Inhibition of Toll-like receptor 9 attenuates sepsis-induced mortality through suppressing excessive inflammatory response

Hu, Dan; Yang, Xiaohua; Xiang, Yianxiao; Li, Hui; Yan, Hui; Zhou, Jun; Caudle, Yi; Zhang, Xiumei; Yin, Deling

doi:10.1016/j.cellimm.2015.03.009

Cited by 39 publications

(30 citation statements)

References 41 publications

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“…We therefore assessed the phosphorylation of AKT in the spleen of vehicle- and human ghrelin-treated mice in sepsis. Similar to a recent finding on the p-AKT level in the spleen of murine CLP-induced sepsis [ 31 ], we also found that sepsis significantly downregulated p-AKT level in the spleen, while the mice treated with human ghrelin significantly increased p-AKT level by 21% as compared to the vehicle-treated septic mice ( Fig 8 ).…”

Section: Resultssupporting

confidence: 91%

The protective role of human ghrelin in sepsis: Restoration of CD4 T cell proliferation

et al. 2018

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Decrease of CD4 T cell numbers causes immunosuppression in sepsis. We previously showed the beneficial role of ghrelin in sepsis. We hypothesize that the protective outcome of ghrelin in sepsis is mediated partially through the restoration of CD4 T cells’ proliferation. Sepsis was induced in mice by cecal ligation and puncture (CLP). The percentage of CD4 T cells in spleen was assessed by flow cytometry and their proliferation was determined by carboxyfluorescein succinimidyl ester (CSFE). Compared to sham mice, the percentages of splenic CD4 T cells were reduced by 20%, 21%, and 29% at day 1, 2 and 3 after CLP, respectively. Human ghrelin was given to 3 day septic mice by s.c. injection at 5 and 24 h after CLP. Treatment with ghrelin restored the loss of CD4 T cells by increasing their proliferation in septic mice. The expression of cyclin D1 and B1 was significantly increased, while the expression of p57 was decreased in ghrelin-treated mice compared to vehicle-treated mice in sepsis. Treatment with human ghrelin significantly increased the p-AKT levels in the spleen compared to vehicle-treated septic mice. Human ghrelin plays an important role in reestablishing the proliferation of CD4 T cells and serves as a promising therapeutic agent in sepsis.

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Section: Resultssupporting

confidence: 91%

The protective role of human ghrelin in sepsis: Restoration of CD4 T cell proliferation

et al. 2018

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“…org/10.1172/JCI127542DS1; refs. [18][19][20]. However, the mechanisms underlying the protection resulting from TLR9 suppression in sepsis are unclear.…”

Section: Tlr9 Signaling In Fibroblastic Reticular Cells Regulates Permentioning

confidence: 99%

“…Previous studies have shown that genetically and pharmacologically blocking TLR9 alleviates inflammation, organ damage, and mortality in mouse polymicrobial sepsis models (18)(19)(20). However, the mechanisms underlying the protective roles of TLR9 inhibition are unclear.…”

Section: Introductionmentioning

confidence: 99%

TLR9 signaling in fibroblastic reticular cells regulates peritoneal immunity

Xu¹,

Li²,

Yang³

et al. 2019

Journal of Clinical Investigation

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Section: Discussionmentioning

confidence: 99%

“…Activation of p38- and ERK-dependent pathways is associated with splenic, pulmonary, and hepatic inflammation 42–44 . Endothelial dysfunction and coagulopathy have also been found to be mediated by these pathways 42–44 . A conceptual challenge of pharmaceutical approaches directed at specific signaling elements is the diversity of signaling molecules that participate in inflammation signaling.…”

Section: Discussionmentioning

confidence: 99%

Milk fat globule-epidermal growth factor-factor VIII–derived peptide MSP68 is a cytoskeletal immunomodulator of neutrophils that inhibits Rac1

Hendricks

Aziz

Yang

et al. 2017

Journal of Surgical Research

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Introduction Prolonged neutrophil infiltration leads to exaggerated inflammation and tissue damage during sepsis. Neutrophil migration requires rearrangement of their cytoskeleton. Milk fat globule-epidermal growth factor-factor VIII (MFG-E8)-derived short peptide 68 (MSP68) has recently been shown to be beneficial in sepsis-induced tissue injury and mortality. We hypothesize that MSP68 inhibits neutrophil migration by modulating small GTPase Rac1 dependent cytoskeletal rearrangements. Methods Bone marrow-derived neutrophils (BMDN) or whole lung digest isolated neutrophils were isolated from 8–10 week old C57BL/6 mice by percoll density gradient centrifugation. The purity of BMDN was verified by flow cytometry with CD11b/Gr-1 staining. Neutrophils were stimulated with f-MLP (10 nM) in presence or absence of MSP68 at10 nM or cecal ligation and puncture (CLP) was utilized to induce sepsis, and MSP68 was administered at 1mg/kg intravenously. Cytoskeletal organization was assessed by phalloidin staining, followed by analysis using fluorescence microscopy. Activity of the Rac1 GTPase in f-MLP or CLP activated BMDN in the presence or absence of MSP68 was assessed by GTPase ELISA (GLISA). Mitogen activated protein (MAP) kinase activity was determined by western blot densitometry. Results BMDN treatment with f-MLP increased cytoskeletal remodeling as revealed by the localization of filamentous actin (F-actin) to the periphery of the neutrophil. By contrast, cells pre-treated with MSP68 had considerably reduced F-actin polymerization. Cytoskeletal spreading is associated with the activation of the small GTPase Rac1. We found BMDN-treated with f-MLP or that were exposed to sepsis by CLP had increased Rac1 signaling, while the cells pre-treated with MSP68 had significantly reduced Rac1 activation (p<0.05). MAP kinases related to cell migration including pP38 and pERK were up-regulated by treatment with f-MLP. Up-regulation of these MAP kinases was also significantly reduced after pre-treatment with MSP68 (p<0.05). Conclusions MSP68 down-regulates actin cytoskeleton dependent, Rac1-MAP kinase-mediated neutrophil motility. Thus, MSP68 is a novel therapeutic candidate for regulating inflammation and tissue damage caused by excessive neutrophil migration in sepsis.

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Inhibition of Toll-like receptor 9 attenuates sepsis-induced mortality through suppressing excessive inflammatory response

Cited by 39 publications

References 41 publications

The protective role of human ghrelin in sepsis: Restoration of CD4 T cell proliferation

The protective role of human ghrelin in sepsis: Restoration of CD4 T cell proliferation

TLR9 signaling in fibroblastic reticular cells regulates peritoneal immunity

Milk fat globule-epidermal growth factor-factor VIII–derived peptide MSP68 is a cytoskeletal immunomodulator of neutrophils that inhibits Rac1

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