen, 361005 Fujian, P.R. China., State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, 361005 Fujian, P.R. China; Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: ., Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX 77030, USA; Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY 10065, USA; Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, TX 77030, USA. Electronic address: .

Abstract:  Type I interferon (IFN) is critical for controlling pathogen infection; however, its regulatory mechanisms in plasmacytoid cells (pDCs) still remain unclear. Here, we have shown that nucleic acid sensors cGAS-, STING-, MDA5-, MAVS-, or transcription factor IRF3-deficient mice produced high amounts of type I IFN-α and IFN-β (IFN-α/β) in the serum and were resistant to lethal plasmodium yoelii YM infection. Robust IFN-α/β production was abolished when gene encoding nucleic acid sensor TLR7, signaling adaptor MyD88, or transcription factor IRF7 was ablated or pDCs were depleted. Further, we identified SOCS1 as a key negative regulator to inhibit MyD88-dependent type I IFN signaling in pDCs. Finally, we have demonstrated that pDCs, cDCs, and macrophages were required for generating IFN-α/β-induced subsequent protective immunity. Thus, our findings have identified a critical regulatory mechanism of type I IFN signaling in pDCs and stage-specific function of immune cells in generating potent immunity against lethal YM infection. 

Retracted: No

PubPeer comments:
 In Figure 5G, the only raw data presented in this article, the Western immunoblots look artificial. When increasing the contrast brightness to the extreme, the backgroun is not changed but a border around the bands appears. In contrast, when a similar adjustment is performed on a random Western blot from another article, the backgrond follows the bands. If you increase the contrast to the extreme, the background will turn black, and the bands will be saturated. ![file] , 
 This IP experiment is overexpression system in 293T and the expression of Flag- and HA-tagged protein were extremely strong, so the exposure time was very short (usually in 1-5 seconds), that is why the background was very bright and bands were sharp. Here we also provide original uncut blots together with MW markers as following: The IP sample was first blotted with anti-Flag antibody, exposure, stripping and then reblotted with anti-HA antibody; and the WCL samples were blotted with anti-Flag and anti-HA together since the MW of Flag and HA-protein were different. ![file] ,