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

Abstract

The 78-kDa glucose-regulated protein (GRP78) is a stress-inducible chaperone that resides primarily 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 the current study, we confirmed that GRP78 impaired the production of lipopolysaccharide-induced pro-inflammatory cytokines in GRP78-treated bone-marrow-derived dendritic cells (DCs). To explore the underlying mechanism, first of all, GRP78 was checked to be bound to the plasma membrane. Interestingly, such binding promoted endocytosis of toll-like receptor (TLR) 4 and reduction in TLR4 on the plasma surface had a key role in desensitization of GRP78-treated DCs to lipopolysaccharide. Given that cluster of differentiation (CD)14 is a crucial regulator of TLR4 endocytosis, interaction of GRP78 with CD14 was investigated next. Data showed that GRP78 co-localized with CD14 on the plasma membrane and glutathione-S-transferase-GRP78 precipitated CD14. In CD14 knockout mice, down-regulation of tumor necrosis factor-α and reduction in TLR4 on the plasma surface were abrogated in GRP78-treated DCs. Overall, these data suggested that GRP78 mediates endocytosis of TLR4 by targeting CD14 to favor the resolution of inflammation.

Tumor-Secreted GRP78 Promotes the Establishment of a Pre-metastatic Niche in the Liver Microenvironment

“…GRP78 was highly expressed in the liver, suggesting a potential role in reshaping the hepatic microenvironment to facilitate liver metastasis. sGRP78 has been implicated in immunomodulation by biding to pattern recognition receptors ( 9 , 18 ). Moreover, intracellular GRP78 levels have been associated with drug resistance and apoptosis in cancers ( 11 , 46 ).…”

“…GRP78 is upregulated during ER stress; GRP78 translocates from the ER to the cell membrane (mGRP78) or is secreted as soluble GRP78 (sGRP78) ( 8 ). sGRP78 has long been recognized as a resolution-associated molecular pattern, facilitating inflammation resolution ( 9 – 11 ). GRP78 is expressed at higher levels in cancer tissues than in adjacent healthy tissues, and its expression levels have been associated with tumor malignancy ( 12 , 13 ).…”

“…Notably, GRP78-deficient macrophages demonstrated adapted UPR with upregulation of activating transcription factor (ATF)-4 and M2-polarization markers ( 17 ). We previously demonstrated that sGRP78 promoted B cell differentiation into IL-10-secreting CD19 hi regulatory B cells ( 18 ) and dendritic cell (DC) differentiation into regulatory DCs (DCreg) ( 9 – 11 ). Moreover, GRP78-treated DCs facilitated the differentiation of regulatory T cells (Tregs) ( 11 ).…”

Human Mesenchymal Stem Cell Secretome from Bone Marrow or Adipose-Derived Tissue Sources for Treatment of Hypoxia-Induced Pulmonary Epithelial Injury

“…Other previous studies have shown that GRPs are negative regulators of inflammatory processes. GRP78 has been shown to inhibit the production of pro-inflammatory cytokines (TNF-α, IL-6 and IFN-β) induced by lipopolysaccharide (LPS) in bone marrow-derived dendritic cells (BMDCs) and bone-marrow-derived macrophages (BMDMs) [ 64 ]. Additionally, transient knockdown of GRP78 has been shown to abolish the secretion of serum ferritin mediated pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) in rat primary activated hepatic stellate cells [ 65 ].…”

CD14 release induced by P2X7 receptor restricts inflammation and increases survival during sepsis

“…The pool of extracellular CD14 in vivo, known as soluble CD14, is detected in different fluids during infection and particularly during sepsis, a life-threating condition resulting from exacerbated inflammation in response to infection (Barratt-Due et al, 2017;Bas et al, 2004). Extracellular CD14 during microbial infection is important for host defense, in particular for bacterial clearance, but little is known about the release of CD14 in vivo (Fang et al, 2017;Knapp et al, 2006;Sahay et al, 2018;Wieland et al, 2005).…”