B7-H3 Blockade Decreases Macrophage Inflammatory Response and Alleviates Clinical Symptoms of Arthritis

2020 ◽  
Author(s):  
Jie Yang ◽  
Yundi Guo ◽  
Li Gu ◽  
Cuiping Liu ◽  
Pingping Wu ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Disease Severity ◽  
Inflammatory Responses ◽  
Clinical Symptoms ◽  
Costimulatory Molecule ◽  
The Body ◽  
Positive Correlation ◽  
Joint Cavity ◽  
Therapeutic Benefits ◽  
Tnf Α

Abstract Background: The costimulatory molecule B7-H3 is an immunoregulatory protein that plays an important role in the course of autoimmune diseases. It is also involved in the regulation of inflammatory responses in the body. Studies have shown that B7-H3 is highly expressed in peripheral blood monocytes of rheumatoid arthritis (RA) patients and its expression is closely related to the clinical parameters of the disease. In this study we aimed to determine what the implication of high B7-H3 expression for the disease severity in human RA and mouse model of arthritis is, and whether targeting this molecule could constitute a new therapeutic approach.Methods: We combined histopathological scoring of the joint cavity of collagen-induced arthritis (CIA) mice with immunofluorescent studies of B7-H3 expression on macrophages. We assessed the function of B7-H3 in relation with the pro-inflammatory role of macrophage through small RNA interference. Then we studied the molecular pathways liking B7-H3 with the pro-inflammatory activity of macrophages by multiplex flow cytometry, western blot and quantitative real-time PCR. The therapeutic benefit of anti-B7-H3 blocking was probed in mouse with CIA.Results: Histopathological and histological examination showed a positive correlation between expression of B7-H3 on macrophages and disease activity score, degree of destruction of the joint cavity, and pannus formation. It was also correlated with increased expression of the pro-inflammatory cytokine TNF-α in the joint cavity tissue and TNF-α level in peripheral serum. Knocking down B7-H3 expression through stable expression of small interfering RNA in human and mouse mononuclear phagocytic cell lines weakened the inflammatory response of the cells. Further molecular analyses indicated that the regulation of the inflammatory response through B7-H3 involved NF-κB signaling. Treatment of CIA mice with anti-B7-H3 reduced the clinical manifestation of arthritis and downregulated the expression of pro-inflammatory cytokines. Conclusions: We confirmed increased expression of B7-H3 in arthritis and established a positive correlation between disease severity and expression of B7-H3 on macrophages. Through functional approaches in vitro and in vivo, we also demonstrated the therapeutic benefits of targeting B7-H3 for dampening macrophages’ inflammatory responses in RA.

scholarly journals Expression of HIF-1α in keloids and its correlation with inflammatory responses and apoptosis

2018 ◽  
Vol 16 ◽  
pp. 205873921881895
Author(s):  
Xiaolong Wu
Keyword(s):  
Inflammatory Response ◽  
Mrna Expression ◽  
Messenger Rna ◽  
Inflammatory Responses ◽  
Normal Skin ◽  
Hypoxia Inducible Factor ◽  
Control Group ◽  
Positive Correlation ◽  
Tnf Α ◽  
Pathological Group

The aim of this study was to investigate the expression of hypoxia-inducible factor-1α (HIF-1α) in keloids and its correlation with inflammatory responses and apoptosis. The keloid specimens resected in our hospital from November 2015 to February 2017 were selected as the pathological group, and the normal skin tissues from our hospital during the same period were selected as the control group. The expression of HIF-1α, inflammatory response cytokines, and apoptotic molecules in the tissues of two groups were detected. The messenger RNA (mRNA) expression of HIF-1α in the keloids in the pathological group was significantly higher than that in the control group, and the mRNA expression of interleukin (IL)-1β, IL-2, IL-6, and tumor necrosis factor (TNF)-α in the pathological group was significantly higher than those in the control group. The mRNA expression of Bax in the pathological group was significantly higher than that in the control group. The mRNA expression of Bcl-2, livin, and hPEBP4 in the pathological group was significantly lower than that in the control group. Pearson test showed that there was a positive correlation between the mRNA expression of HIF-1α and inflammatory cytokines including IL-1β, IL-2, IL-6, and TNF-α. There were also a positive correlation between the mRNA expression of HIF-1α and Bax and a negative correlation between the mRNA expression of HIF-1α and Bcl-2, livin, and hPEBP4. In conclusion, HIF-1α was highly expressed in keloids and closely related to inflammatory response cytokines and apoptosis molecules. Increased expression of HIF-1α in keloids may be an important factor in inflammatory responses and increased apoptosis in skin tissues.

