scholarly journals HDAC6 and CXCL13 Mediate Atopic Dermatitis by Regulating Cellular Interactions and Expression Levels of miR-9 and SIRT1

2021 ◽  
Vol 12 ◽  
Author(s):  
Yoojung Kwon ◽  
Yunji Choi ◽  
Misun Kim ◽  
Myeong Seon Jeong ◽  
Hyun Suk Jung ◽  
...  

Histone deacetylase 6 (HDAC6) has been known to regulate inflammatory diseases. The role of HDAC6 in allergic skin inflammation has not been studied. We studied the role of HDAC6 in atopic dermatitis (AD) and the mechanisms associated with it. The decreased expression or chemical inhibition of HDAC6 suppressed AD by decreasing autophagic flux and cellular features of AD. AD increased expression levels of the Th1 and Th2 cytokines, but decreased expression levels of forkhead box P3 (FoxP3) and interleukin-10 (IL-10) in an HDAC6-dependent manner. CXC chemokine ligand 13 (CXCL13), which was increased in an HDAC6-depenednt manner, mediated AD. MiR-9, negatively regulated by HDAC6, suppressed AD by directly regulating the expression of sirtuin 1 (SIRT1). The downregulation or inhibition of SIRT1 suppressed AD. Experiments employing culture medium and transwell suggested that cellular interactions involving mast cells, keratinocytes, and dermal fibroblast cells could promote AD; HDAC6 and CXCL13 were found to be necessary for these cellular interactions. Mouse recombinant CXCL13 protein increased HDAC6 expression in skin mast cells and dermal fibroblast cells. CXCL13 protein was found to be present in the exosomes of DNCB-treated skin mast cells. Exosomes of DNCB-treated skin mast cells enhanced invasion potentials of keratinocytes and dermal fibroblast cells and increased expression levels of HDAC6, SIRT1 and CXCL13 in keratinocytes and dermal fibroblast cells. These results indicate that HDAC6 and CXCL13 may serve as targets for the developing anti-atopic drugs.

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sireesh Kumar Teertam ◽  
Phanithi Prakash Babu

AbstractCerebral ischemia (CI) is a severe cause of neurological dysfunction and mortality. Sirtuin-1 (Silent information regulator family protein 1, SIRT1), an oxidized nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase, plays an important role in protection against several neurodegenerative disorders. The present study aims to investigate the protective role of SIRT1 after CI in experimental young and aged rats and humans. Also, the study examines the possible regulatory mechanisms of neuronal death in CI settings. Immunoblotting and immunohistochemistry were used to evaluate changes in the expression of SIRT1, JNK/ERK/MAPK/AKT signaling, and pro-apoptotic caspase-3 in experimental rats and CI patients. The study findings demonstrated that, in aged experimental rats, SIRT1 activation positively influenced JNK and ERK phosphorylation and modulated neuronal survival in AKT-dependent manner. Further, the protection conferred by SIRT1 was effectively reversed by JNK inhibition and increased pro-apoptotic caspase-3 expression. In young experimental rats, SIRT1 activation decreased the phosphorylation of stress-induced JNK, ERK, caspase-3, and increased the phosphorylation of AKT after CI. Inhibition of SIRT1 reversed the protective effect of resveratrol. More importantly, in human patients, SIRT1 expression, phosphorylation of JNK/ERK/MAPK/AKT signaling and caspase-3 were up-regulated. In conclusion, SIRT1 could possibly be involved in the modulation of JNK/ERK/MAPK/AKT signaling pathway in experimental rats and humans after CI.


2018 ◽  
Vol 11 (556) ◽  
pp. eaao4354 ◽  
Author(s):  
Ivana Halova ◽  
Monika Bambouskova ◽  
Lubica Draberova ◽  
Viktor Bugajev ◽  
Petr Draber

Chemotaxis of mast cells is one of the crucial steps in their development and function. Non–T cell activation linker (NTAL) is a transmembrane adaptor protein that inhibits the activation of mast cells and B cells in a phosphorylation-dependent manner. Here, we studied the role of NTAL in the migration of mouse mast cells stimulated by prostaglandin E2 (PGE2). Although PGE2 does not induce the tyrosine phosphorylation of NTAL, unlike IgE immune complex antigens, we found that loss of NTAL increased the chemotaxis of mast cells toward PGE2. Stimulation of mast cells that lacked NTAL with PGE2 enhanced the phosphorylation of AKT and the production of phosphatidylinositol 3,4,5-trisphosphate. In resting NTAL-deficient mast cells, phosphorylation of an inhibitory threonine in ERM family proteins accompanied increased activation of β1-containing integrins, which are features often associated with increased invasiveness in tumors. Rescue experiments indicated that only full-length, wild-type NTAL restored the chemotaxis of NTAL-deficient cells toward PGE2. Together, these data suggest that NTAL is a key inhibitor of mast cell chemotaxis toward PGE2, which may act through the RHOA/ERM/β1-integrin and PI3K/AKT axes.


