MicroRNA-19b exacerbates systemic sclerosis through promoting Th9 cells.

Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis of the skin and multiple vital organs, but the immunological pathogenesis of SSc remains unclear. We show here that miR-19b promotes Th9 cells that exacerbate SSc. Specifically, miR-19b and interleukin (IL)-9 increase in CD4+ T cells in experimental SSc in mice induced with bleomycin. Inhibiting miR-19b reduces Th9 cells and ameliorates the disease. Mechanistically, transforming growth factor beta (TGF-ß) plus IL-4 activates pSmad3-Ser213 and TRAF6-K63 ubiquitination by suppressing NLRC3. Activated TRAF6 sequentially promotes TGF-ß-activated kinase 1 (TAK1) and nuclear factor κB (NF-κB) p65 phosphorylation, leading to the upregulation of miR-19b. Notably, miR-19b activated Il9 gene expression by directly suppressing atypical E2F family member E2f8. In patients with SSc, higher levels of IL9 and MIR-19B correlate with worse disease progression. Our findings reveal miR-19b as a key factor in Th9 cell-mediated SSc pathogenesis and should have clinical implications for patients with SSc.

TGF-ß uncouples glycolysis and inflammation in macrophages and controls survival during sepsis.

Changes in metabolism of macrophages are required to sustain macrophage activation in response to different stimuli. We showed that the cytokine TGF-ß (transforming growth factor-ß) regulates glycolysis in macrophages independently of inflammatory cytokine production and affects survival in mouse models of sepsis. During macrophage activation, TGF-ß increased the expression and activity of the glycolytic enzyme PFKL (phosphofructokinase-1 liver type) and promoted glycolysis but suppressed the production of proinflammatory cytokines. The increase in glycolysis was mediated by an mTOR-c-MYC-dependent pathway, whereas the inhibition of cytokine production was due to activation of the transcriptional coactivator SMAD3 and suppression of the activity of the proinflammatory transcription factors AP-1, NF-κB, and STAT1. In mice with LPS-induced endotoxemia and experimentally induced sepsis, the TGF-ß-induced enhancement in macrophage glycolysis led to decreased survival, which was associated with increased blood coagulation. Analysis of septic patient cohorts revealed that the expression of PFKL, TGFBRI (which encodes a TGF-ß receptor), and F13A1 (which encodes a coagulation factor) in myeloid cells positively correlated with COVID-19 disease. Thus, these results suggest that TGF-ß is a critical regulator of macrophage metabolism and could be a therapeutic target in patients with sepsis.

Pyrolyzed deketene curcumin controls regulatory T cell generation and gastric cancer metabolism cooperate with 2-deoxy-d-glucose.

Pyrolyzed deketene curcumin GO-Y022 prevents carcinogenesis in a gastric cancer mouse model. However, it is still less clear if GO-Y022 affects tumor-induced immune suppression. In this study, we found that GO-Y022 inhibited Treg generation in the presence of transforming growth factor beta 1 (TGF-ß). However, GO-Y022 showed less impact on Foxp3+ Tregs in the gastric tumor microenvironment. Gastric tumor cells produce a large amount of L-lactate in the presence of GO-Y022 and diminish the inhibitory role of GO-Y022 against Treg generation in response to TGF-ß. Therefore, naïve CD4+ T cells co-cultured with GO-Y022 treated gastric tumor cells increased Treg generation. GO-Y022-induced tumor cell death was further enhanced by 2-deoxy-d-glucose (2DG), a glycolysis inhibitor. Combination treatment of GO-Y022 and 2DG results in reduced L-lactate production and Treg generation in gastric tumor cells. Overall, GO-Y022-treatment with restricted glucose metabolism inhibits gastric tumor cell survival and promotes anti-tumor immunity.

Opposing functions of circadian protein DBP and atypical E2F family E2F8 in anti-tumor Th9 cell differentiation.

