AUTHOR=Qin Kai , Ma Simin , Li Heli , Wu Min , Sun Yuanli , Fu Mingpeng , Guo Zilong , Zhu Huifen , Gong Feili , Lei Ping , Shen Guanxin 

TITLE=GRP78 Impairs Production of Lipopolysaccharide-Induced Cytokines by Interaction with CD14

JOURNAL=Frontiers in Immunology

VOLUME=Volume 8 - 2017

YEAR=2017

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2017.00579

DOI=10.3389/fimmu.2017.00579

ISSN=1664-3224

ABSTRACT=The 78 kDa glucose-regulated protein (GRP78) is stress-inducible chaperone that mostly resides in the endoplasmic reticulum. GRP78 has been described to be released at times of cellular stress and as having extracellular properties that are anti-inflammatory or favor the resolution of inflammation. In this article, we confirmed that GRP78 impaired the production of pro-inflammatory cytokines TNF-α, IL-1 β, IL-6 and IFN-β in GRP78 treated bone marrow-derived dendritic cells (BMDCs) upon lipopolysaccharide (LPS) stimuli. To explore the underlying mechanism, first of all, GRP78 was checked to be bound with the plasma membrane. Interestingly, such binding promoted Toll like receptor (TLR) 4 endocytosis and the reduction of surface TLR4 played a key role in desensitization of GRP78 treated-DCs to LPS. Given that CD14 is a crucial regulator of TLR4 endocytosis, next, interaction of GRP78 with CD14 was investigated. Data showed that GRP78 colocalized with CD14 at plasma membrane and GST-GRP78 precipitated CD14. In CD14 KO mice, downregulation of TNF-α and reduction of surface TLR4 were abrogated in GRP78 treated-DCs. All these data suggested that GRP78 mediated endocytosis of TLR4 by targeting CD14 to favor the resolution of inflammation.