• Azurin
• Breast cancer
• Chitosan
• Folic acid
• Mesoporous silica nanoparticle

• Animals
• Chitosan/chemistry
• Nanoparticles/chemistry
• Female
• Mice
• Humans
• Silicon Dioxide/chemistry
• Mice, Inbred BALB C
• Breast Neoplasms/drug therapy
• Breast Neoplasms/pathology
• Breast Neoplasms/metabolism
• Folic Acid/chemistry
• MCF-7 Cells
• Apoptosis/drug effects
• Porosity
• Drug Carriers/chemistry

• Breast cancer
• Chemotherapy
• Paclitaxel
• Resistance mechanisms

• Humans
• Breast Neoplasms/drug therapy
• Breast Neoplasms/genetics
• Breast Neoplasms/pathology
• Paclitaxel/therapeutic use
• Paclitaxel/pharmacology
• Drug Resistance, Neoplasm/genetics
• Drug Resistance, Neoplasm/drug effects
• Female
• Antineoplastic Agents, Phytogenic/therapeutic use
• Antineoplastic Agents, Phytogenic/pharmacology
• Tumor Microenvironment/drug effects

• Toll-like receptor 9
• breast cancer
• systematic review

• R01 HL161386 NHLBI NIH HHS

• Toll-like receptors
• breast cancer
• cancer immunity
• immune checkpoint inhibitor
• immunotherapy
• innate immunity

• Humans
• Breast Neoplasms/immunology
• Breast Neoplasms/therapy
• Toll-Like Receptors/metabolism
• Toll-Like Receptors/immunology
• Female
• Immunotherapy/methods
• Animals
• Signal Transduction
• Immunity, Innate

• Breast cancer
• Cancer stem cell
• Dormancy
• Epigenome
• Resistance

• Humans
• Neoplastic Stem Cells/pathology
• Histones/genetics
• Epigenesis, Genetic
• Methyltransferases/genetics
• DNA
• Neoplasms/pathology
• Intracellular Signaling Peptides and Proteins/genetics

• PTX3
• TLR4 signaling pathway
• Triple negative breast cancer (TNBC)

• ID. 18493 Associazione Italiana per la Ricerca sul Cancro
• AIRC IG 2019 - ID.23151 Associazione Italiana per la Ricerca sul Cancro

• Antigen
• Epitope
• KRAS G12C
• KRAS G12D
• KRAS mutant
• Vaccine

• Humans
• Female
• Epitopes
• Proto-Oncogene Proteins p21(ras)/genetics
• Vaccinology
• Cancer Vaccines
• Breast Neoplasms

• Toll-like receptor
• breast cancer
• nanoparticles
• photothermal therapy
• proinflammatory molecules
• therapy-induced inflammation
• tumor recurrence and metastasis

• Female
• Humans
• Breast Neoplasms/pathology
• Cell Line, Tumor
• Multifunctional Nanoparticles
• Nanoparticles/chemistry
• Neoplasm Recurrence, Local
• Phototherapy/methods
• Recurrence
• Inflammation

• UG3 TR002151 NCATS NIH HHS
• UH3 TR002151 NCATS NIH HHS
• R01 AR073935 NIAMS NIH HHS

• Bacillus Calmette-Guerin.
• Toll like receptors
• breast cancer progression
• cell proliferation
• drug resistance
• tumor cells

• Breast cancer
• cancer therapy
• cell signalling
• lipopolysaccharide
• signalling pathway
• toll like receptor 4

• Breast Neoplasms/drug therapy
• Breast Neoplasms/metabolism
• Female
• Humans
• Ligands
• Lipopolysaccharides
• Signal Transduction
• Toll-Like Receptor 4/metabolism
• Toll-Like Receptors

• 81850410555 National Natural Science Foundation of China (NSFC)
• 41-00022303 Southwest Medical University's matching research fund