scholarly journals Carbohydrate response element binding protein (ChREBP) modulates the inflammatory response of mesangial cells in response to glucose

2018 ◽  
Vol 38 (6) ◽  
Author(s):  
Yan Chen ◽  
Yan-Jun Wang ◽  
Ying Zhao ◽  
Jin-Cheng Wang
Keyword(s):  
Diabetes Mellitus ◽  
Inflammatory Response ◽  
Mesangial Cells ◽  
Binding Protein ◽  
The Body ◽  
Mrna Levels ◽  
Diabetic Mice ◽  
Response Element ◽  
Tnf Α ◽  
Element Binding Protein

Diabetic nephropathy (DN) is one of the most devastating complications of diabetes mellitus. Carbohydrate response element binding protein (ChREBP) is a basic helix–loop–helix leucine zipper transcription factor that primarily mediates glucose homeostasis in the body. The present study investigated the role of ChREBP in the pathogenesis of DN. The expression of ChREBP was detected in patients with type 2 diabetes mellitus (T2DM), diabetic mice, and mesangial cells. ELISA was used to measure cytokine production in mesangial cells. Flow cytometry analysis was performed to detect the apoptosis of mesangial cells in the presence of high glucose. The expression levels of ChREBP and several cytokines (TNF-α, IL-1β, and IL-6) were up-regulated in T2DM patients. The mRNA and protein levels of ChREBP were also significantly elevated in the kidneys of diabetic mice. Moreover, glucose treatment promoted mRNA levels of TNF-α, IL-1β, and IL-6 in mesangial cells. Glucose stimulation induced significant apoptosis of SV40 MES 13 cells. In addition, transfection with ChREBP siRNA significantly inhibited ChREBP expression. Consequently, the inflammatory responses and apoptosis were inhibited in SV40 MES 13 cells. These results demonstrated that ChREBP could mediate the inflammatory response and apoptosis of mesangial cells, suggesting that ChREBP may be involved in the pathogenesis of DN.

scholarly journals Proinflammatory responses in SARS-CoV-2 infected and soluble spike glycoprotein S1 subunit activated human macrophages

2021 ◽  
Author(s):  
Kim Chiok ◽  
Kevin Hutchison ◽  
Lindsay Grace Miller ◽  
Santanu Bose ◽  
Tanya A Miura
Keyword(s):  
Virus Infection ◽  
Inflammatory Response ◽  
Virus Replication ◽  
Inflammatory Mediators ◽  
Inflammatory Responses ◽  
Activated Macrophages ◽  
Human Macrophages ◽  
Tnf Α ◽  
Proinflammatory Responses

Critically ill COVID-19 patients infected with SARS-CoV-2 display signs of generalized hyperinflammation. Macrophages trigger inflammation to eliminate pathogens and repair tissue, but this process can also lead to hyperinflammation and resulting exaggerated disease. The role of macrophages in dysregulated inflammation during SARS-CoV-2 infection is poorly understood. We used SARS-CoV-2 infected and glycosylated soluble SARS-CoV-2 Spike S1 subunit (S1) treated THP-1 human-derived macrophage-like cell line to clarify the role of macrophages in pro-inflammatory responses. Soluble S1 upregulated TNF-α and CXCL10 mRNAs, and induced secretion of TNF-α from THP-1 macrophages. While THP-1 macrophages did not support productive SARS-CoV-2 replication, virus infection resulted in upregulation of both TNF-α and CXCL10 genes. Our study shows that S1 is a key viral component inducing inflammatory response in macrophages, independently of virus replication. Thus, virus-infected or soluble S1-activated macrophages may become sources of pro-inflammatory mediators contributing to hyperinflammation in COVID-19 patients.

Comparing the effect of intestinal bacteria from rabbit, pig, and chicken on inflammatory response in cultured rabbit crypt and villus

2019 ◽  
Vol 65 (1) ◽  
pp. 59-67 ◽  
Author(s):  
Hong Xiao Cui ◽  
Xiu Rong Xu
Keyword(s):  
Inflammatory Response ◽  
Inflammatory Responses ◽  
Intestinal Bacteria ◽  
Inflammatory Factors ◽  
Rabbit Ileum ◽  
Necrosis Factor Alpha ◽  
Heat Treated ◽  
Tnf Α ◽  
Factor Alpha ◽  
Anti Inflammatory

