USP22 promotes pro-inflammatory responses in Pseudomonas aeruginosa-induced keratitis by targeting TRAF6

2020 ◽  
Author(s):  
DI CHEN ◽  
DAWEI SONG ◽  
YIBIN MA ◽  
WEIZHAO LU ◽  
JIANFENG QIU ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Vision Loss ◽  
Inflammatory Responses ◽  
Tumor Necrosis Factor Receptor ◽  
Raw264.7 Cells ◽  
Control Plasmid ◽  
Specific Protease ◽  
Inflammatory Processes ◽  
Ubiquitin Specific Protease ◽  
Necrosis Factor

Abstract Background Pseudomonas aeruginosa (PA)-induced keratitis is characterized by inflammatory epithelial edema, stromal infiltration, corneal ulceration, and can lead to vision loss. In the present study, we aim to study the effect of ubiquitin-specific protease 22 (USP22) on PA-induced keratitis. Methods Lentivirus containing control plasmid or shRNA targeting USP22 were used to silence the expression of USP22 in mouse corneas and cultured RAW264.7 cells, the inflammatory processes were detected. Results We found the expression level of USP22 was significantly increased in both mouse corneas and cultured RAW264.7 cells after PA stimulation. In addition, we observed that silencing of USP22 attenuate disease progression, downregulate NF-κB pathway and suppressed the expression of pro-inflammatory cytokines after PA stimulation. Most importantly, we found the expression of tumor necrosis factor receptor-associated factor 6 (TRAF6) was decreased by silencing of USP22, and USP22 was found to remove K48-linked poly-ubiquitination chains from TRAF6 to stabilize TRAF6 expression after PA infection. Conclusion This data indicated USP22 as a positive regulator of pro-inflammatory responses in PA induced keratitis.

scholarly journals Proinflammatory Effects of Ubiquitin-Specific Protease 5 (USP5) in Rheumatoid Arthritis Fibroblast-Like Synoviocytes

2020 ◽  
Vol 2020 ◽  
pp. 1-9 ◽  
Author(s):  
Xiao-Bo Luo ◽  
Jian-Cheng Xi ◽  
Zhen Liu ◽  
Yu Long ◽  
Li-tao Li ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Tumor Necrosis Factor Receptor ◽  
Dependent Manner ◽  
Autoimmune Inflammatory Disease ◽  
Specific Protease ◽  
Inflammatory Processes ◽  
Ubiquitin Specific Protease ◽  
Signaling Activation ◽  
Fibroblast Like Synoviocytes

Rheumatoid arthritis (RA) is a worldwide chronic autoimmune inflammatory disease which is affecting approximately 1% of the total population. It is characterized by abnormal proliferation of fibroblast-like synoviocytes (FLS) and increased production of proinflammatory cytokines. In the current study, we were aiming to investigate the role of ubiquitin-specific protease 5 (USP5) in the inflammatory process in RA-FLS. Expression of USP5 was found upregulated in RA-FLS compared with that in osteoarthritis- (OA-) FLS, and IL-1β stimulation increased USP5 expression in a time-dependent manner. Furthermore, we found that USP5 overexpression significantly aggravated proinflammatory cytokine production and related nuclear factor κB (NF-κB) signaling activation. Consistently, silencing of USP5 decreased the release of cytokines and inhibited the activation of NF-κB. In addition, USP5 was found to interact with tumor necrosis factor receptor-associated factor 6 (TRAF6) and remove its K48-linked polyubiquitination chains therefore stabilizing TRAF6. Our data showed that a USP5-positive cell regulates inflammatory processes in RA-FLS and suggested USP5 as a potential target for RA treatment.

scholarly journals Activated Platelets Induce an Anti-Inflammatory Response of Monocytes/Macrophages through Cross-Regulation of PGE2and Cytokines

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Bona Linke ◽  
Yannick Schreiber ◽  
Bettina Picard-Willems ◽  
Patrick Slattery ◽  
Rolf M. Nüsing ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Cell Types ◽  
Inhibitory Effect ◽  
Innate Immune ◽  
Prostaglandin E ◽  
Murine Bone Marrow ◽  
Activated Platelets ◽  
Monocytes And Macrophages ◽  
Inflammatory Processes ◽  
Necrosis Factor

Platelets are well known for their role in hemostasis and are also increasingly recognized for their roles in the innate immune system during inflammation and their regulation of macrophage activation. Here, we aimed to study the influence of platelets on the production of inflammatory mediators by monocytes and macrophages. Analyzing cocultures of platelets and murine bone marrow-derived macrophages or human monocytes, we found that collagen-activated platelets release high amounts of prostaglandin E2(PGE2) that leads to an increased interleukin- (IL-) 10 release and a decreased tumor necrosis factor (TNF)αsecretion out of the monocytes or macrophages. Platelet PGE2mediated the upregulation of IL-10 in both cell types via the PGE2receptor EP2. Notably, PGE2-mediated IL-10 synthesis was also mediated by EP4 in murine macrophages. Inhibition of TNFαsynthesis via EP2 and EP4, but not EP1, was mediated by IL-10, since blockade of the IL-10 receptor abolished the inhibitory effect of both receptors on TNFαrelease. This platelet-mediated cross-regulation between PGE2and cytokines reveals one mechanism how monocytes and macrophages can attenuate excessive inflammatory responses induced by activated platelets in order to limit inflammatory processes.