Interleukin-9 (IL-9)-producing CD4+ T helper cells (Th9) have been implicated in allergy/asthma and anti-tumor immunity, yet molecular insights on their differentiation from activated T cells, driven by IL-4 and transforming growth factor-beta (TGF-ß), is still lacking. Here we show opposing functions of two transcription factors, D-binding protein (DBP) and E2F8, in controlling Th9 differentiation. Specifically, TGF-ß and IL-4 signaling induces phosphorylation of the serine 213 site in the linker region of the Smad3 (pSmad3L-Ser213) via phosphorylated p38, which is necessary and sufficient for Il9 gene transcription. We identify DBP and E2F8 as an activator and repressor, respectively, for Il9 transcription by pSmad3L-Ser213. Notably, Th9 cells with siRNA-mediated knockdown for Dbp or E2f8 promote and suppress tumor growth, respectively, in mouse tumor models. Importantly, DBP and E2F8 also exhibit opposing functions in regulating human TH9 differentiation in vitro. Thus, our data uncover a molecular mechanism of Smad3 linker region-mediated, opposing functions of DBP and E2F8 in Th9 differentiation.

Unraveling the Simultaneous Enhancement of Selectivity and Durability on Single-Crystalline Gold Particles for Electrochemical CO2 Reduction.

Electrochemical carbon dioxide reduction is a mild and eco-friendly approach for CO2 mitigation and producing value-added products. For selective electrochemical CO2 reduction, single-crystalline Au particles (octahedron, truncated-octahedron, and sphere) are synthesized by consecutive growth and chemical etching using a polydiallyldimethylammonium chloride (polyDDA) surfactant, and are surface-functionalized. Monodisperse, single-crystalline Au nanoparticles provide an ideal platform for evaluating the Au surface as a CO2 reduction catalyst. The polyDDA-Au cathode affords high catalytic activity for CO production, with >90% Faradaic efficiency over a wide potential range between -0.4 and -1.0 V versus RHE, along with high durability owing to the consecutive interaction between dimethylammonium and chloride on the Au surface. The influence of polyDDA on the Au particles, and the origins of the enhanced selectivity and stability are fully investigated using theoretical studies. Chemically adsorbed polyDDA is consecutively affected the initial adsorption of CO2 and the stability of the *CO2 , *COOH, and *CO intermediates during continuous CO2 reduction reaction. The polyDDA functionalization is extended to improving the CO Faradaic efficiency of other metal catalysts such as Ag and Zn, indicating its broad applicability for CO2 reduction.

Electrochemical Generation of Mesopores and Residual Oxygen for the Enhanced Activity of Silver Electrocatalysts.

The development of stable and efficient electrocatalysts is of key importance for the establishment of a sustainable society. The activity of a metal electrocatalyst is determined by its electrochemically active surface area and intrinsic activity, which can be increased using highly porous structures and heteroatomic doping, respectively. Herein, we propose a general strategy of generating mesopores and residual oxygen in metal electrocatalysts by reduction of metastable metal oxides using Ag2O3 electrodeposited onto carbon paper as a model system and demonstrating that the obtained multipurpose porous Ag electrocatalyst has high activity for the electroreduction of O2 and CO2. The presence of mesopores and residual oxygen is confirmed by electrochemical and spectroscopic techniques, and quantum mechanical simulations prove the importance of residual oxygen for electrocatalytic activity enhancement. Thus, the adopted strategy is concluded to allow the synthesis of highly active metal catalysts with controlled mesoporosity and residual oxygen content.

Comprehensive Study of the Growth Mechanism and Photoelectrochemical Activity of a BiVO4/Bi2S3 Nanowire Composite.

A BiVO4/Bi2S3 composite comprising Bi2S3 nanowires on top of a BiVO4 film was prepared via hydrothermal reaction. Because additional Bi3+ ions were not delivered during the reaction, BiVO4 served as the Bi3+ ion source for the development of Bi2S3. A detailed growth mechanism of the nanowire was elucidated by an analysis of the concentration gradient of Bi3+ and S2- ions during the reaction. The in situ growth was followed by the etching of BiVO4 to Bi3+ and VO43- ions and regrowth to Bi2S3, which resulted in the rapid evolution of nanowires on the BiVO4 substrate. The fabricated BiVO4/Bi2S3NW composite exhibited an improved photoelectrochemical activity compared to other Bi2S3 samples. The improved efficiency was mainly attributed to both improved charge separation and effective adhesion obtained by the in situ growth.

Identification of fusidic acid resistance in clinical isolates of Staphylococcus pseudintermedius from dogs in Korea.