2022 ◽  
Vol 12 (3) ◽  
pp. 506-513
Author(s):  
Ying Lv ◽  
Liyan Ye ◽  
Xiujuan Zheng

This study aimed to explore the role of ATI-2341 in Asherman’s syndrome and its impact on menstrual blood-derived mesenchymal stem cells (MenSCs). Following establishment of endometrial injury model, MenSCs were extracted from rats and cultured. They were treated with ATI-2341 TFA at different concentrations (10 ng/mL, 50 ng/mL, 100 ng/mL) and MenSCs treated without ATI-2341 TFA were taken as controls. Flow cytometry was conducted to detect the cell cycle. MTT was carried out to evaluate proliferation of endometrial cells. The expression levels of MMP-9, TIMP-1, CK, and VIM were determined with staining used to reflect morphology of endometrium. Administration with ATI-2341 TFA resulted in decreased expression of MMP-9 and increased expression of TIMP-1 in a dose-dependent manner. Of note, the increase of ATI-2341 TFA concentration was accompanied with elevated cell proliferation rate, increased number of glands in the endometrium, and decreased fibrosis area. As treated with 100 ng/mL ATI-2341 TFA, the cells exhibited more glands than that under other concentrations with uniformly arranged glands and lowest expression levels of CK and VIM, control group had plenty of blue-stained collagen fibers in the intima and least amount of glands. ATI-2341 TFA 100 ng/mL induced endometrial epithelial recruitment effect on MenSCs and promoted endometrial repair more significantly than Gi-3 pathway agonists. Collectively, ATI-2341 TFA enhances MenSC recruitment and facilitates endometrial epithelial cells proliferation and the repair of uterine damage in Asherman’s syndrome through Gi pathway. These findings provide a\ novel insight into the MenSC-based treatment against Asherman’s syndrome and deserve further investigation.


Blood ◽  
2000 ◽  
Vol 96 (6) ◽  
pp. 2172-2180 ◽  
Author(s):  
Kotaro Suzuki ◽  
Hiroshi Nakajima ◽  
Norihiko Watanabe ◽  
Shin-ichiro Kagami ◽  
Akira Suto ◽  
...  

Abstract The regulatory roles of the common cytokine receptor γ chain (γc)– and Jak3-dependent signaling in the proliferation and survival of mast cells were determined using γc-deficient (γc−) and Jak3-deficient (Jak3−) mice. Although the mast cells in γc− and Jak3− mice were morphologically indistinguishable from those in wild-type mice, the number of peritoneal mast cells was decreased in γc− and Jak3− mice as compared with that in wild-type mice. Among γc-related cytokines, interleukin (IL)-4 and IL-9, but not IL-2, IL-7, or IL-15, enhanced the proliferation and survival of bone marrow–derived mast cells (BMMCs) from wild-type mice. However, the effects of IL-4 and IL-9 were absent in BMMCs from γc− and Jak3−mice. In addition, IL-4Rα, γc, and Jak3, but not IL-2Rβ or IL-7Rα, were expressed in BMMCs. In contrast, IL-13 did not significantly induce the proliferation and survival of BMMCs even from wild-type mice, and IL-13Rα1 was not expressed in BMMCs. Furthermore, IL-4 phosphorylated the 65-kd isoform of Stat6 in BMMCs from wild-type mice but not from γc− and Jak3− mice. These results indicate that γc- and Jak3-dependent signaling is essential for IL-4– and IL-9–induced proliferation and survival of murine mast cells, that the effects of IL-4 are mediated by type I IL-4R and that type II IL-4R is absent on mast cells, and that IL-4 phosphorylates the 65-kd isoform of Stat6 in mast cells in a γc- and Jak3-dependent manner.


2020 ◽  
Vol 47 (4) ◽  
pp. 2427-2436 ◽  
Author(s):  
Jagdish Gopal Paithankar ◽  
Avinash Kundadka Kudva ◽  
Shamprasad Varija Raghu ◽  
Rajashekhar K. Patil

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Qinjie Liu ◽  
Jie Wu ◽  
Xufei Zhang ◽  
Xuanheng Li ◽  
Xiuwen Wu ◽  
...  