Rabbit is susceptible to intestinal infection, which often results in severe inflammatory response. To investigate whether the special community structure of rabbit intestinal bacteria contributes to this susceptibility, we compared the inflammatory responses of isolated rabbit crypt and villus to heat-treated total bacteria in pig, chicken, and rabbit ileal contents. The dominant phylum in pig and chicken ileum was Firmicutes, while Bacteroidetes was dominant in rabbit ileum. The intestinal bacteria from rabbit induced higher expression of toll-like receptor 4 (TLR4) in rabbit crypt and villus (P < 0.05). TLR2 and TLR3 expression was obviously stimulated by chicken and pig intestinal bacteria (P < 0.05) but not by those of rabbit. The ileal bacteria from those three animals all increased the expression of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) in crypts and villus (P < 0.05). Chicken and pig ileal bacteria also stimulated the expression of anti-inflammatory factors interferon beta (IFN-β) and IL-10 (P < 0.05), while those of rabbit did not (P > 0.05). In conclusion, a higher abundance of Gram-negative bacteria in rabbit ileum did not lead to more expressive pro-inflammatory cytokines in isolated rabbit crypt and villus, but a higher percentage of Lactobacillus in chicken ileum might result in more expressive anti-inflammatory factors.

scholarly journals Molecular Inflammatory Responses Measured in Blood of Patients with Severe Community-Acquired Pneumonia

2003 ◽  
Vol 10 (5) ◽  
pp. 813-820 ◽  
Author(s):  
Silvia Fernández-Serrano ◽  
Jordi Dorca ◽  
Mercè Coromines ◽  
Jordi Carratalà ◽  
Francesc Gudiol ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Inflammatory Responses ◽  
Community Acquired Pneumonia ◽  
Causative Organism ◽  
Time Interval ◽  
Necrosis Factor Alpha ◽  
Arterial Blood ◽  
Tnf Α ◽  
Intensive Care Unit Admittance ◽  
Severe Community Acquired Pneumonia

ABSTRACT In order to analyze the characteristics of the inflammatory response occurring in blood during pneumonia, we studied 38 patients with severe community-acquired pneumonia. Venous and arterial blood samples were collected at study entry and on days 1, 2, 3, 5, and 7 after inclusion. The concentrations of proinflammatory (tumor necrosis factor alpha [TNF-α], interleukin 1β [IL-1β], IL-6, and IL-8) and anti-inflammatory (IL-10) cytokines were determined in order to detect differences related to the origin of the sample, the causative organism, the clinical variables, and the final outcome of the episode. Legionella pneumonia infections showed higher concentrations of TNF-α, IL-6, IL-8, and IL-10. After 24 h, plasma IL-6, IL-8, and IL-10 concentrations in pneumococcal episodes increased, whereas in the same time interval, cytokine concentrations in Legionella episodes markedly decreased. The characteristics of the inflammatory response in bacteremic pneumococcal episodes were different from those in nonbacteremic episodes, as indicated by the higher plasma cytokine concentrations in the former group. Finally, our analysis of cytokine concentrations with regard to the outcome—in terms of the need for intensive care unit admittance and/or mechanical ventilation as well as mortality—suggests that there is a direct relationship between the intensity of the inflammatory response measured in blood and the severity of the episode.

Soy and the exercise-induced inflammatory response in postmenopausal women

2010 ◽  
Vol 35 (3) ◽  
pp. 261-269 ◽  
Author(s):  
Kristen M. Beavers ◽  
Monica C. Serra ◽  
Daniel P. Beavers ◽  
Matthew B. Cooke ◽  
Darryn S. Willoughby
Keyword(s):  
Inflammatory Response ◽  
Postmenopausal Women ◽  
Controlled Trial ◽  
Exercise Bout ◽  
The Body ◽  
Significant Group ◽  
Oxidative Defense ◽  
Markers Of Inflammation ◽  
Tnf Α ◽  
Before And After

Aging is associated with increasing inflammation and oxidative stress in the body, both of which can have negative health effects. Successful attenuation of such processes with dietary countermeasures has major public health implications. Soy foods, as a source of high-quality protein and isoflavones, may improve such indices, although the effects in healthy postmenopausal women are not well delineated. A single-blind, randomized controlled trial was conducted in 31 postmenopausal women who were assigned to consume 3 servings of soy (n = 16) or dairy (n = 15) milk per day for 4 weeks. Parameters of systemic inflammation (tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6)) and the oxidative defense system (superoxide dismutase (SOD), glutathione peroxidase, cyclooxygenase-2) were measured post supplementation, before and after an eccentric exercise bout performed to elicit an inflammatory response. A significant group-by-time effect for plasma TNF-α was observed (p = 0.02), with values in the dairy group increased post supplementation and then decreasing into the postexercise period. Additionally, significant time effects were observed for plasma SOD (p < 0.0001) and IL-6 (p < 0.0001) in the postexercise period. Overall results from our study do not support the notion that 4 weeks of daily soy milk ingestion can attenuate systemic elevations in markers of inflammation or oxidative defense. However, data do suggest that the downhill-running protocol utilized in this study can be effective in altering systemic markers of inflammation and oxidative defense enzyme activity, and that the ingestion of soy may help prevent fluctuations in plasma TNF-α.

