Getting DAMP(s) Wets the Whistle for Neutrophil Recruitment

Watts, Emily R.; Walmsley, Sarah R.

doi:10.1016/j.immuni.2018.04.027

Cited by 11 publications

(14 citation statements)

References 7 publications

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“…4a and S4A, B). These results were consistent with the previously observed ability of HMGB1 to mobilize neutrophils 26 . Importantly, the number of CD62L dim neutrophils was significantly increased in the 4T1-Conrtrol and EMT6-HMGB1 groups compared with that in the 4T1-shHMGB1 and EMT6-Control groups (Figs.…”

Section: Tumor Cell-derived Hmgb1 Is Responsible For Lung Metastasis supporting

confidence: 93%

Tumor-derived HMGB1 induces CD62Ldim neutrophil polarization and promotes lung metastasis in triple-negative breast cancer

Wang

Yang

et al. 2020

Oncogenesis

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Triple-negative breast cancer (TNBC) is highly aggressive, difficult to treat and commonly develops visceral metastasis, including lung metastasis. We observed that High mobility group box 1 protein (HMGB1) was highly expressed in human TNBC and positively correlated with cancer metastasis. The hypoxic tumor environment is known to regulate HMGB1 secretion, but an understanding of the underlying mechanism by which tumor-derived HMGB1 regulates interstitial components and promotes breast cancer lung metastasis has remained elusive. The results of the present study showed that the number of CD62Ldim neutrophils, which have a strong ability to produce neutrophil extracellular traps (NETs), increased significantly in both peripheral blood and lung tissues in a mouse TNBC model and were regulated by tumor-derived HMGB1 through the TLR2 pathway. Furthermore, serum HMGB1 levels were positively correlated with CD62Ldim neutrophils in 86 breast cancer patients. We demonstrated that CD62Ldim neutrophils accelerated lung metastasis and that interventions targeting the “HMGB1-CD62Ldim neutrophil-NETs” axis could inhibit lung metastasis. Our results suggest that the combination of HMGB1 and CD62Ldim neutrophils is a potential marker for breast cancer lung metastasis and is novel target for future prevention and therapy.

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Section: Tumor Cell-derived Hmgb1 Is Responsible For Lung Metastasis supporting

confidence: 93%

Tumor-derived HMGB1 induces CD62Ldim neutrophil polarization and promotes lung metastasis in triple-negative breast cancer

Wang

Yang

et al. 2020

Oncogenesis

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“…The host responds to both PAMPs and DAMPs by specific PRRs during infection, resulting in increased production of mediators and inflammatory response [33]. excessive inflammatory response induces organ injury.…”

Section: Resultsmentioning

confidence: 99%

STING-mediated intestinal barrier dysfunction contributes to lethal sepsis

et al. 2019

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Background Gut integrity is compromised in abdominal sepsis with increased cellular apoptosis and altered barrier permeability. Intestinal epithelial cells (IEC) form a physiochemical barrier that separates the intestinal lumen from the host's internal milieu and is strongly involved in the mucosal inflammatory response and immune response. Recent research indicates the involvement of the stimulator of interferons genes (STING) pathway in uncontrolled inflammation and gut mucosal immune response. Methods We investigated the role of STING signaling in sepsis and intestinal barrier function using intestinal biopsies from human patients with abdominal sepsis and with an established model of abdominal sepsis in mice. Findings In human abdominal sepsis, STING expression was elevated in peripheral blood mononuclear cells and intestinal biopsies compared with healthy controls, and the degree of STING expression in the human intestinal lamina propria correlated with the intestinal inflammation in septic patients. Moreover, elevated STING expression was associated with high levels of serum intestinal fatty acid binding protein that served as a marker of enterocyte damage. In mice, the intestinal STING signaling pathway was markedly activated following the induction of sepsis induced by cecal ligation perforation (CLP). STING knockout mice showed an alleviated inflammatory response, attenuated gut permeability, and decreased bacterial translocation. Whereas mice treated with a STING agonist (DMXAA) following CLP developed greater intestinal apoptosis and a more severe systemic inflammatory response. We demonstrated that mitochondrial DNA (mtDNA) was released during sepsis, inducing the intestinal inflammatory response through activating the STING pathway. We finally investigated DNase I administration at 5 hours post CLP surgery, showing that it reduced systemic mtDNA and inflammatory cytokines levels, organ damage, and bacterial translocation, suggesting that inhibition of mtDNA-STING signaling pathway protects against CLP-induced intestinal barrier dysfunction. Interpretation Our results indicate that the STING signaling pathway can contribute to lethal sepsis by promoting IEC apoptosis and through disrupting the intestinal barrier. Our findings suggest that regulation of the mtDNA-STING pathway may be a promising therapeutic strategy to promote mucosal healing and protect the intestinal barrier in septic patients. Fund National Natural Science Foundation of China.

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“…The findings of Trompette et al (2018) are complimented by recent study in Science by Zhao et al (2018). Zhao et al (2018) integrated human and mouse studies to show that a HFD selectively caused an increase in SCFA-producing bacteria that were associated with a significant reduction in symptoms associated with type 2 diabetes (T2D). In this study, control and treatment T2D patient groups received standard of care therapies supplemented with acarbose, an amylase inhibitor that increased the bioavailability of fermentable fiber to intestinal bacteria.…”

mentioning

confidence: 76%

“…Fascinatingly, in analysis of the HFDassociated microbiota, both Zhao et al (2018) and Trompette et al (2018) uncovered a significant enrichment for Bifidobacterium spp., a well-known producer of SCFAs. Zhao et al (2018) found that Bifidobacterium pseudocatenulatum correlated with improved HbA1c in T2D patients. Moreover, gavage of B. pseudocatenulatum in mice improved metabolic outcomes in a model of high-fat dietinduced obesity.…”

mentioning

confidence: 99%

“…T2D is associated with a relative increase in inflammatory macrophages and a decrease in AAMs (Odegaard and Chawla, 2011). Although not tested directly by Zhao et al (2018), it will be important to determine whether the positive effects of a HFD on T2D patients are immunologically mediated, and specifically whether SCFAs can regulate the production of in-flammatory cytokines from macrophages that negatively affect insulin signaling (Odegaard and Chawla, 2011). Fascinatingly, in analysis of the HFDassociated microbiota, both Zhao et al (2018) and Trompette et al (2018) uncovered a significant enrichment for Bifidobacterium spp., a well-known producer of SCFAs.…”

mentioning

confidence: 99%

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