scholarly journals Collagen XV Promotes ER Stress-Induced Inflammation through Activating Integrin β1/FAK Signaling Pathway and M1 Macrophage Polarization in Adipose Tissue

2021 ◽  
Vol 22 (18) ◽  
pp. 9997
Author(s):  
Changxing Li ◽  
Yuexia Liu ◽  
Yizhou Li ◽  
Ruiqing Tai ◽  
Zhuwen Sun ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Er Stress ◽  
Macrophage Polarization ◽  
Ecm Remodeling ◽  
Homologous Protein ◽  
M1 Macrophage ◽  
Abnormal Accumulation ◽  
New Ideas ◽  
Factor Α ◽  
Collagen Xv

Collagen XV (Col XV), a basement membrane (BM) component, is highly expressed in adipose tissue, and studies have found that Col XV is related to extracellular matrix (ECM) remodeling involving in adipose tissue fibrosis and inflammation. Furthermore, the ECM is essential for maintaining normal development and tissue function. In this study, we found that Col XV is related to the endoplasmic reticulum stress (ERS) and inflammation of adipose tissue. Moreover, we found that overexpression of Col XV in mice could cause macrophages to infiltrate white adipose tissue (iWAT). At the same time, the expression of the ERS sensor IRE1α (Inositol-Requiring Enzyme-1α) was significantly up-regulated, which intensified the inflammation of adipose tissue and the polarization of M1 macrophages after the overexpression of Col XV in mice. In addition, after overexpression of Col XV, the intracellular Ca2+ concentration was significantly increased. Using focal adhesion kinase (FAK) inhibitor PF573228, we found that PF-573228 inhibited the phosphorylation of FAK and reversed the upward trend of Col XV-induced protein expression levels of IRE1α, C/EBP-homologous protein (CHOP), and 78 kDa glucose-regulated protein (GRP78). After treatment with IRE1α inhibitor STF-083010, the results showed that the expression of adipocyte inflammation-related genes interleukin 6 (IL-6) and tumor necrosis factor α (TNFα) significantly were decreased. Our results demonstrate that Col XV induces ER-stress in adipocytes by activating the Integrinβ1/FAK pathway and disrupting the intracellular Ca2+ balance. At the same time, Col XV regulates the inflammation induced by ER stress in adipocytes by promoting IRE1α/XBP1 (X-Box binding protein 1) signaling. Our study provides new ideas for solving the problems of adipose tissue metabolism disorders caused by abnormal accumulation of ECM.

Targeted inhibition of CD74 attenuates adipose COX-2-MIF-mediated M1 macrophage polarization and retards obesity-related adipose tissue inflammation and insulin resistance

2018 ◽  
Vol 132 (14) ◽  
pp. 1581-1596 ◽  
Author(s):  
Pei-Chi Chan ◽  
Ting-Ni Wu ◽  
Ying-Chuan Chen ◽  
Chieh-Hua Lu ◽  
Martin Wabitsch ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Inflammatory Responses ◽  
Macrophage Polarization ◽  
Mrna Levels ◽  
Model Assessment ◽  
M1 Macrophage ◽  
Cox 2 ◽  
Highly Correlated ◽  
Targeted Inhibition