BACKGROUND: Staphylococcus pseudintermedius is a major bacterial species associated with canine pyoderma and otitis. Fusidic acid is used to treat skin infections caused by Gram-positive bacteria. The incidence of resistance to fusidic acid in S. pseudintermedius has importance in terms of limiting treatment options for bacterial infections. HYPOTHESIS/OBJECTIVES: To evaluate the occurrence and mechanisms of fusidic acid resistance in clinical isolates of S. pseudintermedius. ANIMALS: Fifty-two S. pseudintermedius isolates were collected from dogs with pyoderma (n = 36) or otitis (n = 16). METHODS AND MATERIALS: The disk diffusion method determined that isolates <24 mm were resistant to fusidic acid. Minimum inhibitory concentrations (MICs) were measured by the E-test in those with confirmed resistance to fusidic acid by the disk diffusion method. Phenotypically fusidic acid resistant isolates were subjected to PCR to detect the presence of resistance-related genes (fusA, fusB, fusC and fusD) and fusA was further sequenced to identify point mutations. RESULTS: Fourteen of 52 (27%) S. pseudintermedius isolates were resistant to fusidic acid and all of these showed low-level resistance. Among fusidic acid resistant isolates, fusA point mutations were confirmed in 11 isolates and amino acid substitutions were found in five. fusC was detected in seven isolates, but neither fusB nor fusD was detected. CONCLUSIONS AND CLINICAL IMPORTANCE: This study demonstrates the occurrence and resistance mechanisms to fusidic acid in clinical isolates of S. pseudintermedius. Continuous monitoring for fusidic acid resistance is recommended.

Different macrophage polarization between drug-susceptible and multidrug-resistant pulmonary tuberculosis.

BACKGROUND: Macrophages play a key role in the infection process, and alternatively activated macrophages (M2 polarization) play important roles in persistent infection via the immune escape of pathogens. This suggests that immune escape of pathogens from host immunity is an important factor to consider in treatment failure and multidrug-resistant tuberculosis (MDR-TB)/extensively drug-resistant tuberculosis (XDR-TB). In this study, we investigated the association between macrophage polarization and MDR-TB/XDR-TB and the association between macrophage polarization and the anti-TB drugs used. METHODS: iNOS and arginase-1, a surface marker of polarized macrophages, were quantified by immunohistochemical staining and imaging analysis of lung tissues of patients who underwent surgical treatment for pulmonary TB. Drug susceptibility/resistance and the type and timing of anti-tuberculosis drugs used were investigated. RESULTS: The M2-like polarization rate and the ratio of the M2-like polarization rate to the M1-like polarization rate were significantly higher in the MDR-TB/XDR-TB group than in the DS-TB group. The association between a high M2-like polarization rate and MDR-TB/XDR-TB was more pronounced in patients with a low M1-like polarization rate. Younger age and a higher M2-like polarization rate were independent associated factors for MDR-TB/XDR-TB. The M2-like polarization rate was significantly higher in patients who received anti-TB drugs containing pyrazinamide continuously for 4 or 6 weeks than in those who received anti-TB drugs not containing pyrazinamide. CONCLUSIONS: The M2-like polarization of macrophages is associated with MDR-TB/XDR-TB and anti-TB drug regimens including pyrazinamide or a combination of pyrazinamide, prothionamide and cycloserine.

M1 macrophage dependent-p53 regulates the intracellular survival of mycobacteria.

Tumor suppressor p53 is not only affects immune responses but also contributes to antibacterial activity. However, its bactericidal function during mycobacterial infection remains unclear. In this study, we found that the p53-deficient macrophages failed to control Mycobacterium tuberculosis (Mtb), manifested as a lower apoptotic cell death rate and enhanced intracellular survival. The expression levels of p53 during Mtb infection were stronger in M1 macrophages than in M2 macrophages. The TLR2/JNK signaling pathway plays an essential role in the modulation of M1 macrophage polarization upon Mtb infection. It facilitates p53-mediated apoptosis through the production of reactive oxygen species, nitric oxide and inflammatory cytokines in Mtb-infected M1 macrophages. In addition, nutlin-3 effectively abrogated the intracellular survival of mycobacteria in both TB patients and healthy controls after H37Ra infection for 24 h, indicating that the enhancement of p53 production effectively suppressed the intracellular survival of Mtb in hosts. These results suggest that p53 can be a new therapeutic target for TB therapy.

Correction to: M1 macrophage dependent-p53 regulates the intracellular survival of mycobacteria.