• Apoptosis
• Breast cancer
• Caspase-3
• MyD88
• NF-κB
• Toll like receptor
• Verbascoside

• 5-Fluorouracil
• Breast cancer
• Chemosensitivity
• Potentiate
• Quercetin

• CXCL1
• breast cancer stem cells
• chemokines
• immunity genes
• triple-negative breast cancer
• tumor microenvironment

• Pain
• Substance P
• TLR-4
• Tumor Progression

The role of commensal bacterial microbiota in the pathogenesis of human malignancies has been a research field of incomparable progress in recent years. Although breast tissue is commonly assumed to be sterile, recent studies suggest that human breast tissue may contain a bacterial microbiota. In this study, we used an immune‐competent orthotopic breast cancer mouse model to explore the existence of a unique and independent bacterial microbiota in breast tumors. We observed some similarities in breast cancer microbiota with skin; however, breast tumor microbiota was mainly enriched with Gram‐negative bacteria, serving as a primary source of lipopolysaccharide (LPS). In addition, dextran sulfate sodium (DSS) treatment in late‐stage tumor lesions increased LPS levels in the breast tissue environment. We also discovered an increased expression of S100A7 and low level of TLR4 in late‐stage tumors with or without DSS as compared to early‐stage tumor lesions. The treatment of breast cancer cells with LPS increased the expression of S100A7 in breast cancer cells in vitro. Furthermore, S100A7 overexpression downregulated TLR4 and upregulated RAGE expression in breast cancer cells. Analysis of human breast cancer samples also highlighted the inverse correlation between S100A7 and TLR4 expression. Overall, these findings suggest that the commensal microbiota of breast tissue may enhance breast tumor burden through a novel LPS/S100A7/TLR4/RAGE signaling axis.

• LPS
• Microbiota
• RAGE
• S100A7
• TLR4
• breast cancer

• atractylenolide-I
• breast cancer
• nuclear factor-κB
• toll-like receptor 4
• tumorigenesis

Fetuin‐A is a serum glycoprotein synthesized and secreted into blood by the liver and whose main physiological function is the inhibition of ectopic calcification. However, a number of studies have demonstrated that it is a multifunctional protein. For example, endocytic uptake of fetuin‐A by tumor cells resulting in rapid cellular adhesion and spreading has been reported. The precise uptake mechanism, however, has been elusive. The present studies were done to determine whether Toll‐like receptor‐4 (TLR4), which has been previously shown to be a receptor for fetuin‐A and is commonly expressed in immune cells, could take part in the rapid uptake (< 3 min) of fetuin‐A by tumor cells. Rapid uptake of fetuin‐A was inhibited by the specific TLR4 inhibitor CLI‐095 and also attenuated in TLR4 knockdown prostate tumor cells. Inhibition of TLR4 by CLI‐095 also attenuated the rapid adhesion of tumor cells as well as invasion through a bed of Matrigel. The data suggest mechanisms by which TLR4 modulates the adhesion and growth of tumor cells.

• LPS
• TLR4
• adhesion
• endocytosis
• fetuin-A
• receptor

Breast cancer is the most frequent malignancy in females in terms of both incidence and mortality. Underlying the high mortality rate is the presence of cancer stem cells, which divide indefinitely and are resistant to conventional chemotherapies, so causing tumor relapse. In the present study, we identify miR-216a-5p as a downregulated microRNA in breast cancer stem cells vs. the differentiated counterpart. We demonstrate that overexpression of miR-216a-5p impairs stemness markers, mammosphere formation, ALDH activity, and the level of Toll-like receptor 4 (TLR4), which plays a significant role in breast cancer progression and metastasis by leading to the release of pro-inflammatory molecules, such as interleukin 6 (IL-6). Indeed, miR-216a regulates the crosstalk between cancer cells and the cells of the microenvironment, in particular cancer-associated fibroblasts (CAFs), through regulation of the TLR4/IL6 pathway. Thus, miR-216a has an important role in the regulation of stem phenotype, decreasing stem-like properties and affecting the cross-talk between cancer cells and the tumor microenvironment.