AbstractThe STING pathway and its induction of autophagy initiate a potent immune defense response upon the recognition of pathogenic DNA. However, this protective response is minimal, as STING activation worsens organ damage, and abnormal autophagy is observed during progressive sepsis. Whether and how the STING pathway affects autophagic flux during sepsis-induced acute lung injury (sALI) are currently unknown. Here, we demonstrate that the level of circulating mtDNA and degree of STING activation are increased in sALI patients. Furthermore, STING activation was found to play a pivotal role in mtDNA-mediated lung injury by evoking an inflammatory storm and disturbing autophagy. Mechanistically, STING activation interferes with lysosomal acidification in an interferon (IFN)-dependent manner without affecting autophagosome biogenesis or fusion, aggravating sepsis. Induction of autophagy or STING deficiency alleviated lung injury. These findings provide new insights into the role of STING in the regulatory mechanisms behind extrapulmonary sALI.


2020 ◽  
Author(s):  
Xiao-Yue Chen ◽  
Po-Hao Feng ◽  
Yi-Ying Chen ◽  
Chih-Da Wu ◽  
Sheng-Ming Wu ◽  
...  

Abstract Background: Inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) is considered a type II acute-phase protein; however, the role of ITIH4 in the lungs after exposure to fine particulate matter (PM2.5) remains unclear. The objective of this study was to investigate the role of ITIH4 in the lungs in response to PM2.5 exposure.Results: ITIH4 expression in bronchoalveolar lavage fluid (BAL) of 47 healthy subjects and of SD rats exposed to PM2.5 was determined, and the underlying anti-apoptotic and matrix-stabilizing pathways in A549 cells by diesel exhaust particles (DEPs) were also investigated. First, we observed that an interquartile range (IQR) increase in PM2.5 accounted for a decrease of 2.673 ng/mL in ITIH4, an increase of 1.104 pg/mL in 8-isoprostane, and an increase of 6.918 pg/mL in interleukin (IL)-6 in human BAL. Increases in 8-isoprostane and IL-6 in the lungs and decreases in ITIH4 in the BAL, lungs, and serum were observed after PM2.5 exposure. ITIH4 was correlated with lung lysates and BAL samples (r=0.377, p<0.01), whereas ITIH4 was correlated with IL-6 in BAL (r=-0.420, p<0.01). ITIH4 expression was significantly reduced in alveolar epithelial cells by PM2.5. ITIH4 expression decreased after DEP exposure in a dose-dependent manner. A decrease in sirtuin 1 (Sirt1) and increases in phosphorylated extracellular signal-regulated kinase (p-ERK) and caspase-3 were observed after DEP exposure. Conclusions: In conclusion, PM2.5 decreased ITIH4 in the lungs, which was associated with alveolar epithelial cell senescence and apoptosis. ITIH4 could be a vital protein in regulating alveolar destruction, and its deficiency occurs due to PM2.5.


Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3184-3184 ◽  
Author(s):  
Hans Michael Kvasnicka ◽  
Juergen Thiele ◽  
Carlos E. Bueso-Ramos ◽  
Shilpa Kamalanabhaiah ◽  
Jorge E. Cortes ◽  
...  

