Rapamycin regulates macrophage activation by inhibiting NLRP3 inflammasome-p38 MAPK-NFκB pathways in autophagy- and p62-dependent manners

Tubular injury is one of the crucial determinants of progressive renal failure in diabetic nephropathy (DN), while epithelial-to-mesenchymal transition (EMT) of tubular cells contributes to the accumulation of matrix protein in the diabetic kidney. Activation of the nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome leads to the maturation of interleukin (IL)-1B and is involved in the pathogenic mechanisms of diabetes. In this study, we explored the role of NLRP3 inflammasome on high glucose (HG) or transforming growth factor-B1 (TGFB1)-induced EMT in HK-2 cells. We evaluated EMT through the expression of α-smooth muscle actin (α-SMA) and E-cadherin as well as the induction of a myofibroblastic phenotype. Reactive oxygen species (ROS) was observed using the confocal microscopy. HG was shown to induce EMT at 48 h, which was blocked byNLRP3silencing or antioxidant N-acetyl-L-cysteine (NAC). We found thatNLRP3interference could inhibit HG-induced ROS. Knockdown ofNLRP3could prevent HG-induced EMT by inhibiting the phosphorylation of SMAD3, P38 MAPK and ERK1/2. In addition, P38 MAPK and ERK1/2 might be involved in HG-induced NLRP3 inflammasome activation. Besides, TGFB1 induced the activation of NLRP3 inflammasome and the generation of ROS, which were blocked byNLRP3interference or NAC. Tubular cells exposed to TGFB1 also underwent EMT, and this could be inhibited byNLRP3shRNA or NAC. These results indicated that knockdown ofNLRP3antagonized HG-induced EMT by inhibiting ROS production, phosphorylation of SMAD3, P38MAPK and ERK1/2, highlighting NLRP3 as a potential therapy target for diabetic nephropathy.

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Dysifragilone A inhibits LPS‑induced RAW264.7 macrophage activation by blocking the p38 MAPK signaling pathway

Molecular Medicine Reports ◽

10.3892/mmr.2017.7884 ◽

2017 ◽

Cited By ~ 1

Author(s):

Huixiang Li ◽

Qian Zhang ◽

Xin Jin ◽

Xiaowen Zou ◽

Yuexuan Wang ◽

...

Keyword(s):

Signaling Pathway ◽

P38 Mapk ◽

Macrophage Activation ◽

Mapk Signaling ◽

Mapk Signaling Pathway ◽

Raw264.7 Macrophage

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Palmitoleic acid prevents palmitic acid-induced macrophage activation and consequent p38 MAPK-mediated skeletal muscle insulin resistance

Molecular and Cellular Endocrinology ◽

10.1016/j.mce.2014.06.010 ◽

2014 ◽

Vol 393 (1-2) ◽

pp. 129-142 ◽

Cited By ~ 46

Author(s):

Nicola A. Talbot ◽

Caroline P. Wheeler-Jones ◽

Mark E. Cleasby

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Palmitic Acid ◽

P38 Mapk ◽

Macrophage Activation ◽

Palmitoleic Acid ◽

Muscle Insulin Resistance ◽

Skeletal Muscle Insulin Resistance

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Characterization of polysaccharide from longan pulp as the macrophage stimulator

RSC Advances ◽

10.1039/c5ra16044h ◽

2015 ◽

Vol 5 (118) ◽

pp. 97163-97170 ◽

Cited By ~ 21

Author(s):

Yang Yi ◽

Hongxun Wang ◽

Ruifen Zhang ◽

Ting Min ◽

Fei Huang ◽

...

Keyword(s):

Signaling Pathways ◽

P38 Mapk ◽

Macrophage Activation

A 44.7-kDa polysaccharide LPIIa from longan pulp was mainly composed of →6)-Glc-(1→, →5)-Ara-(1→, →4)-Man-(1→ and →6)-Gal-(1→. It stimulated macrophage activation partlyviaTLR4 and TLR2, followed by p38 MAPK- and NF-κB-dependent signaling pathways.

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Infectious bursal disease virus infection induces macrophage activation via p38 MAPK and NF-κB pathways

Virus Research ◽

10.1016/j.virusres.2005.11.015 ◽

2006 ◽

Vol 118 (1-2) ◽

pp. 70-77 ◽

Cited By ~ 49

Author(s):

Mahesh Khatri ◽

Jagdev M. Sharma

Keyword(s):

Virus Infection ◽

Disease Virus ◽

P38 Mapk ◽

Infectious Bursal Disease Virus ◽

Macrophage Activation ◽

Infectious Bursal Disease ◽

Bursal Disease

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SARS-CoV-2 spike glycoprotein S1 induces neuroinflammation in BV-2 microglia

10.1101/2020.12.29.424619 ◽

2020 ◽

Author(s):

Olumayokun A Olajide ◽

Victoria U Iwuanyanwu ◽

Oyinkansola D Adegbola

Keyword(s):

