scholarly journals Susceptibility rhythm to bacterial endotoxin in myeloid clock-knockout mice

2019 ◽  
Author(s):  
Veronika Lang ◽  
Sebastian Ferencik ◽  
Bharath Ananthasubramaniam ◽  
Achim Kramer ◽  
Bert Maier
Keyword(s):  
Knockout Mice ◽  
Endotoxic Shock ◽  
Time Of Day ◽  
Conditional Knockout ◽  
Constant Darkness ◽  
Cell Trafficking ◽  
Immune Functions ◽  
Lps Challenge ◽  
Circadian Time ◽  
Circadian Physiology

AbstractLocal circadian clocks are active in most cells of our body. However, their impact on circadian physiology is still under debate. Mortality by endotoxic (LPS) shock is highly time-of-day dependent and local circadian immune function such as the cytokine burst after LPS challenge has been assumed to be causal for the large differences in survival. Here, we investigate the roles of light and myeloid clocks on mortality by endotoxic shock. Strikingly, mice in constant darkness (DD) show a three-fold increased susceptibility to LPS as compared to mice in light-dark conditions. Mortality by endotoxic shock as a function of circadian time is independent of light-dark cycles as well as myeloid CLOCK or BMAL1 as demonstrated in conditional knockout mice. Unexpectedly, despite the lack of a myeloid clock these mice still show rhythmic patterns of pro- and anti-inflammatory cytokines such as TNFα, MCP-1, IL-18 and IL-10 in peripheral blood as well as time-of-day and site dependent traffic of myeloid cells. We speculate that systemic time-cues are sufficient to orchestrate innate immune response to LPS by driving immune functions such as cell trafficking and cytokine expression.

scholarly journals Susceptibility rhythm to bacterial endotoxin in myeloid clock-knockout mice

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Veronika Lang ◽  
Sebastian Ferencik ◽  
Bharath Ananthasubramaniam ◽  
Achim Kramer ◽  
Bert Maier
Keyword(s):  
Knockout Mice ◽  
Endotoxic Shock ◽  
Time Of Day ◽  
Conditional Knockout ◽  
Constant Darkness ◽  
Immune Functions ◽  
Lps Challenge ◽  
Circadian Time ◽  
Tnf Α ◽  
Circadian Physiology

Local circadian clocks are active in most cells of our body. However, their impact on circadian physiology is still under debate. Mortality by endotoxic (LPS) shock is highly time-of-day dependent and local circadian immune function such as the cytokine burst after LPS challenge has been assumed to be causal for the large differences in survival. Here, we investigate the roles of light and myeloid clocks on mortality by endotoxic shock. Strikingly, mice in constant darkness (DD) show a three-fold increased susceptibility to LPS as compared to mice in light-dark conditions. Mortality by endotoxic shock as a function of circadian time is independent of light-dark cycles as well as myeloid CLOCK or BMAL1 as demonstrated in conditional knockout mice. Unexpectedly, despite the lack of a myeloid clock these mice still show rhythmic patterns of pro- and anti-inflammatory cytokines such as TNF,α MCP-1, IL-18 and IL-10 in peripheral blood as well as time-of-day and site dependent traffc of myeloid cells. We speculate that systemic time-cues are sufficient to orchestrate innate immune response to LPS by driving immune functions such as cell traffcking and cytokine expression.

scholarly journals A conserved long noncoding RNA, GAPLINC, modulates the immune response during endotoxic shock

2021 ◽  
Vol 118 (7) ◽  
pp. e2016648118
Author(s):  
Apple Cortez Vollmers ◽  
Sergio Covarrubias ◽  
Daisy Kuang ◽  
Aaron Shulkin ◽  
Justin Iwuagwu ◽  
...  
Keyword(s):  
Immune Response ◽  
Knockout Mice ◽  
Noncoding Rna ◽  
Target Genes ◽  
Blood Clot ◽  
Multiorgan Failure ◽  
Endotoxic Shock ◽  
Negative Regulator ◽  
Inflammatory Genes ◽  
Lps Challenge