• Breast cancer
• cancer stem cells
• microRNA
• tumor microenvironment

• Breast/metabolism
• Breast Neoplasms/genetics
• Breast Neoplasms/metabolism
• Cancer-Associated Fibroblasts/metabolism
• Cell Line, Tumor
• Cell Movement
• Disease Progression
• Down-Regulation
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Inflammation/metabolism
• Interleukin-6/metabolism
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Neoplasm Metastasis
• Neoplasm Recurrence, Local/genetics
• Neoplasm Recurrence, Local/metabolism
• Neoplastic Stem Cells/metabolism
• Signal Transduction
• Toll-Like Receptor 4/metabolism
• Tumor Microenvironment/physiology

• Polymorphism
• Psoriasis
• SNP
• TLRs

• Adult
• Case-Control Studies
• Female
• Gene Frequency
• Genetic Association Studies
• Genetic Predisposition to Disease
• Genotype
• Humans
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Psoriasis/genetics
• Toll-Like Receptor 2/genetics
• Turkey

• genetic association
• osteoarthritis
• single nucleotide polymorphisms

Breast cancer (BC) cells (BCCs) can retain cellular quiescence for decades, a phenomenon referred to as dormancy. BCCs show preference for the bone marrow (BM) where they can remain dormant for decades. Targeting BCCs within the BM is a challenge since the dormant BCCs reside within BM stroma, also residence for hematopoietic stem cells (HSCs). Dormant BCCs could behave as cancer stem cells (CSCs). The CSCs and HSCs are similar by function and also, by commonly expressed genes. The method by which dormant BCCs transition into clinically metastatic cells remains unclear. This study tested the hypothesis that macrophages (MΦs) within BM stroma, facilitates dormancy or reverse this state into metastatic cells. MΦs exhibiting an M2 phenotype constitute ~10% of cultured BM stroma. The M2 MΦs form gap junctional intercellular communication (GJIC) with CSCs, resulting in cycling quiescence, reduced proliferation and carboplatin resistance. In contrast, MΦs expressing the M1 phenotype reversed BC dormancy. Activation of M2a MΦs via the toll-like receptor 4 (TLR4) switched to M1 phenotype. The switch can occur by direct activation of M2a MΦs, or indirectly through activation of mesenchymal stem cells. M1 MΦ-derived exosomes activated NFкB to reverse quiescent BCCs to cycling cells. Using an in vivo model of BC dormancy, injected Mi MOs sensitized BCCs to carboplatin and increased host survival. In summary, we have shown how BM stromal MΦs, through exosomes, regulate the behavior of BCCs, by either inducing or reversing dormancy.

• Bcl-2
• CDK4
• caspase-3
• cyclin D1
• human breast cancer
• p53

This study investigated the clinical significance of serum soluble Toll-like receptor 4 (sTLR4) in non-small cell lung cancer (NSCLC). A total of 54 NSCLC patients and 13 healthy volunteers were enrolled from January 2012 to December 2013. The patients with NSCLC were characterized by significantly higher serum levels of sTLR4 compared with those in healthy controls (P < 0.01). A positive correlation between serum sTLR4 and tumor stage was found in patients with stages I–III NSCLC. However, serum sTLR4 in patients with metastatic NSCLC was significantly decreased compared with those with stage III NSCLC (P < 0.05). Furthermore, low serum sTLR4 was identified as a prognostic marker for poor survival of early-stage NSCLC patients who received surgical resection. In conclusion, our present study identified sTLR4 as a potential serum biomarker of NSCLC.