Adipose tissue (AT) inflammation is crucial to the development of obesity-associated insulin resistance. Our aim was to investigate the contribution of cyclooxygenase-2 (COX-2)/macrophage migration inhibitory factor (MIF)-mediated cross-talk between hypertrophic adipocytes and macrophages to the etiology of AT inflammation and the involvement of CD74 using human SGBS adipocytes, THP-1 macrophages and mice fed a high-fat (HF) diet. The MIF and CD74 mRNA levels in the adipocytes and stromal vascular cells (SVCs) of white fat were highly correlated with body weight (BW), homeostatic model assessment for insulin resistance (HOMA-IR), and adipose macrophage marker expression levels, especially those in SVCs. COX-2 inhibition suppressed the elevation of MIF production in HF white adipocytes as well as palmitate and hypoxic-treated SGBS adipocytes. Treatment of adipocytes transfected with shCOX-2 and siMIF or subjected to MIF depletion in the medium reversed the pro-inflammatory responses in co-incubated THP-1 cells. Inhibition of NF-κB activation reversed the COX2-dependent MIF secretion from treated adipocytes. The targeted inhibition of macrophage CD74 prevented M1 macrophage polarization in the above co-culture model. The COX-2-dependent increases in CD74 gene expression and MIF release in M1-polarized macrophages facilitated the expression of COX-2 and MIF in co-cultured SGBS adipocytes. CD74 shRNA intravenous injection suppressed HF-induced AT M1 macrophage polarization and inflammation as well as insulin resistance in mice. The present study suggested that COX-2-mediated MIF secretion through NF-κB activation from hypertrophic and hypoxic adipocytes as well as M1 macrophages might substantially contribute to the phenotypic switch of AT macrophages through CD74 in obesity. Inhibition of CD74 could attenuate AT inflammation and insulin resistance in the development of HF diet-induced obesity.

scholarly journals The USP14–NLRC5 pathway inhibits titanium particle–induced osteolysis in mice by suppressing NF-κB and PI3K/AKT activities

2020 ◽  
Vol 295 (20) ◽  
pp. 7018-7032 ◽  
Author(s):  
Guibin Fang ◽  
Yuan Fu ◽  
Shixun Li ◽  
Junxiong Qiu ◽  
Manyuan Kuang ◽  
...  
Keyword(s):  
Macrophage Polarization ◽  
Wear Particle ◽  
Wear Particles ◽  
Titanium Particle ◽  
Pathway Activation ◽  
M1 Macrophage ◽  
Phosphoinositide 3 Kinase ◽  
Factor Α

Total hip arthroplasty (THA) is a widely-used surgical intervention for treating patients with end-stage degenerative and inflammatory osteoarthropathy. However, wear particles from the artificial titanium joint can induce osteolysis, limiting the long-term survivorship of THA. Monocyte/macrophage lineage cells are the key players in the response to wear particles, and the proinflammatory NF-κB and phosphoinositide 3-kinase (PI3K)–AKT Ser/Thr kinase (AKT)-signaling pathways have been shown to be the most important contributors to wear particle–induced osteolysis. In contrast, ubiquitin-specific protease 14 (USP14) specifically removes the polyubiquitin chains from the nucleotide-binding and oligomerization domain (NOD)-like receptor family Caspase recruitment domain (CARD)–containing 5 (NLRC5) and thereby enhances the NLRC5-mediated inhibition of NF-κB signaling. In this study, we aimed to clarify the role of the USP14–NLRC5 pathway in wear particle–induced osteolysis in vitro and in vivo. We found that NLRC5 or USP14 overexpression inhibits titanium particle–induced proinflammatory tumor necrosis factor α (TNFα) production and NF-κB pathway activation, and it also decreases M1 macrophage polarization and PI3K/AKT pathway activation. Of note, NLRC5 and USP14 overexpression attenuated titanium particle–induced cranial osteolysis in mice. In conclusion, the findings of our study indicate that the USP14–NLRC5 pathway inhibits titanium particle–induced osteolysis by suppressing the NF-κB and PI3K/AKT pathways both in vitro and in vivo.

scholarly journals High-Intensity Interval Training Reversed High-Fat Diet–Induced M1-Macrophage Polarization in Rat Adipose Tissue via Inhibition of NOTCH Signaling

2020 ◽  
Vol Volume 13 ◽  
pp. 165-174 ◽  
Author(s):  
Mehrnoosh Shanaki ◽  
Maryam Khosravi ◽  
Arezoo Khoshdooni-Farahani ◽  
Alireza Dadashi ◽  
Mohammad Foad Heydari ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Notch Signaling ◽  
High Fat Diet ◽  
Macrophage Polarization ◽  
Interval Training ◽  
High Intensity Interval Training ◽  
High Fat ◽  
M1 Macrophage ◽  
High Intensity Interval ◽  
Rat Adipose Tissue

scholarly journals ErbB4 deletion predisposes to development of metabolic syndrome in mice