scholarly journals S100A6 Promotes Inflammation and Infiltration of Mononuclear/Macrophages via the p-P38 and p-JNK Pathways in Acute Liver Injury

2021 ◽  
Author(s):  
He Tong ◽  
Li Wang ◽  
Kefan Zhang ◽  
Jing Shi ◽  
yongshuai Wu ◽  
...  
Keyword(s):  
Liver Injury ◽  
Inflammatory Response ◽  
Inflammatory Responses ◽  
Acute Liver Injury ◽  
S100 Protein ◽  
Inflammatory Cells ◽  
Liver Cells ◽  
Danger Signal ◽  
Tnf Α

Abstract BackgroundThe phagocytic S100 protein, which mediates inflammatory responses and recruits inflammatory cells to sites of tissue damage, has long been known to be expressed in cells of myeloid origin. S100A6 belongs to the A group of the S100 protein family of Ca2+-binding proteins. Currently, the mechanism by which S100A6 mediates the inflammatory response and recruits inflammatory cells to the tissue injury site is unknown.MethodsA mouse model of carbon tetrachloride (CCl4)-induced acute liver injury (ALI) was established, and the transcriptomes of postinjury 2d and 5d liver tissues were sequenced. Enzyme-linked immunosorbent assay was used to determine the expression of inflammatory factors (TNF-α, IL-1β, IL-6, and IL-8) in the supernatant of the liver. Immunohistochemical analysis confirmed the expression of S100A6 in the liver cells. In vitro experiments proved the pro-inflammatory function of S100A6, and western blotting (WB) showed that the pathways were activated. The transwell experiment showed the infiltration of mononuclear/macrophages.ResultsWe found that S100A6 is highly expressed in liver cells during the most severe period of ALI, suggesting that it acts as an endogenous danger signal and has a pro-inflammatory function. In vitro, the mouse S100A6 recombinant protein was used to stimulate liver Kupffer cells to promote the secretion of TNF-α, IL-1β, IL-6, and IL-8. Further mechanistic experiments revealed that S100A6 acts as an endogenous danger signal to activate p-P38 and p-JNK downstream of the TLR4 and P65 pathways. Similarly, transcriptome data showed that S100A6 can activate the inflammatory response in Kuffer cells. WB revealed that S100A6 had no significant effect on cell apoptosis. To continue to explore the mechanism of monocyte/macrophage infiltration, we found that TNF-α stimulates liver cells as the main source of CCL2. TNF-α can initiate the p-P38 and p-JNK pathways of liver cells to produce CCL2, thereby recruiting the infiltration of mononuclear/macrophages. ConclusionsTaken together, S100A6 is an endogenous danger signal that mediates inflammatory responses and recruits inflammatory cells to sites of tissue damage.

scholarly journals Expression of AXL receptor tyrosine kinase relates to monocyte dysfunction and severity of cirrhosis

2019 ◽  
Vol 3 (1) ◽  
pp. e201900465 ◽  
Author(s):  
Robert Brenig ◽  
Oltin T Pop ◽  
Evangelos Triantafyllou ◽  
Anne Geng ◽  
Arjuna Singanayagam ◽  
...  
Keyword(s):  
Disease Severity ◽  
T Cell Activation ◽  
Cell Activation ◽  
Inflammatory Responses ◽  
Ex Vivo ◽  
Infectious Complications ◽  
Receptor Expression ◽  
Tnf Α ◽  
Acute Decompensation

Infectious complications in patients with cirrhosis frequently initiate episodes of decompensation and substantially contribute to the high mortality. Mechanisms of the underlying immuneparesis remain underexplored. TAM receptors (TYRO3/AXL/MERTK) are important inhibitors of innate immune responses. To understand the pathophysiology of immuneparesis in cirrhosis, we detailed TAM receptor expression in relation to monocyte function and disease severity prior to the onset of acute decompensation. TNF-α/IL-6 responses to lipopolysaccharide were attenuated in monocytes from patients with cirrhosis (n = 96) compared with controls (n = 27) and decreased in parallel with disease severity. Concurrently, an AXL-expressing (AXL+) monocyte population expanded. AXL+ cells (CD14+CD16highHLA-DRhigh) were characterised by attenuated TNF-α/IL-6 responses and T cell activation but enhanced efferocytosis and preserved phagocytosis of Escherichia coli. Their expansion correlated with disease severity, complications, infection, and 1-yr mortality. AXL+ monocytes were generated in response to microbial products and efferocytosis in vitro. AXL kinase inhibition and down-regulation reversed attenuated monocyte inflammatory responses in cirrhosis ex vivo. AXL may thus serve as prognostic marker and deserves evaluation as immunotherapeutic target in cirrhosis.

