Adoptive transfer of GRP78-treated dendritic cells alleviates insulitis in NOD mice

Abstract

The 78‐kDa glucose‐regulated protein (GRP78) has extracellular, anti‐inflammatory properties that can aid resolving inflammation. It has been established previously that GRP78 induced myeloid CD11c+ cell differentiation into distinct tolerogenic cells. This tolerance induction makes GRP78 a potential therapeutic agent for transplanted allogeneic grafts and autoimmune diseases, such as type 1 diabetes. In this research, it is revealed that rmGRP78‐treated NOD mice bone marrow‐derived CD11c+ cells (GRP78‐DCs) highly expressed B7‐H4 but down‐regulated CD86 and CD40, and retained a tolerogenic signature even after stimulation by LPS. In the assessment of in vivo therapeutic efficacy after the adoptive transfer of GRP78‐DCs into NOD mice, fluorescent imaging analyses revealed that the transfer specifically homed in inflamed pancreases, promoting β‐cell survival and alleviating insulitis in NOD mice. The adoptive transfer of GRP78‐DCs also helped reduce Th1, Th17, and CTL, suppressing inflammatory cytokine production in vivo. The findings suggest that adoptive GRP78‐DC transfer is critical to resolving inflammation in NOD mice and may have relevance in a clinical setting.

Effects of GRP78 on Endoplasmic Reticulum Stress and Inflammatory Response in Macrophages of Large Yellow Croaker (Larimichthys crocea)

“…Furthermore, the results from the present study indicated that the inflammatory response under different treatments was consistent with the ER stress response. GRP78 has been indicated to be anti-inflammatory and promote the resolution of inflammation [ 12 , 13 , 14 ]. A previous study revealed that GRP78 mediated the endocytosis of TLR4 by targeting CD14, which is conducive to the regression of an inflammatory response [ 13 ].…”

“…A previous study revealed that GRP78 mediated the endocytosis of TLR4 by targeting CD14, which is conducive to the regression of an inflammatory response [ 13 ]. Moreover, an adoptive GRP78–DC transfer was essential to resolve the inflammatory response in NOD mice [ 14 ]. The results suggested that the inflammatory response may be regulated by GRP78 on the one hand and be regulated by ER stress on the other hand.…”

“…GRP78 also has been found to regulate inflammation. GRP78 is known as part of the resolution-associated molecular patterns (RAMPs) family that can be anti-inflammatory and promote the resolution of inflammation [ 12 , 13 , 14 ]. GRP78 regulates FAT10 expression by modulating the NF-κB pathway; to be more specific, the activation of the NF-κB pathway can increase the expression of FAT10, which is a gene counteracting the tumor suppressor p53 [ 15 ].…”

Secreted glucose regulated protein78 ameliorates DSS-induced mouse colitis

“…Secreted GRP78 acts as a resolution-associated molecular pattern (RAMP) to favor the resolution of inflammation ( 17 ) by generation of regulatory T-cell ( 18 ) and B-cell ( 19 ) population, by affecting maturation of dendritic cells ( 20 , 21 ) and by targeting CD14 to impair production of LPS-induced proinflammatory cytokines ( 22 ). sGRP78 helps resolve inflammation in NOD mice ( 23 ) and contributes to tumor growth and metastasis by promoting immune tolerance to remodel the tumor microenvironment ( 24 ). Hence, both the cytoprotective property of intracellular GRP78 and the immune modulatory property of sGRP78 provide a direction towards determining GRP78’ ability in IBD.…”

Exploring the role of SWI/SNF complex subunit BAF60c in lipid metabolism and inflammation in fish

“…GRP78 was an important regulator of ER homeostasis. 23 Prior studies have demonstrated that GRP78 played multiple roles, such as regulating apoptosis 24 , 25 , 26 , 27 and autophagy, 28 , 29 , 30 participating in cancer and tumor metabolism, 31 , 32 , 33 mediating energy metabolism, 34 , 35 , 36 , 37 regulating inflammatory response, 38 , 39 , 40 and so on. However, the interaction between BAF60c and GRP78 has not been reported.…”