2018 ◽  
Vol 315 (4) ◽  
pp. E583-E593 ◽  
Author(s):  
Fenghua Zeng ◽  
Yinqiu Wang ◽  
Lance A. Kloepfer ◽  
Suwan Wang ◽  
Raymond C. Harris
Keyword(s):  
Metabolic Syndrome ◽  
Adipose Tissue ◽  
Glucose Uptake ◽  
Egf Receptor ◽  
Macrophage Polarization ◽  
Wild Type ◽  
M1 Macrophage ◽  
Egf Receptor Family ◽  
Diabetes And Obesity

ErbB4, a member of the EGF receptor family, plays a variety of roles in physiological and pathological states. Genetic studies have indicated a link between ErbB4 and type 2 diabetes and obesity, but its role in metabolic syndrome (MetS) has not been reported. In the current study we found that mice with ErbB4 deletion developed MetS after 24 wk on a medium-fat diet (MFD), as indicated by development of obesity, dyslipidemia, hepatic steatosis, hyperglycemia, hyperinsulinemia, and insulin resistance, compared with wild-type mice. ErbB4 deletion mice also exhibited increased amounts of subcutaneous and visceral fat, with increased serum leptin levels, compared with wild-type mice, whereas levels of adiponectin were not significantly different. Histologically, severe inflammation, indicated by F4/80 immunostaining and M1 macrophage polarization, was detected in inguinal and epididymal white adipose tissue in ErbB4 deletion mice. ErbB4 expression decreased during 3T3-L1 preadipocyte differentiation. Administration of neuroregulin 4, a specific ligand for ErbB4, to 3T3-L1 adipocytes had no effect on adipogenesis and lipolysis but significantly inhibited lipogenesis, promoted browning, induced GLUT4 redistribution to the cell membrane, and increased glucose uptake. Neuroregulin 4 also significantly increased glucose uptake in adipocytes isolated from wild-type mice, while these effects were significantly decreased in adipocytes isolated from ErbB4 deletion mice. In conclusion, our results indicate that ErbB4 may play an important role in glucose homeostasis and lipogenesis. ErbB4 deficiency-related obesity and adipose tissue inflammation may contribute to the development of MetS.

scholarly journals Increased Adipose Tissue Expression of Interferon Regulatory Factor (IRF)-5 in Obesity: Association with Metabolic Inflammation

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1418 ◽  
Author(s):  
Sardar Sindhu ◽  
Reeby Thomas ◽  
Shihab Kochumon ◽  
Ajit Wilson ◽  
Mohamed Abu-Farha ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Protein Expression ◽  
Macrophage Polarization ◽  
Interferon Regulatory Factor ◽  
Regulatory Factor ◽  
Metabolic Inflammation ◽  
M1 Macrophage ◽  
Gene And Protein Expression ◽  
Local Expression