scholarly journals Oxidative Stress, Antioxidant Defenses, COVID-19 and Pollution

2020 ◽  
Vol 8 (10) ◽  
Author(s):  
Selva Rivas-Arancibia ◽  
Jennifer Balderas-Miranda ◽  
Lizbeth Belmont-Zúñiga ◽  
Martín Martínez-Jáquez ◽  
Eduardo Hernández-Orozco ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Trace Elements ◽  
Immune System ◽  
Inflammatory Response ◽  
Inflammatory Responses ◽  
The Body ◽  
Antioxidant Defenses ◽  
Cochrane Library ◽  
Antioxidant Systems ◽  
Low Levels

Patients with degenerative diseases present a chronic oxidative stress state, which puts them at a disadvantage when facing viral infections such as COVID-19. This is because there is a close relationship between redox signaling and this inflammatory response. Therefore, chronic changes in the redox balance cause alterations in the regulation of the immune system. An inflammatory response that must be reparative and self-limited loses its function and remains over time. In a chronic state of oxidative stress, there is a deficiency of antioxidants. This results in low levels of hormones, vitamins and trace elements, which are essential for the regulation of these systems. Furthermore, low levels of antioxidants imply a diminished capacity for a regulated inflammatory responses are much more vulnerable to a cytokine storm that mainly attacks the lungs, since they present a vicious circle between the null or diminished response of the antioxidant systems and the loss of regulation of the inflammatory process. Therefore, these patients are at a disadvantage in counteracting the response of defense systems to infection from SAR-COV19. A plausible option may be to restore the levels of Vitamins A, B, C, D, E and of essential trace elements such as manganese, selenium, zinc, in the body, which are key to either preventing or reducing the severity of the response of the immune system to the disease caused by SAR-CoV2. For the present review, we searched the specific sites of the Cochrane library database, PubMed and Medscape. The inclusion criteria were documents written in English or Spanish, published during the last 10 years.

scholarly journals Serum adipokines play different roles in type I and II ketosis

2020 ◽  
Vol 33 (12) ◽  
pp. 1930-1939
Author(s):  
Liuhong Shen ◽  
Yingkun Zhu ◽  
Jinbang Xiao ◽  
Bolin Qian ◽  
Liuchao You ◽  
...  
Keyword(s):  
Energy Balance ◽  
Significant Positive Correlation ◽  
Significant Negative Correlation ◽  
Negative Energy ◽  
Serum Glucose ◽  
The Body ◽  
Type I ◽  
Type Ii ◽  
Positive Correlation ◽  
Tnf Α

Objective: This study was conducted to investigate the differences in several serum adipokines in perinatal dairy cows with type I and II ketosis, and the correlations between these adipokines and the two types of ketosis.Methods: Serum adiponectin (ADP), leptin (LEP), resistin, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) levels, and energy balance indicators related to ketosis were measured. Type I and II ketosis were distinguished by serum glucose (Glu) and Y values and the correlations between adipokines in the two types of ketosis were analyzed.Results: β-Hydroxybutyric acid of type I ketosis cows was significantly negatively correlated with insulin (INS) and LEP and had a significant positive correlation with serum ADP. In type II ketosis cows, ADP and LEP were significantly negatively correlated, and INS and resistin were significantly positively correlated. Revised quantitative INS sensitivity check index (RQUICKI) values had a significantly positive correlation with ADP and had a very significant and significant negative correlation with resistin, TNF-α, and IL-6. ADP was significantly negatively correlated with resistin and TNF-α, LEP had a significantly positive correlation with TNF-α, and a significantly positive correlation was shown among resistin, IL-6, and TNF-α. There was also a significant positive correlation between IL-6 and TNF-α.Conclusion: INS, ADP, and LEP might exert biological influences to help the body recover from negative energy balance, whereas resistin, TNF-α, and IL-6 in type II ketosis cows exacerbated INS resistance and inhibited the production and secretion of ADP, weakened INS sensitivity, and liver protection function, and aggravated ketosis.

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