Recent studies have identified thousands of long noncoding RNAs (lncRNAs) in mammalian genomes that regulate gene expression in different biological processes. Although lncRNAs have been identified in a variety of immune cells and implicated in immune response, the biological function and mechanism of the majority remain unexplored, especially in sepsis. Here, we identify a role for a lncRNA—gastric adenocarcinoma predictive long intergenic noncoding RNA (GAPLINC)—previously characterized for its role in cancer, now in the context of innate immunity, macrophages, and LPS-induced endotoxic shock. Transcriptome analysis of macrophages from humans and mice reveals that GAPLINC is a conserved lncRNA that is highly expressed following macrophage differentiation. Upon inflammatory activation, GAPLINC is rapidly down-regulated. Macrophages depleted of GAPLINC display enhanced expression of inflammatory genes at baseline, while overexpression of GAPLINC suppresses this response. Consistent with GAPLINC-depleted cells, Gaplinc knockout mice display enhanced basal levels of inflammatory genes and show resistance to LPS-induced endotoxic shock. Mechanistically, survival is linked to increased levels of nuclear NF-κB in Gaplinc knockout mice that drives basal expression of target genes typically only activated following inflammatory stimulation. We show that this activation of immune response genes prior to LPS challenge leads to decreased blood clot formation, which protects Gaplinc knockout mice from multiorgan failure and death. Together, our results identify a previously unknown function for GAPLINC as a negative regulator of inflammation and uncover a key role for this lncRNA in modulating endotoxic shock.

Pleiotropic functions of TNF-α determine distinct IKKβ-dependent hepatocellular fates in response to LPS

2007 ◽  
Vol 292 (1) ◽  
pp. G242-G252 ◽  
Author(s):  
Rana Dajani ◽  
Salih Sanlioglu ◽  
Yulong Zhang ◽  
Qiang Li ◽  
Martha M. Monick ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Viral Vectors ◽  
Endotoxic Shock ◽  
Lethal Dose ◽  
Dominant Negative ◽  
Endotoxin Challenge ◽  
Lps Challenge ◽  
Differential Outcomes ◽  
Tnf Α ◽  
Pleiotropic Functions

TNF-α influences morbidity and mortality during the course of endotoxemia. However, the complex pleiotropic functions of TNF-α remain poorly understood. We evaluated how hepatic induction of NF-κB and TNF-α influence survival and hepatocellular death in a lethal murine model of endotoxic shock. Using dominant-negative viral vectors to inhibit the IKK complex, we demonstrate through this study that the liver is a major source of TNF-α during the course of lethal endotoxemia and that IKKβ (but not IKKα) is predominantly responsible for activating NF-κB and TNF-α in the liver after LPS administration. Using TNF-α knockout mice and hepatic-specific inhibition of IKKβ, we demonstrate that the status of TNF-α and NF-κB balances necrotic and apoptotic fates of hepatocytes in the setting of endotoxemia. In the presence of TNF-α, inhibiting hepatic IKKβ resulted in increased survival, reduced serum proinflammatory cytokines, and reduced hepatocyte necrosis in response to a lethal dose of endotoxin. In contrast, inhibiting hepatic IKKβ in TNF-α knockout mice resulted in decreased survival and increased caspase 3-mediated hepatocyte apoptosis after endotoxin challenge, despite a reduced proinflammatory cytokine response. In the presence of TNF-α, NF-κB-dependent hepatocellular necrosis predominated, while in the absence of TNF-α, NF-κB primarily influenced apoptotic fate of hepatocytes. Changes in JNK phosphorylation after LPS challenge were also dynamically affected by both IKKβ and TNF-α; however, this pathway could not solely explain the differential outcomes in hepatocellular fates. In conclusion, our studies demonstrate that induction of NF-κB and TNF-α balances protective (antiapoptotic) and detrimental (proinflammatory) pathways to determine hepatocellular fates during endotoxemia.

Ankyrin-G heterozygous conditional knockout mice display increased sensitivity to social defeat stress

2021 ◽  
Author(s):  
Zachary A. Cordner ◽  
Seva G. Khambadkone ◽  
Shanshan Zhu ◽  
Justin Bai ◽  
Rasadokht Forati ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Social Defeat ◽  
Conditional Knockout ◽  
Social Defeat Stress ◽  
Conditional Knockout Mice ◽  
Ankyrin G ◽  
Increased Sensitivity

Reduced hippocampal ten-eleven translocation 3 (Tet3) protein expression in Tet3 conditional knockout mice