The original version of this article unfortunately contains an error in the acknowledgement section. The text "Brain Korea 21 PLUS Project for Medical Science, Chungnam National University" was omitted by mistake. The correct and complete acknowledgment is given below: Acknowledgments This work was supported by the research fund of Chungnam National University and the Brain Korea 21 PLUS Project for Medical Science, Chungnam National University. The funders had no role in study design, data collection and analysis decision to publish, or preparation of the manuscript.

Characterisation of genes differentially expressed in macrophages by virulent and attenuated Mycobacterium tuberculosis through RNA-Seq analysis.

Tuberculosis (TB) remains a global healthcare issue. Understanding the host-pathogen interactions in TB is vital to develop strategies and therapeutic tools for the control of Mycobacterium tuberculosis (Mtb). In this study, transcriptome analyses of macrophages infected with either the virulent Mtb strain H37Rv (Rv) or the avirulent Mtb strain H37Ra (Ra) were carried out and 750 differentially expressed genes (DEGs) were identified. As expected, the DEGs were mainly involved in the induction of innate immune responses against mycobacterial infections. Among the DEGs, solute carrier family 7 member 2 (Slc7a2) was more strongly expressed in Ra-infected macrophages. Induction of SLC7A2 was important for macrophages to control the intracellular survival of Mtb. Our results imply that SLC7A2 plays an important role in macrophages during Mtb infection. Our findings could prove useful for the development of new therapeutic strategies to control TB infection.

Phagocytosis influences the intracellular survival of Mycobacterium smegmatis via the endoplasmic reticulum stress response.

BACKGROUND: Mycobacterium smegmatis, a rapidly growing non-tuberculosis mycobacterium, is a good model for studying the pathogenesis of tuberculosis because of its genetic similarity to Mycobacterium tuberculosis (Mtb). Macrophages remove mycobacteria during an infection. Macrophage apoptosis is a host defense mechanism against intracellular bacteria. We have reported that endoplasmic reticulum (ER) stress is an important host defense mechanism against Mtb infection. RESULTS: In this study, we found that M. smegmatis induced strong ER stress. M. smegmatis-induced reactive oxygen species (ROS) play a critical role in the induction of ER stress-mediated apoptosis. Pretreatment with an ROS scavenger suppressed M. smegmatis-induced ER stress. Elimination of ROS decreased the ER stress response and significantly increased the intracellular survival of M. smegmatis. Interestingly, inhibition of phagocytosis significantly decreased ROS synthesis, ER stress response induction, and cytokine production. CONCLUSIONS: Phagocytosis of M. smegmatis induces ROS production, leading to production of proinflammatory cytokines. Phagocytosis-induced ROS is associated with the M. smegmatis-mediated ER stress response in macrophages. Therefore, phagocytosis plays a critical role in the induction of ER stress-mediated apoptosis during mycobacterial infection.

TNF-α-mediated ER stress causes elimination of Mycobacterium fortuitum reservoirs by macrophage apoptosis.

Mycobacterium fortuitum (MF), a rapidly growing nontuberculosis mycobacterium, is recognized as an important human pathogen. We investigated whether the endoplasmic reticulum (ER) stress response is associated with the apoptosis of MF-infected macrophages. The expression of ER molecular chaperones was significantly induced by MF infection. We found that MF-induced reactive oxygen species (ROS) generation plays a critical role in the induction of ER stress-mediated apoptosis. Excess TNF-α in the ER led to ER stress-mediated apoptosis during MF infection. The intracellular survival of MF was significantly increased by TNF-α knockdown compared with the control. This is the first report of MF-induced TNF-α as a cause of ER stress in macrophages. Furthermore, we found that TLR2-mediated ER stress response contributed to the elimination of intracellular MF in vivo. These results suggest that TNF-α-mediated ER stress during MF infection contributes to the suppression of intracellular survival of MF in macrophages. Our findings provide new insight into the importance of ER stress in mycobacterial infection.-Oh, S.-M., Lim, Y.-J., Choi, J.-A., Lee, J., Cho, S.-N., Go, D., Kim, S.-H., Song, C.-H. TNF-α-mediated ER stress causes elimination of Mycobacterium fortuitum reservoirs by macrophage apoptosis.

Enhancement of the antimycobacterial activity of macrophages by ajoene.

