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Toll-Like Receptor 4 Signaling Licenses the Cytosolic Transport of Lipopolysaccharide From Bacterial Outer Membrane Vesicles

Gu, Lan*,‡; Meng, Ran*,‡; Tang, Yiting†,‡; Zhao, Kai*,‡; Liang, Fang*,‡; Zhang, Rui*,‡; Xue, Qianqian*,‡; Chen, Fangping*; Xiao, Xianzhong§; Wang, Huadong||; Wang, Haichao; Billiar, Timothy R.**; Lu, Ben*,‡,§,||

doi: 10.1097/SHK.0000000000001129
Basic Science Aspects
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ABSTRACT Outer membrane vesicles (OMVs), released by variety of bacteria, are membrane-enclosed entities enriched in microbial components, toxins, and virulent factors. OMVs could deliver lipopolysaccharide (LPS) into the cytosol of host cells and subsequently activate caspase-11, which critically orchestrates immune responses and mediates septic shock. Although it is known that caspase-11 is activated by intracellular LPS, how OMVs deliver LPS into the cytosol remains largely unknown. Here we show that the activation of toll-like receptor 4 (TLR4), a LPS receptor on the cytoplasmic membrane, licenses macrophages to transport LPS from OMVs into the cytosol through TIR domain-containing adaptor-inducing interferon-β (TRIF). TRIF-mediated cytosolic delivery of LPS from OMVs depends on the production of type 1 interferon and the expression of guanylate-binding proteins (GBPs). Deletion of TRIF or GBPs prevents pyroptosis and lethality induced by OMVs or OMVs-releasing Escherichia coli. Together, these findings provide novel insight into how host coordinates extracellular and intracellular LPS sensing to orchestrate immune responses during gram-negative bacterial infection.

*Department of Hematology and Key Laboratory of Non-Resolving Inflammation and Cancer of Human Province, The 3rd Xiangya Hospital, Central South University, Changsha, Hunan Province, PR China

Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan Province, PR China

Key Laboratory of Medical Genetics, School of Biological Science and Technology, Central South University, Changsha, Hunan Province, PR China

§Key Laboratory of Sepsis and Translational Medicine, School of Basic Medical Science, Central South University, Changsha, Hunan Province, PR China

||Department of Pathophysiology, School of Basic Medical Science, Jinan University, Guangzhou, Guangdong Province, PR China

Department of Emergency Medicine, North Shore University Hospital, Northwell Health, Manhasset, NY

**Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA

Address reprint requests to Ben Lu, PhD, MD, 138 Yuelu Road, Changsha, Hunan 410013, PR China. E-mail: xybenlu@csu.edu.cn

Received 5 January, 2018

Revised 29 January, 2018

Accepted 12 February, 2018

Authors’ contributions: LG designed and performed the experiments, analyzed data, and wrote the article. MR, YT, KZ, FL, RZ, and QX provided experimental help and technical support. FC, XX, HW, HW, and TRB designed the study and discussed the results. BL supervised the work, designed the study, and wrote the article.

This work was supported by National key scientific project 2015CB910700 (BL), National Natural Science Foundation of China (No. 81422027 [BL], No. 81400149 [YT], No. 81700127 [FL], No. 81470345 [BL]).

The authors report no conflicts of interest.

© 2019 by the Shock Society