• biomarker
• high-mobility group box 1 (HMGB1)
• non-small cell lung cancer (NSCLC)
• soluble Toll-like receptor 4 (sTLR4)

Docosahexaenoic acid (DHA) oil is an important polyunsaturated fatty acid for the human body. Evidence has demonstrated that DHA is beneficial for inhibiting mammary carcinogenesis. However, the mechanisms of DHA mediating apoptosis induction have not been fully elucidated. Thus, in the present study, the activity levels of total-superoxide dismutase (t-SOD), catalase (CAT), glutathione-peroxidase (GSH-PX) and the concentration of malondialdehyde (MDA) were determined in DHA oil-treated human malignant breast tissues. The results revealed that compared with control, DHA significantly increased the main antioxidant enzymes levels, including t-SOD, CAT, and GSH-PX, but decreased the MDA concentration in the DHA oil treated breast cancer tissues. Furthermore, DHA significantly increased the ratio of cyclic (c)AMP/cGMP levels and promoted the expression of Toll-like receptor 4 (TLR-4) and peroxisome proliferator activated receptor (PPAR)-α, thus DHA induced breast cancer cell apoptosis. We hypothesized that the levels of TLR-4 and PPAR-α are involved in the antitumorigenesis properties of DHA in breast cancer. The results of the present study hold significance for the further clinical development of DHA oil in breast cancer treatment.

• Toll-like receptor 4
• antioxidant enzymes
• apoptosis
• breast cancer
• cAMP/cGMP
• docosahexaenoic acid

• osteoarthritis
• single nucleotide polymorphism
• toll-like receptor

Though TRAIL has been hailed as a promising drug for tumour treatment, it has been observed that many tumour cells have developed escape mechanisms against TRAIL-induced apoptosis. As a receptor of LPS, TLR 4, which is expressed on a variety of cancer cells, can be associated with TRAIL-resistance of tumour cells and tumour progression as well as with the generation of an anti-tumour immune response.

In this study, the sensitivity to TRAIL-induced apoptosis as well as the influence of LPS-co-stimulation on the cell viability of the pancreatic cancer cell lines PANC-1, BxPC-3 and COLO 357 was examined by FACS analyses and a cell viability assay. Subsequently, the expression of TRAIL-receptors was detected via FACS analyses. Levels of osteoprotegerin (OPG) were also determined using an enzyme-linked immunosorbent assay.

PANC-1 cells were shown to be resistant to TRAIL-induced apoptosis. This was accompanied by significantly increased osteoprotegerin levels and a significantly decreased expression of DR4.

In contrast, TRAIL significantly induced apoptosis in COLO 357 cells and to a lesser degree in BxPC-3 cells. Co-stimulation of COLO 357 as well as BxPC-3 cells combining TRAIL and LPS resulted in a significant decrease in TRAIL-induced apoptosis. In COLO 357 cells TRAIL-stimulation decreased the levels of OPG thereby not altering the expression of the TRAIL-receptors 1–4 resulting in a high susceptibility to TRAIL-induced apoptosis. Co-stimulation with LPS and TRAIL completely reversed the effect of TRAIL on OPG levels reaching a 2-fold increase beyond the level of non-stimulated cells resulting in a lower susceptibility to apoptosis.

In BxPC-3, TRAIL stimulation decreased the expression of DR4 and significantly increased the decoy receptors TRAIL-R3 and TRAIL-R4 leading to a decrease in TRAIL-induced apoptosis. OPG levels remained unchanged. Co-stimulation with TRAIL and LPS further enhanced the changes in TRAIL-receptor-expression promoting apoptosis resistance.

Here it has been shown that TRAIL-resistance in pancreatic cancer cells can be mediated by the inflammatory molecule LPS as well as by different expression patterns of functional and non-functional TRAIL-receptors.