Ajoene, a garlic-derived sulfur-containing compound, has broad-spectrum antimicrobial activity. To assess the potential of ajoene for treating tuberculosis (TB), we determined whether it induces the stress response of the endoplasmic reticulum (ER), which plays an important role in TB. We showed that ajoene stimulation induced the production of ER stress sensor molecules and reactive oxygen species (ROS) levels. Ajoene-induced ROS production was dependent on c-Jun N-terminal kinase (JNK) activation. Interestingly, the inhibition of JNK activity and suppression of ROS production reduced ajoene-induced CHOP production in macrophages. Because ER stress activates autophagy, the activation of which suppresses the growth of mycobacteria, we investigated the ajoene-induced production of autophagy-related factors, including LC3-II, P62 and Beclin-1. As expected, ajoene treatment increased the levels of these factors in RAW 264.7 cells. Remarkably, the total amount of Mycobacterium tuberculosis (Mtb) H37Rv was significantly reduced in ajoene-treated RAW 264.7 cells. The treatment of macrophages with ajoene resulted in the activation of JNK, induction of ROS synthesis and accumulation of ROS, possibly leading to the activation of ER stress and autophagy. These results reveal the mechanism of the antimycobacterial effects of ajoene against Mtb H37Rv. Our findings might facilitate the development of novel therapies for patients with TB.

Calreticulin modulates the intracellular survival of mycobacteria by regulating ER-stress-mediated apoptosis.

Endoplasmic reticulum (ER)-stress-mediated apoptosis is a host defense mechanism against Mycobacterium tuberculosis (Mtb) infection. Calreticulin (CRT) is the major calcium-binding chaperone protein. Previous reports have suggested a close relationship between the cell-surface expression of CRT and apoptosis. In this study, the role of CRT during Mtb infection was examined. The results showed that Mtb infection induces CRT production by macrophages and that CRT levels are correlated with the degree of apoptotic cell death. The enhanced production of CRT was associated with the ER stress induced by Mtb infection. A significant increase in CRT translocation from the cytosol to the plasma membrane after 24 h of infection suggested the importance of CRT localization in the induction of apoptosis during Mtb infection. An investigation of the factors associated with CRT translocation and the ability of ectopically expressed CRT to induce apoptosis showed that pretreatment with a reactive oxygen species scavenger decreased Mtb-induced CRT expression, leading to the reduction of CHOP and caspase-3 activation. The intracellular survival of Mtb was significantly higher in macrophages transfected with a CRT-specific small interfering RNA than in control cells. The key role of CRT in inducing apoptosis included its interaction with CXCR1 and TNFR1 in Mtb-infected macrophages. The CRT/CXCR1/TNFR1 complex was shown to induce the extrinsic apoptotic pathway during Mtb infection. Together, these results demonstrate that CRT is critical for the intracellular survival of Mtb, via ER-stress-induced apoptosis, as well as the importance of ER stress-mediated CRT localization in the pathogenesis of tuberculosis.

Roles of endoplasmic reticulum stress-mediated apoptosis in M1-polarized macrophages during mycobacterial infections.

Alteration of macrophage function has an important regulatory impact on the survival of intracellular mycobacteria. We found that macrophages infected with attenuated Mycobacterium tuberculosis (Mtb) strain H37Ra had elevated expression of M1-related molecules, whereas the M2 phenotype was dominant in macrophages infected with virulent Mtb H37Rv. Further, the TLR signalling pathway played an important role in modulating macrophage polarization against Mtb infection. Interestingly, endoplasmic reticulum (ER) stress was significantly increased in M1 polarized macrophages and these macrophages effectively removed intracellular Mtb, indicating that ER stress may be an important component of the host immune response to Mtb in M1 macrophages. This improved understanding of the mechanisms that regulate macrophage polarization could provide new therapeutic strategies for tuberculosis.

The Role of Prostate Apoptosis Response-4 (Par-4) in Mycobacterium tuberculosis Infected Macrophages.