Protein Expression ◽

P38 Mapk ◽

Nlrp3 Inflammasome ◽

Neuropsychiatric Symptoms ◽

Spike Glycoprotein ◽

Caspase 1 ◽

Global Pandemic ◽

Protein Expressions ◽

Pre Treatment ◽

Culture Supernatants

The emergence of SARS‐CoV‐2 has resulted in a global pandemic. In addition to respiratory complications as a result of SARS‐CoV‐2 illness, accumulating evidence suggests that neurological and neuropsychiatric symptoms are associated with the disease caused by the virus. In this study, we investigated the effects of the SARS‐CoV‐2 spike glycoprotein S1 stimulation on neuroinflammation in BV-2 microglia. Analyses of culture supernatants revealed an increase in the production of TNFα, IL-6, IL-1β and iNOS/NO. SARS‐CoV‐2 spike glycoprotein S1 increased protein expressions of phospho-p65 and phospho-IκB, as well as enhancing DNA binding and transcriptional activity of NF-κB. Pro-inflammatory effects of the glycoprotein effects were reduced in the presence of BAY11-7082 (1 μM). The presence of SARS‐CoV‐2 spike glycoprotein S1 in BV-2 microglia increased the protein expression of NLRP3, as well as caspase-1 activity. However, pre-treatment with CRID3 (1 μM) or BAY11-7082 (1 μM) resulted in the inhibition of NLRP3 inflammasome/caspase-1. It was also observed that CRID3 attenuated SARS‐CoV‐2 spike glycoprotein S1-induced increase in IL-1β production. Increased protein expression of p38 MAPK was observed in BV-2 microglia stimulated with the spike glycoprotein S1, and was reduced in the presence of SKF 86002. These results have provided the first evidence demonstrating SARS-CoV-2 spike S1 glycoprotein-induced neuroinflammation in BV-2 microglia. We propose that promotion of neuroinflammation by this glycoprotein is mediated through activation of NF-κB, NLRP3 inflammasome and p38 MAPK. These results are significant because of their relevance to our understanding of neurological and neuropsychiatric symptoms observed in patients infected with SARS-CoV-2.

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Acute Glucose Shift Induces the Activation of the NLRP3 Inflammasome in THP-1 Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22189952 ◽

2021 ◽

Vol 22 (18) ◽

pp. 9952

Author(s):

Ji Yeon Lee ◽

Yup Kang ◽

Hae Jin Kim ◽

Dae Jung Kim ◽

Kwan Woo Lee ◽

...

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

P38 Mapk ◽

Diabetic Complications ◽

Nlrp3 Inflammasome ◽

High Glucose ◽

Glucose Concentration ◽

Oxygen Species ◽

Normal Glucose ◽

Acute Changes

We aimed to investigate the effect of acute glucose shift on the activation of the NLRP3 inflammasome, IL-1β secretion, and underlying signaling pathways in THP-1 cells. THP-1 cells were divided into four groups and exposed to the following glucose concentrations for 24 h: constant normal glucose (NG, 5.5 mM), constant high glucose (HG, 25 mM), normal to high glucose shift (NG-to-HG, 5.5 to 25 mM), and high to normal glucose shift (HG-to-NG, 25 to 5.5 mM). Cell viability, oxidative stress, and the levels of NLRP3 inflammasome components were assessed. Both directions of the acute glucose shift increased the activation of the NLRP3 inflammasome, generation of reactive oxygen species (ROS), and expression of phosphorylated p38 MAPK, JNK, and NF-κB compared with either constant NG or HG. Treatment with N-acetylcysteine, a pharmacological antioxidant, inhibited the acute glucose shift-induced generation of ROS, activation of NLRP3 inflammasome, and upregulation of MAPK-NF-κB. Further analysis using inhibitors of p38 MAPK, JNK, and NF-κB indicated that acute glucose shifts promoted IL-1β secretion by activating the signaling pathway in a ROS-MAPK-NF-κB-NLRP3 inflammasome in THP-1 cells. These findings suggested that acute changes in glucose concentration might cause monocyte inflammation, which is associated with diabetic complications.

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Effects of the Cytoplasm and Mitochondrial Specific Hydroxyl Radical Scavengers TA293 and mitoTA293 in Bleomycin-Induced Pulmonary Fibrosis Model Mice

Antioxidants ◽

10.3390/antiox10091398 ◽

2021 ◽

Vol 10 (9) ◽

pp. 1398

Author(s):

Takahiro Sakai ◽

Hidetsugu Takagaki ◽

Noriyuki Yamagiwa ◽

Michio Ui ◽

Shinichi Hatta ◽

...

Keyword(s):

Epithelial Cells ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Hydroxyl Radical ◽

P38 Mapk ◽

Cellular Senescence ◽

Nlrp3 Inflammasome ◽

Lung Fibrosis ◽

Alveolar Epithelial Cells ◽

Alveolar Epithelial

Lung fibrosis is the primary pathology in idiopathic pulmonary fibrosis and is considered to result from an increase in reactive oxygen species (ROS) levels in alveolar epithelial cells. However, the exact mechanism underlying lung fibrosis remains unclear and there is no effective therapy. The hydroxyl radical (•OH) has the strongest oxidizing potential among ROS. Recently, •OH localized to the cytoplasm (cyto •OH) was reported to induce cellular senescence, while mitochondria-localized •OH (mt •OH) was reported to induce apoptosis. We developed the cyto •OH- and mt •OH-scavenging antioxidants TA293 and mitoTA293 to evaluate the effects of cyto •OH and mt •OH in a bleomycin (BLM)-induced pulmonary fibrosis model. Treatment of BLM-induced pulmonary fibrosis mice with TA293 suppressed the induction of cellular senescence and fibrosis, as well as inflammation in the lung, but mitoTA293 exacerbated these. Furthermore, in BLM-stimulated primary alveolar epithelial cells, TA293 suppressed the activation of the p-ATMser1981/p-p53ser15/p21, p-HRI/p-eIF2ser51/ATF4/p16, NLRP3 inflammasome/caspase-1/IL-1β/IL1R/p-p38 MAPK/p16, and p21 pathways and the induction of cellular senescence. However, mitoTA293 suppressed the induction of mitophagy, enhanced the activation of the NLRP3 inflammasome/caspase-1/IL1β/IL1R/p-p38 MAPK/p16 and p21 pathways, and exacerbated cellular senescence, inflammation, and fibrosis. Our findings may help develop new strategies to treat idiopathic pulmonary fibrosis.

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