• Apoptosis
• Cell lines
• LPS
• Pancreas cancer
• TRAIL

• Invasion
• MD-2 (myeloid differentiation factor 2)
• TLR4
• Tumor angiogenesis
• Vascular endothelial growth factor (VEGF) and human umbilical vein endothelial cell (HUVEC)

The aim of this study was to investigate the association of the common polymorphisms of Toll-like receptor 4 (TLR-4) with breast cancer development in the Saudi Arabian population. Four TLR-4 polymorphisms (rs2770150, rs10759931, rs10759932, and rs4986790) were studied using 127 breast cancer patients and 117 controls. Relative expression of TLR-4 protein in the breast tumor and the matched normal breast tissues was determined in a large cohort of 70 clinical breast samples in a tissue micro-array format by immunohistochemistry using a specific anti-TLR-4 antibody. Our results demonstrated an increase in TLR-4 expression in estrogen receptor (ER)−, postmenopausal breast cancer patients compared to normal. We also demonstrated that the G allele of single-nucleotide polymorphism rs10759931 was found to be significantly higher in frequency among patients (36.3%) compared to the control group (26.7%), suggesting that this polymorphism is strongly associated with the development of breast cancer in this ethnic population. In addition, the TLR-4 polymorphism rs2770150 was shown to be highly correlated with breast cancer in patients over 48 years of age. The TLR-4 polymorphism rs4986790 was also found to be associated with this malignancy in the ER− patient groups. Our results suggested firstly that the variation in TLR-4 gene expression may influence breast cancer development and secondly a closely linked association between TLR-4 gene polymorphism and ER status. Our study provides support for a better understanding of the implication of TLR-4 polymorphism in breast tumorigenesis and for its eventual use as a cancer biomarker.

• Saudi population
• Toll-like receptor 4
• breast cancer
• estrogen receptor
• innate immunity
• single-nucleotide polymorphisms

Ganoderma lucidum exerts antitumor activity, but the mechanism of G. lucidum polysaccharides on cancer is unclear. Here, we demonstrated that a fucose-containing fraction of Ling-Zhi (FFLZ) reduced tumor size and suppressed metastasis in vivo. Furthermore, FFLZ inhibited breast cancer cell migration and altered the epithelial-to-mesenchymal transition (EMT) phenotype. Transforming growth factor-β receptor (TGFR) pathways act as key mediators to promote tumor progression and metastasis. We found that FFLZ down-regulated TGFR and downstream signaling pathways, including the phosphorylation of Smad2/3 and the expression of Smad4. In an investigation of the underlying mechanisms, we found that FFLZ enhanced the Smurf2-dependent ubiquitination of TGFR by disrupting the balance of the lipid rafts, promoted the “re-localization” of the TGFR to the caveolae, and facilitated the degradation of TGFR. Together, our data indicated that FFLZ is associated with the inhibition of EMT and the prevention of metastasis by promoting ubiquitination-dependent TGFR degradation and abolishing TGFR signaling pathways. Moreover, the combination of FFLZ and trastuzumab synergistically inhibited the viability of certain trastuzumab-resistant human breast cancer cells. In summary, our current findings indicate that FFLZ is a potential therapeutic or dietary supplemental agent for cancer patients and that it functions via the caveolin-1/Smad7/Smurf2-dependent ubiquitin-mediated degradation of TGFR.

• Bullous pemphigoid
• Innate immunity
• Pemphigus
• Toll-like receptor 2
• Toll-like receptor 4
• Toll-like receptor 9

Systemic approaches are essential in the discovery of disease-specific genes, offering a different perspective and new tools on the analysis of several types of molecular relationships, such as gene co-expression or protein-protein interactions. However, due to lack of experimental information, this analysis is not fully applicable. The aim of this study is to reveal the multi-potent contribution of statistical network inference methods in highlighting significant genes and interactions. We have investigated the ability of statistical co-expression networks to highlight and prioritize genes for breast cancer subtypes and stages in terms of: (i) classification efficiency, (ii) gene network pattern conservation, (iii) indication of involved molecular mechanisms and (iv) systems level momentum to drug repurposing pipelines. We have found that statistical network inference methods are advantageous in gene prioritization, are capable to contribute to meaningful network signature discovery, give insights regarding the disease-related mechanisms and boost drug discovery pipelines from a systems point of view.

