PER1 prevents excessive innate immune response during endotoxin-induced liver injury through regulation of macrophage recruitment in mice

Wang, Tingyan; Wang, Z; Yang, Ping; Xia, Lin; Zhou, Mengyi; Wang, S; Du, Jie; Zhang, J

doi:10.1038/cddis.2016.9

Cited by 64 publications

(50 citation statements)

References 53 publications

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“…Animal protocols were approved by the Animal Care and Use Committee of Anhui Medical University, Hefei, China. C57BL/6 (20 ± 2 g) male mice were purchased from the Experimental Animal Center of Anhui Medical University for the LPS+D-GAIN model [2] . ALI was established by intraperitoneal injection of LPS (3 μg/kg) + D-GAIN (200 mg/kg, Sigma Aldrich, St Louis, MO, USA).…”

Section: Lps+d-gain Acute Liver Injury Modelmentioning

confidence: 99%

“…under treatment with LPS, KCs secrete different inflammatory cytokines, including interleukin-1 (IL-1), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-α (TNF-α). these proinflammatory cytokines can induce hepatocyte death and ultimately resulting in ALF [2] . Two types of macrophages exert their immunological…”

Section: Introductionmentioning

confidence: 99%

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Blockage of Kv1.3 regulates macrophage migration in acute liver injury by targeting δ-catenin through RhoA signaling

Liu

Bian

et al. 2020

Int. J. Biol. Sci.

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Background: Activation of macrophages and infiltration are key events in acute liver injury (ALI). Kv1.3 plays an important role in regulating immunologic functions of macrophages and is extensively recognized as a potential ion channel for immunological diseases. Objective: We hypothesized that blockage of Kv1.3 may influence ALI by inhibiting macrophages infiltration in damaged liver tissues. Methods: Margatoxin was administered into the peritoneal cavity of ALI mice. The impact of this treatment on ALI and macrophage migration in vivo and in vitro was determined using immunohistochemistry, transwell migration, and wound healing assays. Results: MgTX treatment alleviated ALI in mice, as evidenced by reduced macrophage infiltration in liver tissues and lower serum levels of liver ALT and AST. RNA-seq profiling analysis showed that the most obvious change by MgTX treatment was downregulation of δ-catenin, a protein known to be associated with macrophage migration. The effect of MgTX on macrophage migration and involvement of δ-catenin was confirmed by transwell and wound healing assays. Overexpression of δ-catenin in RAW264.7 cells promoted migration, an event that was suppressed upon silencing of δ-catenin. Mechanistically, the expression of RhoA was regulated by the overexpression or knockdown of δ-catenin. Conclusion: These findings suggest a role for blockage of Kv1.3 channel in macrophage migration and reveal a new target in the treatment of ALI.

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Section: Lps+d-gain Acute Liver Injury Modelmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Blockage of Kv1.3 regulates macrophage migration in acute liver injury by targeting δ-catenin through RhoA signaling

Liu

Bian

et al. 2020

Int. J. Biol. Sci.

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“…However, whether AMSC-Exo-based therapy can ameliorate ALF and modulate NLRP3 inflammasome is unclear. Lipopolysaccharide and d -galactosamine (LPS/GalN)-induced liver injury is widely used to simulate ALF [ 15 ]. The present study aimed to investigate the effects and underlying mechanisms of AMSC-Exo on LPS/GalN-induced ALF.…”

Section: Introductionmentioning

confidence: 99%

AMSC-derived exosomes alleviate lipopolysaccharide/d-galactosamine-induced acute liver failure by miR-17-mediated reduction of TXNIP/NLRP3 inflammasome activation in macrophages