Prostate apoptosis response-4 (Par-4) is a tumor suppressor protein that forms a complex with glucose-regulated protein 78 (GRP78) to induce apoptosis. Previously, we reported that ER stress-induced apoptosis is a critical host defense mechanism against Mycobacterium tuberculosis (Mtb). We sought to understand the role of Par-4 during ER stress-induced apoptosis in response to mycobacterial infection. Par-4 and GRP78 protein levels increased in response Mtb (strain: H37Ra) infection. Furthermore, Par-4 and GRP78 translocate to the surface of Mtb H37Ra-infected macrophages and induce apoptosis via caspase activation. NF-κB activation, Mtb-mediated ER stress, and Par-4 production were significantly diminished in macrophages with inhibited ROS production. To test Par-4 function during mycobacterial infection, we analyzed intracellular survival of Mtb H37Ra in macrophages with Par-4 overexpression or knockdown. Mtb H37Ra growth was significantly reduced in Par-4 overexpressing macrophages and increased in knockdown macrophages. We also observed increased Par-4, GRP78, and caspases activation in Bacillus Calmette-Guérin (BCG)-infected prostate cancer cells. Our data demonstrate that Par-4 is associated with ER stress-induced apoptosis resulting in reduced intracellular survival of mycobacteria. BCG treatment increases Par-4-dependent caspase activation in prostate cancer cells. These results suggest ER stress-induced Par-4 acts as an important defense mechanism against mycobacterial infection and regulates cancer.

Mycobacterium tuberculosis 38-kDa antigen induces endoplasmic reticulum stress-mediated apoptosis via toll-like receptor 2/4.

Endoplasmic reticulum (ER) stress responses play critical roles in the pathogenesis of tuberculosis. To investigate the regulatory role of the ER stress response in 38-kDa antigen-induced apoptosis, we examined the relationship between the ER stress response and apoptosis in bone marrow-derived macrophages (BMDMs) stimulated with Mycobacterium tuberculosis antigen (38-kDa Ag). The expression of ER molecular chaperones, including C/EBP homologous protein (CHOP), glucose-regulated protein (Bip) and phosphorylated alpha subunit of eukaryotic initiation factor 2, was induced in BMDMs stimulated with the 38-kDa Ag. Interestingly, 38-kDa Ag-stimulation induced apoptosis via activation of caspase-12, -9 and -3. However, 38-kDa Ag-induced apoptosis was significantly reduced in TLR2- and TLR4-deficient macrophages. Because toll-like receptors (TLRs) initiate the activation of mitogen-activated protein kinase (MAPK) signaling cascades, we evaluated the effect of MAPK activation on ER stress. The 38-kDa Ag activated Jun N-terminal kinase, extracellular signal-regulated kinase and p38 phosphorylation. MAPK signaling induced the secretion of proinflammatory cytokines such as MCP-1, TNF-α and IL-6. The 38-kDa Ag-induced MCP-1 was especially associated with the induction of MCP-1-induced protein (MCPIP), which increased the generation of reactive oxygen species (ROS) and ER stress. To investigate the role of MCPIP in ROS-induced ER stress by 38-kDa Ag stimulation, we transfected MCPIP siRNA into RAW264.7 cells before 38-kDa Ag stimulation, and measured the generation of ROS and expression of ER molecular chaperones. ROS production and CHOP expression were decreased by the silencing of MCPIP induction. Our results demonstrate that the expression of MCPIP by 38-kDa Ag stimulation is increased through a TLR-MAPK-dependent signaling pathway, and leads to ER stress-induced apoptosis. In conclusion, MCPIP is important for host defense mechanisms in mycobacterial pathogenesis.

Staphylococcus aureus enterotoxin B-induced endoplasmic reticulum stress response is associated with chronic rhinosinusitis with nasal polyposis.

OBJECTIVE: Staphylococcus aureus enterotoxin B (SEB) might participate in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). However, the exact mechanism of polyp formation in CRSwNP remains unclear. Since the endoplasmic reticulum (ER) stress response is closely associated with chronic inflammation, we investigated the association between ER stress and SEB in the pathogenesis of CRSwNP. DESIGN AND METHODS: Twenty-three CRSwNP patients with eosinophilic polyps (EP) or non-eosinophilic polyps (NEP) and 10 healthy subjects who were undergoing septoplasty were enrolled in this study. ER stress response was investigated using immunohistochemical staining and Western blotting. RESULTS: We show in this study that there are significantly more SEB-positive cells and higher production of reactive oxygen species (ROS) in the epithelial layer of EP than NEP or control tissue. Both SEB and protein A were detected strongly in tissues from patients with CRSwNP. We observed SEB induced the ER stress response in RPMI 2650 cells. GRP78 elevation by SEB was reduced by ROS scavenger pretreatment. In addition, the induction of GRP78 and p47 phox was increased significantly in EP compared with NEP or control mucosa. CONCLUSIONS: SEB may induce ER stress via ROS production in CRSwNP. Therefore, we suggest that SEB-induced ER stress may play important roles in the pathogenesis of nasal polyposis.