Abstract Background: Macrophages (MAC) are key regulators of malignant progression in solid tumors by promoting tumor cell invasion, migration and angiogenesis. Only few studies have investigated the role of activated MAC phenotypes, such as M1 and M2, in the bone marrow (BM) microenvironment of myelofibrosis (MF). MAC are generally increased in the BM of patients (pts) with MF and recent studies have also identified mast cells (MC) as playing an important role in regulating the underlying inflammatory process in MF. With regard to the substantial improvement in the mostly cytokine-driven constitutional symptoms following JAK inhibition therapy, we have investigated the effect of ruxolitinib (RUX) on BM MAC subtypes and MC and their association with BM fibrosis. Methods: A total of 63 pts with high-risk MF were included in this analysis. All pts had both baseline (BL) and sequential BM trephine biopsy at 24 months (mo) following RUX therapy. Using specific immunohistochemical stains, we analyzed assorted MAC markers, including CD68 and CD163. CD68 is a pan-MAC marker that recognizes both M1 and anti-inflammatory M2 subtypes. CD163 is a scavenger receptor upregulated by MAC within an anti-inflammatory environment and regarded as a highly specific monocyte/macrophage marker for the M2 subtype. Anti-Mast Cell Tryptase was applied as specific antibody to identify BM MC. All sections were stained following routine procedures and quantification of positivity was performed for each marker by consensus after independent review by 3 pathologists. Cytokine expression levels (TNF-alpha, MIP-1-alpha, IgE) at week 4 and 24 mo following RUX therapy were available for a subset of 23 and 16 pts. Individual changes were categorized as increase, stable, or decrease and correlated to the degree of WHO BM fibrosis grade and hematological features. Results: At BL, 81.0% of MF pts presented with an advanced fibrotic stage of disease (WHO grade 2 or 3). Grade of BM fibrosis significantly correlated with the frequency of CD68+ and CD168+ MAC. Furthermore, advanced fibrosis was associated with a higher frequency of BM MC. Following RUX treatment, 14.3% of cases showed an improvement in BM fibrosis, while 58.7% showed stabilization. RUX induced in 48.3% of cases a significant decrease in the overall amount of BM CD68+ MAC, whereas a further increase was observed in only 6.9%. Similar results were obtained for the specific CD163+ anti-inflammatory M2 subtype. Post-RUX a significant reduction of this cell lineage was seen in 47.6%, while 12.7% of cases revealed a further increase. Improvement in BM fibrosis was highly correlated with an overall reduction of CD68+ MAC, and in particular with modulation of the CD163+ M2 subtype. RUX therapy induced a profound reduction in the expression of associated cytokines such as TNF-alpha and MIP-1-alpha, both at 4 weeks and 24 mo. Frequency of BM MC was reduced in 26.3% of pts during therapy, however, in 49.1% therapy showed no change. Pts with improvement in BM fibrosis revealed in most cases lower frequencies of MC, but this association did not reach statistical significance. In contrast, expression levels of IgE were strongly reduced in almost all pts at week 4 and 24 mo. The amount of MAC or MC did not correlate with BL hematological or clinical parameters such as BL spleen size, anemia or platelet counts. Following RUX, decreases in M1 and M2 MAC were associated with changes in hemoglobin levels and spleen size reduction. Conclusions: Our results significantly extend previous observations on the role of the BM microenvironment in MF. RUX treatment meaningfully and directionally impacts the amount of activated anti-inflammatory MAC in BM of MF patients. Overall, our data advocate the strong disease modulation capacity of anti-JAK therapy. Disclosures Kvasnicka: Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Honoraria. Thiele:Novartis: Consultancy, Honoraria; Incyte Corporation: Consultancy, Honoraria. Kantarjian:Novartis: Research Funding. Verstovsek:NS Pharma, Inc: Research Funding.


2019 ◽  
Vol 317 (4) ◽  
pp. C674-C686 ◽  
Author(s):  
Leandro Henrique Manfredi ◽  
Joshur Ang ◽  
Nesibe Peker ◽  
Ruben K. Dagda ◽  
Craig McFarlane

G protein-coupled receptor kinase 2 (GRK2) is an important protein involved in β-adrenergic receptor desensitization. In addition, studies have shown GRK2 can modulate different metabolic processes in the cell. For instance, GRK2 has been recently shown to promote mitochondrial biogenesis and increase ATP production. However, the role of GRK2 in skeletal muscle and the signaling mechanisms that regulate GRK2 remain poorly understood. Myostatin is a well-known myokine that has been shown to impair mitochondria function. Here, we have assessed the role of myostatin in regulating GRK2 and the subsequent downstream effect of myostatin regulation of GRK2 on mitochondrial respiration in skeletal muscle. Myostatin treatment promoted the loss of GRK2 protein in myoblasts and myotubes in a time- and dose-dependent manner, which we suggest was through enhanced ubiquitin-mediated protein loss, as treatment with proteasome inhibitors partially rescued myostatin-mediated loss of GRK2 protein. To evaluate the effects of GRK2 on mitochondrial respiration, we generated stable myoblast lines that overexpress GRK2. Stable overexpression of GRK2 resulted in increased mitochondrial content and enhanced mitochondrial/oxidative respiration. Interestingly, although overexpression of GRK2 was unable to prevent myostatin-mediated impairment of mitochondrial respiratory function, elevated levels of GRK2 blocked the increased autophagic flux observed following treatment with myostatin. Overall, our data suggest a novel role for GRK2 in regulating mitochondria mass and mitochondrial respiration in skeletal muscle.


2012 ◽  
Vol 129 (2) ◽  
pp. AB36
Author(s):  
M. Oh ◽  
Z. Zhu ◽  
J. Yu ◽  
T. Zheng
Keyword(s):  

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