et al. 2018

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BackgroundMesenchymal stem cell (MSC)-derived exosome administration has been considered as a novel cell-free therapy for liver diseases through cell-cell communication. This study was aimed to determine the effects and mechanisms of AMSC-derived exosomes (AMSC-Exo) for acute liver failure (ALF) treatment.MethodsAMSC-Exo were intravenously administrated into the mice immediately after lipopolysaccharide and D-galactosamine (LPS/GalN)-exposure and their effects were evaluated by liver histological and serum biochemical analysis. To elucidate its mechanisms in ALF therapy, the expression levels of miRNAs and inflammasome-related genes in macrophages were evaluated by qPCR and Western blot analysis, respectively. The exosomes from miR-17-knockdowned AMSCs (AMSC-ExomiR-17-KD) were used for further determine the role of miR-17 in AMSC-Exo-based therapy.FindingsAMSC-Exo administration significantly ameliorated ALF as determined by reduced serum alanine aminotransferase and aspartate aminotransferase levels and hepatic inflammasome activation. Further experiments revealed that AMSC-Exo were colocalized with hepatic macrophages and could reduce inflammatory factor secretion by suppressing inflammasome activation in macrophages. Moreover, miR-17, which can suppress NLRP3 inflammasome activation by targeting TXNIP, was abundant in AMSC-Exo cargo. While, the therapeutic effects of AMSC-ExomiR-17-KD on ALF were significantly abolished as they could not effectively suppress TXNIP expression and consequent inflammasome activation in vitro and in vivo.Interpretation: Exosome-shuttled miR-17 plays an essential role in AMSC-Exo therapy for ALF by targeting TXNIP and suppressing inflammasome activation in hepatic macrophages. AMSC-Exo-based therapy may present as a promising approach for TXNIP/NLRP3 inflammasome-related inflammatory liver diseases.FundKey R&D projects of Zhejiang province (2018C03019) and National Natural Science Fund (81470851 and 81500616).

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“…The change in WBC count over the day would suggest that the likelihood of a black subject failing to be included because of BEN is higher in the morning than later in the day since diurnal variation would further lower their WBC count. The mechanism of diurnal variation in neutrophil numbers is probably not related to the endogenous molecular clock (Ella et al, 2016;Wang et al, 2016). Neutrophils have a high turnover rate and cortisol inhibits their apoptosis (Zen et al, 2011).…”

Section: Biological Explanations and Consequences For The Observed Ramentioning

confidence: 99%

Time- and Race-Specific Haematological Reference Intervals for Healthy Volunteer Trials: A Retrospective Analysis of Pooled Data From Multiple Phase I Trials

Coates¹,

Wang

Pierscionek³

et al. 2020

Front. Pharmacol.

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Most UK hospitals, laboratories, and research institutions use uniform reference intervals (RI) that do not take into account known diurnal and racial variation in total white blood cells (WBC) count and its constituent parameters. These risks of excluding potentially suitable ethnic minority volunteers from participating in phase I clinical trials could call into question the validity of a trial's findings or limit its scientific applications and ability to accurately observe drug effects upon WBC parameters. This study pools data from multiple phase I trials, assesses the effects of race and time of day on WBC count, and compares it to the existing literature to establish race and time-specific RIs. A total 13,332 venous blood samples obtained from 7,157 healthy male and female volunteers at the time of screening or admission (predosing) who took part in 35 phase I trials over a period of seven years were pooled and the data were analyzed using generalised estimating equation models. Adjusted RI of total WBC count and its individual parameters were then calculated according to time of day (morning vs. evening) for both black and nonblack populations. This study indicates that black individuals on average had lower total WBC, neutrophil, monocyte, eosinophil, and basophil counts than individuals from nonblack racial groups. Black volunteers had higher mean lymphocyte counts relative to their nonblack counterparts. These differences were deemed statistically significant. Statistically significant increases in total WBC, neutrophil, lymphocyte, and monocyte counts were also observed over the course of daily sampling. Eosinophil counts decreased during this time period, but this finding was only statistically significant in the nonblack population. Despite an observed mild diurnal increase in basophil count in both populations, this was not considered statistically significant. This high-powered study adds significant weight to the known evidence for diurnal and racial variation in WBC parameters. Importantly, it proposes specific RIs that more precisely reflect race and time of day. These could ensure increased participation of black volunteers in clinical trials for improved population representation. Furthermore, the proposed RIs allow for more

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PER1 prevents excessive innate immune response during endotoxin-induced liver injury through regulation of macrophage recruitment in mice

Cited by 64 publications

References 53 publications

Blockage of Kv1.3 regulates macrophage migration in acute liver injury by targeting δ-catenin through RhoA signaling

Blockage of Kv1.3 regulates macrophage migration in acute liver injury by targeting δ-catenin through RhoA signaling

AMSC-derived exosomes alleviate lipopolysaccharide/d-galactosamine-induced acute liver failure by miR-17-mediated reduction of TXNIP/NLRP3 inflammasome activation in macrophages

Time- and Race-Specific Haematological Reference Intervals for Healthy Volunteer Trials: A Retrospective Analysis of Pooled Data From Multiple Phase I Trials

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