Interferon regulatory factor (IRF)-5 is known to be involved in M1 macrophage polarization, however, changes in the adipose expression of IRF5 in obesity and their relationship with the local expression of proinflammatory cytokines/chemokines are unknown. Therefore, IRF5 gene expression was determined in the subcutaneous adipose tissue samples from 53 non-diabetic individuals (6 lean, 18 overweight, and 29 obese), using real-time RT-PCR. IRF5 protein expression was also assessed using immunohistochemistry and/or confocal microscopy. Adipose gene expression of signature immune metabolic markers was also determined and compared with adipose IRF5 gene expression. Systemic levels of C-reactive protein and adiponectin were measured by ELISA. The data show that adipose IRF5 gene (P = 0.008) and protein (P = 0.004) expression was upregulated in obese compared with lean individuals. IRF5 expression changes correlated positively with body mass index (BMI; r = 0.37/P = 0.008) and body fat percentage (r = 0.51/P = 0.0004). In obese, IRF5 changes associated positively with HbA1c (r = 0.41/P = 0.02). A good agreement was found between gene and protein expression of IRF5 in obese subjects (r = 0.65/P = 0.001). IRF5 gene expression associated positively with adipose inflammatory signatures including local expression of TNF-α, IL-6, CXCL8, CCL-2/5, IL-1β, IL-18, CXCL-9/10, CCL7, CCR-1/2/5, TLR-2/7/8/9, IRF3, MyD88, IRAK-1, and inflammatory macrophage markers (P < 0.05). Interestingly, IRF5 gene expression correlated positively with CRP (r = 0.37, P = 0.03) and negatively with adiponectin levels (r = −0.43, P = 0.009). In conclusion, elevated adipose IRF5 expression in obesity concurs with the typical inflammatory signatures, locally and systemically. Hence, the IRF5 upregulation may represent a novel adipose tissue marker for metabolic inflammation.

Vaticanol B, a resveratrol tetramer, regulates endoplasmic reticulum stress and inflammation

2007 ◽  
Vol 293 (1) ◽  
pp. C411-C418 ◽  
Author(s):  
Yoshiyuki Tabata ◽  
Katsura Takano ◽  
Tetsuro Ito ◽  
Munekazu Iinuma ◽  
Tanihiro Yoshimoto ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Membrane Integrity ◽  
Prostaglandin E ◽  
Unfolded Protein ◽  
Homologous Protein ◽  
Anti Inflammatory ◽  
Factor Α ◽  
Protein Response ◽  
Protein Load

Enhanced endoplasmic reticulum (ER) stress has been implicated in various pathological situations including inflammation. During a search for compounds that regulate ER stress, we identified vaticanol B, a tetramer of resveratrol, as an agent that protects against ER stress-induced cell death. Vaticanol B suppressed the induction of unfolded protein response-targeted genes such as glucose-regulated protein 78 ( GRP78) and C/EBP-homologous protein ( CHOP) after cells were treated with ER stressors. Analysis in the mouse macrophage cell line RAW 264.7 revealed that vaticanol B also possesses a strong anti-inflammatory activity. Production of a variety of inflammatory modulators such as tumor necrosis factor-α, nitric oxide, and prostaglandin E2 was inhibited by vaticanol B to a much greater extent than by monomeric or dimeric resveratrol after exposure of cells to lipopolysaccharide. Further investigations to determine the common mechanisms underlying the regulation of ER stress and inflammation by vaticanol B disclosed an important role for vaticanol B in regulation of basic gene expression and in prevention of the protein leakage from the ER into the cytosol in both conditions. These results suggest that vaticanol B is a novel anti-inflammatory agent that improves the ER environment by reducing the protein load on the ER and by maintaining the membrane integrity of the ER.

Decreased M1 macrophage polarization in dabigatran-treated Ldlr-deficient mice: Implications for atherosclerosis and adipose tissue inflammation

2019 ◽  
Vol 287 ◽  
pp. 81-88 ◽  
Author(s):  
Kathrin Feldmann ◽  
Maria Grandoch ◽  
Christina Kohlmorgen ◽  
Birte Valentin ◽  
Stephen Gerfer ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Macrophage Polarization ◽  
Adipose Tissue Inflammation ◽  
Tissue Inflammation ◽  
M1 Macrophage ◽  
Deficient Mice

scholarly journals p-Coumaric Acid Enriched-Peanut Sprout Improves High Fat Diet-Induced Obesity and Insulin Resistance by Inhibiting Macrophage Recruitment

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 407-407
Author(s):  
Sang-Mi Jo ◽  
Seok Hee Seo ◽  
Inhae Kang
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Macrophage Polarization ◽  
Visceral Obesity ◽  
Acid Oxidation ◽  
Coumaric Acid ◽  
High Fat ◽  
Metabolic Complications ◽  
M1 Macrophage ◽  
Mitochondrial Fatty Acid