scholarly journals Epigenetic Silencing of Ubiquitin Specific Protease 4 by Snail1 Contributes to Macrophage-Dependent Inflammation and Therapeutic Resistance in Lung Cancer

Cancers ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 148 ◽  
Author(s):  
Chao-Yang Lai ◽  
Da-Wei Yeh ◽  
Chih-Hao Lu ◽  
Yi-Ling Liu ◽  
Yu-Chen Chuang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Survival Data ◽  
Inflammatory Responses ◽  
Chemotherapy Resistance ◽  
Lung Cancer Cells ◽  
Lung Cancer Patients ◽  
Specific Protease ◽  
Ubiquitin Specific Protease

There is a positive feedback loop driving tumorigenesis and tumor growth through coordinated regulation of epigenetics, inflammation, and stemness. Nevertheless, the molecular mechanism linking these processes is not well understood. In this study, we analyzed the correlation of de-ubiquitinases (DUBs) expression with survival data from the OncoLnc database. Among the DUBs analyzed, ubiquitin specific protease 4 (USP4) had the lowest negative Cox coefficient. Low expression of USP4 was associated with poor survival among lung cancer patients and was inversely correlated with expression of stemness and inflammation markers. Expression of USP4 were reduced at more advanced stages of lung cancer. Mechanistically, expression of USP4 was downregulated in snail1-overexpressing and stemness-enriched lung cancer cells. Snail1 was induced in lung cancer cells by interaction with macrophages, and epigenetically suppressed USP4 expression by promoter methylation. Stable knockdown of USP4 in lung cancer cells enhanced inflammatory responses, stemness properties, chemotherapy resistance, and the expression of molecules allowing escape from immunosurveillance. Further, mice injected with USP4 knockdown lung cancer cells demonstrated enhanced tumorigenesis and tumor growth. These results reveal that the Snail1-mediated suppression of USP4 is a potential mechanism to orchestrate epigenetic regulation, inflammation and stemness for macrophage-promoted tumor progression.

scholarly journals Cigarette smoke extract modulates Pseudomonas aeruginosa bacterial load via USP25/HDAC11 axis in lung epithelial cells

2020 ◽  
Vol 318 (2) ◽  
pp. L252-L263 ◽  
Author(s):  
Chen Long ◽  
Yandong Lai ◽  
Tiao Li ◽  
Toru Nyunoya ◽  
Chunbin Zou
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Epithelial Cells ◽  
Cigarette Smoking ◽  
Protein Level ◽  
Bacterial Load ◽  
Lung Epithelial Cells ◽  
Microbial Infection ◽  
Lung Epithelial ◽  
Specific Protease ◽  
Ubiquitin Specific Protease

Cigarette smoking increases susceptibility for microbial infection in respiratory system. However, the underlying molecular mechanism(s) is not fully elucidated. Here we report that cigarette smoking extract (CSE) increases bacterial load in lung epithelial cells via downregulation of the ubiquitin-specific protease 25 (USP25)/histone deacetylase 11 (HDAC11) axis. CSE treatment decreases HDAC11 at protein level in lung epithelial cells without significant changes of its transcription. Concomitantly, CSE treatment accelerates a ubiquitin-specific protease USP25 ubiquitination and degradation. Coimmunoprecipitation studies showed that USP25 associated with HDAC11. USP25 catalyzes deubiquitination of HDAC11, which regulates HDAC11 protein stability. CSE-mediated degradation of USP25 thereafter reduces HDAC11 at the protein level. Interestingly, CSE-downregulated USP25/HDAC11 axis increases the bacterial load of Pseudomonas aeruginosa in lung epithelial cells. These findings suggest that CSE-downregulated USP25 and HDAC11 may contribute to high susceptibility of bacterial infection in the cigarette smoking population.

scholarly journals Leptospira santorosaiSerovar Shermani Detergent Extract Induces an Increase in Fibronectin Production through a Toll-Like Receptor 2-Mediated Pathway

2010 ◽  
Vol 79 (3) ◽  
pp. 1134-1142 ◽  
Author(s):  
Ya-Chung Tian ◽  
Cheng-Chieh Hung ◽  
Yi-Jung Li ◽  
Yung-Chang Chen ◽  
Ming-Yang Chang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Inflammatory Responses ◽  
Tumor Necrosis Factor Receptor ◽  
Nuclear Factor Κb ◽  
Renal Tubulointerstitial Fibrosis ◽  
Toll Like Receptor 2 ◽  
Mechanistic Basis ◽  
Myeloid Differentiation Factor ◽  
Necrosis Factor