Toll-like receptors (TLRs) belong to the group of pathogen recognition receptors known to play a crucial role in the innate immune system. In cancer, TLR expression is still debated controversially due to contradictory results reporting that both induction of apoptosis as well as tumor progression could depend on TLR signaling, whereby recent data rather indicate a pro-tumorigenic effect. The biological phenomenon of cell fusion has been associated with cancer progression due to findings revealing that fusion-derived hybrid cells could exhibit properties like an increased metastatogenic capacity and an increased drug resistance. Thus, M13MDA435 hybrid cell lines, which derived from spontaneous fusion events between human M13SV1-EGFP-Neo breast epithelial cells and human MDA-MB-435-Hyg breast cancer cells, were investigated. Cultivation of cells in the presence of the TLR4 ligand LPS potently induced apoptosis in all hybrid clones, but not in parental cells, which was most likely attributed to differential kinetics of the TLR4 signal transduction cascade. Activation of this pathway concomitant with NF-κB nuclear translocation and TNF-α expression was solely observed in hybrid cells. However, induction of LPS mediated apoptosis was not TNF-α dependent since TNF-α neutralization was not correlated to a decreased amount of dead cells. In addition to TNF-α, LPS also caused IFN-β expression in hybrid clones 1 and 3. Interestingly, hybrid clones differ in the mode of LPS induced apoptosis. While neutralization of IFN-β was sufficient to impair the LPS induced apoptosis in M13MDA435-1 and -3 hybrids, the amount of apoptotic M13MDA435-2 and -4 hybrid cells remained unchanged in the presence of neutralizing IFN-β antibodies. In summary, the fusion of non-LPS susceptible parental human breast epithelial cells and human breast cancer cells gave rise to LPS susceptible hybrid cells, which is in view with the cell fusion hypothesis that hybrid cells could exhibit novel properties.

• Apoptosis
• Breast Neoplasms/pathology
• Cell Fusion
• Cell Line, Tumor
• Cell Nucleus/metabolism
• Cell Proliferation
• Disease Progression
• Drug Resistance, Neoplasm
• Enzyme-Linked Immunosorbent Assay
• Epithelial Cells/cytology
• Female
• Humans
• Hybrid Cells/cytology
• Interferon-beta/metabolism
• Ligands
• Lipopolysaccharides
• NF-kappa B/metabolism
• Signal Transduction
• Toll-Like Receptor 4/metabolism
• Tumor Cells, Cultured
• Tumor Necrosis Factor-alpha/metabolism

• Animals
• Anti-Inflammatory Agents/chemistry
• Anti-Inflammatory Agents/pharmacology
• Anti-Inflammatory Agents/therapeutic use
• Carbohydrate Sequence
• Cells, Cultured
• Dendritic Cells/drug effects
• Glycolipids/chemistry
• Glycolipids/pharmacology
• Glycolipids/therapeutic use
• Humans
• Lipopolysaccharides
• Mannosides/chemistry
• Mannosides/pharmacology
• Mannosides/therapeutic use
• Mice
• Mice, Inbred BALB C
• Pneumonia/chemically induced
• Pneumonia/drug therapy
• Protein Serine-Threonine Kinases/antagonists & inhibitors
• Structure-Activity Relationship
• Toll-Like Receptor 4/antagonists & inhibitors
• NF-kappaB-Inducing Kinase

• Chlorpyrifos
• High-mobility group box 1
• Inflammatory
• Interleukin-6
• Nuclear factor kappa B
• Tumor necrosis factor-α