2021 ◽  
Vol 26 (5) ◽  
pp. 1425-1425
Author(s):  
Cláudia Antunes ◽  
Jorge D. Da Silva ◽  
Sónia Guerra-Gomes ◽  
Nuno D. Alves ◽  
Fábio Ferreira ◽  
...  
Keyword(s):  
Protein Expression ◽  
Knockout Mice ◽  
Conditional Knockout ◽  
Conditional Knockout Mice

scholarly journals Sirt1 deacetylates and stabilizes p62 to promote hepato-carcinogenesis

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Lifeng Feng ◽  
Miaoqin Chen ◽  
Yiling Li ◽  
Muchun Li ◽  
Shiman Hu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Overall Survival ◽  
Cell Growth ◽  
Knockout Mice ◽  
Liver Tumors ◽  
Underlying Mechanism ◽  
Carcinoma Cells ◽  
Conditional Knockout

Abstractp62/SQSTM1 is frequently up-regulated in many cancers including hepatocellular carcinoma. Highly expressed p62 promotes hepato-carcinogenesis by activating many signaling pathways including Nrf2, mTORC1, and NFκB signaling. However, the underlying mechanism for p62 up-regulation in hepatocellular carcinoma remains largely unclear. Herein, we confirmed that p62 was up-regulated in hepatocellular carcinoma and its higher expression was associated with shorter overall survival in patients. The knockdown of p62 in hepatocellular carcinoma cells decreased cell growth in vitro and in vivo. Intriguingly, p62 protein stability could be reduced by its acetylation at lysine 295, which was regulated by deacetylase Sirt1 and acetyltransferase GCN5. Acetylated p62 increased its association with the E3 ligase Keap1, which facilitated its poly-ubiquitination-dependent proteasomal degradation. Moreover, Sirt1 was up-regulated to deacetylate and stabilize p62 in hepatocellular carcinoma. Additionally, Hepatocyte Sirt1 conditional knockout mice developed much fewer liver tumors after Diethynitrosamine treatment, which could be reversed by the re-introduction of exogenous p62. Taken together, Sirt1 deacetylates p62 at lysine 295 to disturb Keap1-mediated p62 poly-ubiquitination, thus up-regulating p62 expression to promote hepato-carcinogenesis. Therefore, targeting Sirt1 or p62 is a reasonable strategy for the treatment of hepatocellular carcinoma.

scholarly journals Ultrastructural pathological changes in the cochlear cells of connexin 26 conditional knockout mice

2013 ◽  
Vol 8 (4) ◽  
pp. 1029-1036 ◽  
Author(s):  
LAN LIN ◽  
YUN-FENG WANG ◽  
SHU-YI WANG ◽  
SHAO-FENG LIU ◽  
ZHANG YU ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Conditional Knockout ◽  
Connexin 26 ◽  
Pathological Changes ◽  
Conditional Knockout Mice

Effect of somatostatin on circadian rhythms of firing and 2-deoxyglucose uptake in rat suprachiasmatic slices

1993 ◽  
Vol 265 (5) ◽  
pp. R1199-R1204 ◽  
Author(s):  
T. Hamada ◽  
S. Shibata ◽  
A. Tsuneyoshi ◽  
K. Tominaga ◽  
S. Watanabe
Keyword(s):  
Circadian Rhythm ◽  
Vasoactive Intestinal Polypeptide ◽  
Phase Changes ◽  
Circadian Clocks ◽  
Constant Darkness ◽  
Phase Resetting ◽  
Firing Activity ◽  
Light Pulses ◽  
Circadian Time

In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus appears to act as a circadian clock. The SCN vasoactive intestinal polypeptide-like immunoreactive neurons, which may act to mediate photic information in the SCN, receive input from neurons immunoreactive for somatostatin (SST). Therefore we investigated the role of SST as a transmitter for entrainment by analyzing the phase-resetting effect of SST on the circadian rhythm of SCN firing activity. Perfusion of SST increased 2-deoxyglucose uptake at circadian time (CT) 18, but not at CT6. A 1-h or 15-min treatment with SST produced phase delays when it was administered at CT13-14 and phase advances at CT22-23. Thus SST-induced phase changes are similar to those for light pulses to animals under constant darkness. The present findings suggest that SST is a transmitter for mediating information of entrainment to circadian clocks within the SCN.

Sign in / Sign up

Export Citation Format

Share Document