Abstract Objectives We have previously reported that Peanut Sprout Extract (PSE) inhibited adipogenesis through augmentation of mitochondrial fatty acid oxidation. However, it is unknown whether PS consumption reduced visceral obesity and obesity-mediated metabolic complications in vivo. Methods To test this question, obesity-prone C57BL/6 male mice were randomly assigned into three different group; 1) low-fat (LF) diets (11% calories from fat), 2) high-fat (HF) diets (60% calories from fat) or 2) HF diets plus PS (4% in diet, HF-P). Results HF diet for 8 weeks resulted in a significant increase in body weight, liver, and adipose tissue mass compared to LF alone. PS supplementation reduced 1) body weight gain, 2) lipid profile, 3) up-regulated glucose levels, and 4) recruitment of adipose tissue macrophage in HF diet-induced obese C57BL6 mice. In parallel, lipopolysaccharide (LPS)-mediated induction of inflammation was reversed by PSE treatment in macrophages and adipocytes with significant suppression of MAP kinase and NF-kB activation. PSE also reduced LPS-mediated M1 macrophage polarization in bone marrow stem cells. Additionally, we found that, among constitutes of PSE, p-coumaric acid has been identified as responsible polyphenol that exclusively showed a similar trends as PSE. Conclusions Collectively, these data suggest that p-coumaric acid enriched-Peanut Sprout attenuates visceral obesity and obesity-mediated metabolic complications by inhibiting adipose inflammation. Funding Sources This work has supported by the National Research Foundation of Korea(NRF) grant funded by the Korea government (MSIT).

scholarly journals NFATc3 deficiency reduces the classical activation of adipose tissue macrophages

2018 ◽  
Vol 61 (3) ◽  
pp. 79-89 ◽  
Author(s):  
Li Hu ◽  
Fengli He ◽  
Meifeng Huang ◽  
Meihua Peng ◽  
Zhiguang Zhou ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Transcriptional Activation ◽  
Macrophage Polarization ◽  
Liver Fat ◽  
M2 Macrophage ◽  
Activated T Cells ◽  
M1 Macrophage ◽  
Proinflammatory Factors

Nuclear factors of activated T cells (NFAT) c3 have a prominent role in the regulation of proinflammatory factors in immune cells. The classically activated M1 macrophages are key players in the initiation and maintenance of adipose tissue (AT) inflammation. The role of NFATc3 in obesity and AT inflammation is unknown. We set out to determine how deficiency of NFATc3 effected macrophage polarization, inflammation and insulin resistance in visceral AT of high-fat diet (HFD)-fed mice. Nfatc3−/− and WT mice were fed a HFD for 8–17 weeks. Epididymal white AT (eWAT) F4/80(+) cells were characterized by fluorescence-activated cell sorting and quantitative RT-PCR. Results showed that Nfatc3−/− mice developed HFD-induced obesity similar to WT mice, but insulin sensitivity and glucose tolerance were improved, and liver fat accumulation was reduced in Nfatc3−/− mice compared to WT control mice. Moreover, M1 macrophage content and proinflammatory factors were reduced, whereas the alternatively activated M2 macrophage content was increased in eWAT of HFD-fed Nfatc3−/− mice compared to that of WT mice. In addition, eWAT insulin signaling was improved in HFD-fed Nfatc3−/− mice. Importantly, after bone-marrow-derived macrophages had been isolated from Nfatc3−/− mice and cultured in vitro, treatment of these cells with interferon-γ and lipopolysaccharide resulted in reduction of M1 inflammatory markers, suggesting that NFATc3 promoted M1 polarization by a cell-autonomous mechanism. The results demonstrated that NFATc3 played an important role in M1 macrophage polarization, AT inflammation and insulin resistance in response to obesity through transcriptional activation of proinflammatory genes.

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