• Amygdala/drug effects
• Amygdala/growth & development
• Amygdala/immunology
• Amygdala/metabolism
• Animals
• Animals, Newborn
• Chlorpyrifos/toxicity
• Cytokines/metabolism
• Encephalitis/chemically induced
• Encephalitis/immunology
• Encephalitis/metabolism
• Encephalitis/prevention & control
• Glycyrrhizic Acid/pharmacology
• HMGB1 Protein/antagonists & inhibitors
• HMGB1 Protein/metabolism
• Inflammation Mediators/metabolism
• Microglia/drug effects
• Microglia/immunology
• Microglia/metabolism
• NF-kappa B/metabolism
• Pesticides/toxicity
• Protein Transport
• Rats, Sprague-Dawley
• Signal Transduction/drug effects
• Time Factors
• Toll-Like Receptor 4/metabolism

Breast cancer-induced inflammation in the tumor reactive stroma supports invasion and malignant progression and is contributed to by a variety of host cells including macrophages and fibroblasts. Inflammation appears to be initiated by tumor cells and surrounding host fibroblasts that secrete pro-inflammatory cytokines and chemokines and remodel the extracellular matrix (ECM) to create a pro-inflammatory “cancerized” or tumor reactive microenvironment that supports tumor expansion and invasion. The tissue polysaccharide hyaluronan (HA) is an example of an ECM component within the cancerized microenvironment that promotes breast cancer progression. Like many ECM molecules, the function of native high-molecular weight HA is altered by fragmentation, which is promoted by oxygen/nitrogen free radicals and release of hyaluronidases within the tumor microenvironment. HA fragments are pro-inflammatory and activate signaling pathways that promote survival, migration, and invasion within both tumor and host cells through binding to HA receptors such as CD44 and RHAMM/HMMR. In breast cancer, elevated HA in the peri-tumor stroma and increased HA receptor expression are prognostic for poor outcome and are associated with disease recurrence. This review addresses the critical issues regarding tumor-induced inflammation and its role in breast cancer progression focusing specifically on the changes in HA metabolism within tumor reactive stroma as a key factor in malignant progression.

• CD44
• RHAMM/HMMR
• breast cancer
• hyaluronan
• inflammation
• macrophage
• tumor microenvironment

High mobility group box-1 (HMGB1), a typical damage-associated molecular pattern (DAMP) protein, is associated with inflammatory conditions and tissue damage. Our recent study found that circulating HMGB1 levels could reflect the disease activity of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The current study aimed to investigate whether HMGB1 participated in ANCA-induced neutrophil activation, which is one of the most important pathogenic aspects in the development of AAV.

The various effects of HMGB1 in ANCA-induced neutrophil activation were measured. Antagonists for relevant receptors and signaling molecules were employed.

ANCA antigens translocation on neutrophils primed with HMGB1 was significantly higher than non-primed neutrophils. The levels of respiratory burst and degranulation increased significantly in HMGB1-primed neutrophils activated with ANCA-positive IgG, as compared with non-primed neutrophils. Furthermore, blocking Toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE), rather than TLR2, resulted in a significant decrease in HMGB1-induced ANCA antigens translocation, respiratory burst and degranulation. Similar effects were also found when blocking MyD88 and NF-κB.

HMGB1 could prime neutrophils by increasing ANCA antigens translocation, and the primed neutrophils could be further induced by ANCA, resulting in the respiratory burst and degranulation. This process is TLR4- and RAGE-dependent through the MyD88/NF-κB pathway.

The online version of this article (doi:10.1186/s13075-015-0587-4) contains supplementary material, which is available to authorized users.

• Breast cancer
• Cell cycle progression
• MicroRNA
• NF-κB signaling

• adoptive cell transfer
• checkpoint blockers
• dendritic cell-based interventions
• dna-based vaccines
• immunostimulatory cytokines
• peptide-based vaccines
• oncolytic viruses
• toll-like receptor agonists

• Animals
• Humans
• Immunotherapy/methods
• Neoplasms/immunology
• Neoplasms/therapy

• UL1 TR000430 NCATS NIH HHS
• P30 CA010815 NCI NIH HHS
• P50 CA121973 NCI NIH HHS
• P30 CA008748 NCI NIH HHS
• R01 CA109542 NCI NIH HHS