ABSTRACTLeptospirosis can activate inflammatory responses through Toll-like receptors (TLRs) and may cause renal tubulointerstitial fibrosis characterized by the accumulation of extracellular matrix (ECM). We have previously demonstrated thatLeptospira santorosaiserovar Shermani detergent extract stimulates ECM accumulationin vitro. The aim of this study was to examine the mechanistic basis of these previous observations and, in particular, to examine the potential involvement of TLRs. The addition of serovar Shermani detergent extract led to an increase in fibronectin gene expression and production. Inhibition of TLR2 but not TLR4 expression abrogated serovar Shermani detergent extract-mediated increases in fibronectin production. This response was also blocked by the knockdown of the gene expression of the TLR2 downstream transducers myeloid differentiation factor 88 (MyD88) and tumor necrosis factor receptor-associated factor 6 (TRAF6). Serovar Shermani detergent extract also activated nuclear factor-κB, and its inhibition by curcumin-attenuated serovar Shermani detergent extract induced increases in fibronectin production. These effects were also mimicked by the specific TLR2 agonist, Pam(3)CsK(4), a response that was also abrogated by the knockdown of MyD88 and TRAF6. Similarly, the administration of live leptospires to cells also induced fibronectin production that was blocked by inhibition of TLR2 and MyD88 expression. In conclusion, serovar Shermani detergent extract can induce fibronectin production through the TLR2-associated cascade, providing evidence of an association between TLRs and leptospirosis-mediated ECM deposition.

scholarly journals TLR3 is an endogenous sensor of tissue necrosis during acute inflammatory events

2008 ◽  
Vol 205 (11) ◽  
pp. 2609-2621 ◽  
Author(s):  
Karen A. Cavassani ◽  
Makoto Ishii ◽  
Haitao Wen ◽  
Matthew A. Schaller ◽  
Pamela M. Lincoln ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Tissue Injury ◽  
Cytokine Levels ◽  
Inflammatory Chemokines ◽  
Inflammatory Processes ◽  
Factor Α ◽  
Injury Models ◽  
Dying Cells ◽  
Necrosis Factor

Ligands from dying cells are a source of Toll-like receptor (TLR) activating agents. Although TLR3 is known to respond to RNA from necrotic cells, the relative importance of this response in vivo during acute inflammatory processes has not been fully explored. We observed the involvement of TLR3 activation during experimental polymicrobial septic peritonitis and ischemic gut injury in the absence of an exogenous viral stimulus. In TLR3-deficient mice, increased chemokine/cytokine levels and neutrophil recruitment characterized the initial inflammatory responses in both injury models. However, the levels of inflammatory chemokines and tumor necrosis factor α quickly returned to baseline in tlr3−/− mice, and these mice were protected from the lethal effects of sustained inflammation. Macrophages from tlr3−/− mice responded normally to other TLR ligands but did not respond to RNA from necrotic neutrophils. Importantly, an immunoneutralizing antibody directed against TLR3 attenuated the generation of inflammatory chemokines evoked by byproducts from necrotic neutrophils cultured with wild-type macrophages. In vivo, anti-TLR3 antibody attenuated the tissue injury associated with gut ischemia and significantly decreased sepsis-induced mortality. Collectively, these data show that TLR3 is a regulator of the amplification of immune response and serves an endogenous sensor of necrosis, independent of viral activation.

scholarly journals Revisiting TNF Receptor-Associated Periodic Syndrome (TRAPS): Current Perspectives

2020 ◽  
Vol 21 (9) ◽  
pp. 3263 ◽  
Author(s):  
Cornelia Cudrici ◽  
Natalie Deuitch ◽  
Ivona Aksentijevich
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Inflammatory Responses ◽  
Treatment Options ◽  
Tumor Necrosis Factor Receptor ◽  
Periodic Syndrome ◽  
Pathogenic Variants ◽  
Tnfrsf1a Gene ◽  
Receptor Shedding ◽  
Necrosis Factor

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant autoinflammatory syndrome characterized by prolonged and recurrent episodes of fever, abdominal and/or chest pain, arthralgia, myalgia, and erythematous rash. TRAPS is associated with heterozygous variants in the TNFRSF1A gene, which encodes the TNFR1 (tumor necrosis factor receptor 1) receptor. Disease-causing variants are found exclusively in the extracellular domain of TNFR1 and affect receptor structure and binding to the TNF ligand. The precise mechanism of the disease is still unclear, but it is thought that intracellular accumulation of misfolded mutant protein leads to endoplasmic reticulum stress and enhanced inflammatory responses through constitutive activation of various immune pathways. Other possible mechanisms contributing to the disease pathogenesis include defective receptor shedding, TNF-induced cell death, production of reactive oxygen species, and autophagy impairment. Patients’ leucocytes are hyperresponsive to stimulation and produce elevated levels of proinflammatory cytokines. Systemic autoimmune (AA) amyloidosis is an important cause of morbidity and mortality in TRAPS. Over the last two decades, new therapies have changed the progression and outcome of the disease. In this review, we summarize clinical data from 209 patients with validated pathogenic variants reported in the literature and discuss TRAPS diagnosis, pathogenesis, and treatment options.

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