Gut homeostasis and regulatory T cell induction depend on molecular chaperone gp96 in CD11c+ cells

Hua, Yunpeng; Yang, Yi; Sun, Shaoli; Iwanowycz, Stephen; Westwater, Caroline; Reizis, Boris; Li, Zihai; Liu, Bei

doi:10.1038/s41598-017-02415-7

Cited by 17 publications

(20 citation statements)

References 73 publications

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“…20,21,32,37 We found that deletion of gp96 in DCs rendered them unresponsive to stimulation by TLR2, TLR4, and TLR9 ligands. 32 Thus, our DC-specific gp96-deficient mice present a DC-specific pan TLR KO mouse model. To determine the effect of DCintrinsic gp96 in endotoxin shock, WT and KO mice were administrated intraperitoneally with a lethal dose of LPS.…”

Section: Attenuation Of Lps-induced Endotoxemia In Dendritic Cell-spementioning

confidence: 83%

“…DC-specific gp96-deficient mice (CD11cCre þ Hsp90b1 flox/flox ) and control littermates (CD11cCre À Hsp90b1 flox/flox ) were generated by crossing Hsp90b1 flox/flox mice with CD11c-Cre transgenic mice. 32…”

Section: Micementioning

confidence: 99%

“…Consistent with the report that intestinal IgA coating represents ongoing inflammatory conditions, we also found that DCspecific gp96 KO mice had significantly higher levels of IgA and IgG1 in the sera compared with WT controls at baseline, and the level of fecal IgA was also significantly higher in KO mice. 32 Next, we examined whether deletion of gp96 in DCs affects systemic Ig production in CLP-Induced septic mice. Indeed, we found that sham KO mice had significantly higher levels of IgA (Figure 4a), IgG1 (Figure 4b), and IgG2c (Figure 4d) but not IgG2b (Figure 4c), IgG3 (Figure 4e), and IgM ( Figure 4f) compared with sham WT controls.…”

Section: Deletion Of Gp96 In Dcs Significantly Increases the Systemicmentioning

confidence: 99%

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Regulation of dendritic cell function improves survival in experimental sepsis through immune chaperone

Zhao

Fan

et al. 2019

Innate Immun

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Dendritic cells (DCs) are professional Ag-presenting cells that play a critical role in both innate and adaptive immune responses. DCs recognize and respond to bacteria through multiple PRRs, including TLRs. Heat shock protein gp96/grp94 is a master essential chaperone for TLRs in the endoplasmic reticulum. We generated DC-specific gp96-knockout (KO) mice and showed that gp96 KO DCs were unable to respond to multiple TLR ligands. TLR-mediated hyperinflammatory response can lead to sepsis. However, the roles of neither DCs nor the DC-intrinsic gp96 in the process are completely understood. In a LPS-induced sepsis model, we hereby found that deletion of gp96 in DCs significantly reduced serum TNF-α levels and improved survival. Furthermore, using the well-defined polymicrobial sepsis model of cecal ligation and puncture, we found that DC-specific ablation of gp96 improved survival with significantly attenuated liver and renal injuries, decreased circulating inflammatory cytokines, altered DC maturation and activation, and increased serum Ig. Collectively, we demonstrate that deletion of gp96 in DCs is beneficial in protecting mice against sepsis induced by both endotoxemia and polymicrobial infections. We conclude that targeting gp96 in DCs may provide a potential novel approach for reducing the morbidity and mortality of sepsis.

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Section: Attenuation Of Lps-induced Endotoxemia In Dendritic Cell-spementioning

confidence: 83%

Section: Micementioning

confidence: 99%

Section: Deletion Of Gp96 In Dcs Significantly Increases the Systemicmentioning

confidence: 99%

See 1 more Smart Citation

Regulation of dendritic cell function improves survival in experimental sepsis through immune chaperone

Zhao

Fan

et al. 2019

Innate Immun

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“…These data are in line with our previous findings, showing a clear expression of TLR 2 and 4 on inflammation-associated IMACs in CD patients [ 18 , 27 ], in which gp96 expression is strongly reduced or even completely absent in IMACs [ 19 , 28 ]. Of interest, it has recently been reported that gp96 is essential for CD11c+ cells to preserve the gut homeostasis and to induce regulatory T cells, showing the important role of this chaperone in immune responses [ 29 ]. Our present study expands our previous observations and points to an impaired phosphorylation of ERK and p38 kinases upon loss of gp96.…”

Section: Discussionmentioning

confidence: 99%

Gp96 deficiency affects TLR4 functionality and impairs ERK and p38 phosphorylation

et al. 2018

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Gp96 is an endoplasmic reticulum chaperone for multiple protein substrates. Its lack in intestinal macrophages of Crohn’s disease (CD) patients is correlated with loss of tolerance against the host gut flora. Gp96 has been stablished to be an essential chaperone for Toll-like receptors (TLRs). We studied the impact of gp96-knockdown on TLR-function in macrophages. TLR2 and TLR4 expression was only decreased but not abolished when gp96 was knocked-down in cell lines, whereas in a monocyte/macrophage specific knock-out mouse model (LysMCre) TLR4 was abolished, while TLR2 was still present. Lipopolysaccharide (LPS)-induced NF-κB activation was still observed in the absence of gp96, and gp96-deficient macrophages were able to up-regulate surface TLR4 upon LPS treatment, suggesting that there is another chaperone involved in the folding of TLR4 upon stress responses. Moreover, LPS-dependent pro-inflammatory cytokines were still expressed, although to a lesser extent in the absence of gp96, which reinforces the fact that gp96 is involved in regulating signaling cascades downstream of TLR4 are impaired upon loss of gp96. In addition, we have also found a reduced phosphorylation of ERK and p38 kinases and an impaired response upon CSF1R activation in gp96 deficient macrophages. Our findings indicate that the loss of gp96 not only impairs TLR4 signaling, but is also associated with a diminished phosphorylation of ERK and mitogen-activated stress kinases resulting in an impaired signalling through several receptors, including CSF1R.

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“…RA-producing DC are, in fact, naturally found in the mucosa ( 24 , 25 ), and their role is suggested to be one of maintenance of a stable immunoregulatory state preventing the exacerbation of gut inflammation ( 24 , 25 ). There is evidence that such RA-producing DC also express CD103 and, at least in the mucosa and more recently in the pancreas, CD103+ DC exert a tolerogenic effect ( 26 – 29 ) even though they can be immunostimulatory under specific conditions ( 30 – 33 ). Tolerogenic DC that express CD103 act via their ability to induce Foxp3 expression in T-cells ( 28 , 34 – 42 ), especially in the presence of TGF-β in an RA-dependent manner ( 22 , 43 – 46 ).…”

Section: Introductionmentioning

confidence: 99%

Co-Stimulation-Impaired Bone Marrow-Derived Dendritic Cells Prevent Dextran Sodium Sulfate-Induced Colitis in Mice

et al. 2018

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Dendritic cells (DC) are important in the onset and severity of inflammatory bowel disease (IBD). Tolerogenic DC induce T-cells to become therapeutic Foxp3+ regulatory T-cells (Tregs). We therefore asked if experimental IBD could be prevented by administration of bone marrow-derived DC generated under conventional GM-CSF/IL-4 conditions but in the presence of a mixture of antisense DNA oligonucleotides targeting the primary transcripts of CD40, CD80, and CD86. These cell products (which we call AS-ODN BM-DC) have demonstrated tolerogenic activity in preventing type 1 diabetes and preserving beta cell mass in new-onset type 1 diabetes in the NOD mouse strain, in earlier studies. In addition to measuring efficacy in prevention of experimental IBD, we also sought to identify possible mechanism(s) of action. Weight, behavior, stool frequency, and character were observed daily for 7–10 days in experimental colitis in mice exposed to dextran sodium sulfate (DSS) following injection of the AS-ODN BM-DC. After euthanasia, the colons were processed for histology while spleen and mesenteric lymph nodes (MLNs) were made into single cells to measure Foxp3+ Treg as well as IL-10+ regulatory B-cell (Breg) population frequency by flow cytometry. AS-ODN BM-DC prevented DSS-induced colitis development. Recipients of these cells exhibited significant increases in Foxp3+ Treg and IL-10+ Breg in MLN and spleen. Histological examination of colon sections of colitis-free mice remained largely architecturally physiologic and mostly free of leukocyte infiltration when compared with DSS-treated animals. Although DSS colitis is mainly an innate immunity-driven condition, our study adds to the growing body of evidence showing that Foxp3+ Treg and IL-10 Bregs can suppress a mainly innate-driven inflammation. The already-established safety of human DC generated from monocytic progenitors in the presence of the mixture of antisense DNA targeting the primary transcripts of CD40, CD80, and CD86 in humans offers the potential to adapt them for clinical IBD therapy.

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Gut homeostasis and regulatory T cell induction depend on molecular chaperone gp96 in CD11c+ cells

Cited by 17 publications

References 73 publications

Regulation of dendritic cell function improves survival in experimental sepsis through immune chaperone

Regulation of dendritic cell function improves survival in experimental sepsis through immune chaperone

Gp96 deficiency affects TLR4 functionality and impairs ERK and p38 phosphorylation

Co-Stimulation-Impaired Bone Marrow-Derived Dendritic Cells Prevent Dextran Sodium Sulfate-Induced Colitis in Mice

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