scholarly journals NAD+ prevents septic shock by non-canonical inflammasome blockade and IL-10

2020 ◽  
Author(s):  
Jasper Iske ◽  
Rachid El Fatimy ◽  
Yeqi Nian ◽  
Siawosh K. Eskandari ◽  
Hector Rodriguez Cetina Biefer ◽  
...  
Keyword(s):  
Septic Shock ◽  
Signaling Pathway ◽  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Therapeutic Potential ◽  
Endotoxic Shock ◽  
Immune Homeostasis ◽  
Inflammasome Activation ◽  
Specific Inhibition ◽  
Inflammatory Cytokine Production

AbstractNon-canonical inflammasome activation is crucial in the development of septic shock promoting pyroptosis and pro-inflammatory cytokine production via caspase-11 and Gasdermin-D (GSDMD). Here, we show that NAD+ treatment protected mice towards bacterial and LPS induced endotoxic shock by blocking the non-canonical inflammasome specifically. NAD+ administration impeded systemic IL-1β and IL-18 production and GSDMD-mediated pyroptosis of macrophages via the IFN-β/STAT-1 signaling machinery. More importantly, NAD+ administration not only improved casp-11-/- survival but rendered WT mice completely resistant to septic shock via the IL-10 signaling pathway that was independent from the non-canonical inflammasome. Here, we delineated a two-sided effect of NAD+ blocking septic shock through a specific inhibition of the non-canonical inflammasome and promoting immune homeostasis via IL-10, underscoring its unique therapeutic potential.SummaryNAD+ protects against septic shock by blocking the non-canonical inflammasome specifically and via a systemic production of IL-10 cytokine

PAF and the inflammasome

2019 ◽  
Vol 12 (602) ◽  
pp. eaaz7370
Author(s):  
John F. Foley
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Inflammasome Activation ◽  
Inflammatory Cytokine Production ◽  
Nlrp3 Inflammasome Activation

The phospholipid PAF stimulates NLRP3 inflammasome activation and inflammatory cytokine production independently of its GPCR.

scholarly journals Trimetazidine protects retinal ganglion cells from acute glaucoma via the Nrf2/Ho-1 pathway

2017 ◽  
Vol 131 (18) ◽  
pp. 2363-2375 ◽  
Author(s):  
Peixing Wan ◽  
Wenru Su ◽  
Yingying Zhang ◽  
Zhidong Li ◽  
Caibin Deng ◽  
...  
Keyword(s):  
Inflammatory Cytokine ◽  
Molecular Mechanisms ◽  
Cytokine Production ◽  
Therapeutic Potential ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Retinal Ganglion ◽  
Inflammatory Cytokine Production ◽  
Acute Glaucoma

Acute glaucoma is one of the leading causes of irreversible vision impairment characterized by the rapid elevation of intraocular pressure (IOP) and consequent retinal ganglion cell (RGC) death. Oxidative stress and neuroinflammation have been considered critical for the pathogenesis of RGC death in acute glaucoma. Trimetazidine (TMZ), an anti-ischemic drug, possesses antioxidative and anti-inflammatory properties, contributing to its therapeutic potential in tissue damage. However, the role of TMZ in acute glaucoma and the underlying molecular mechanisms remain elusive. Here, we report that treatment with TMZ significantly attenuated retinal damage and RGC death in mice with acute glaucoma, with a significant decrease in reactive oxygen species (ROS) and inflammatory cytokine production in the retina. Furthermore, TMZ treatment directly decreased ROS production and rebalanced the intracellular redox state, thus contributing to the survival of RGCs in vitro. TMZ treatment also reduced the production of inflammatory cytokines in vitro. Mechanistically, the TMZ-mediated inhibition of apoptosis and inflammatory cytokine production in RGCs occurred via the regulation of the nuclear factor erythroid 2-related factor 2/heme oxygenase 1/caspase-8 pathway. Moreover, the TMZ-mediated neuroprotection in acute glaucoma was abrogated when an HO-1 inhibitor, SnPP, was used. Our findings identify potential mechanisms of RGC apoptosis and propose a novel therapeutic agent, TMZ, which exerts a precise neuroprotective effect against acute glaucoma.

scholarly journals Tobacco, but not nicotine and flavor-less electronic cigarettes, induces ACE2 and immune dysregulation

2020 ◽  
Author(s):  
Abby C. Lee ◽  
Jaideep Chakladar ◽  
Wei Tse Li ◽  
Chengyu Chen ◽  
Eric Y. Chang ◽  
...  
Keyword(s):  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Electronic Cigarettes ◽  
Immune Dysregulation ◽  
Cellular Receptor ◽  
Inflammasome Activation ◽  
Inflammatory Cytokine Production ◽  
Expression Of Genes ◽  
Key Genes ◽  
Cytokine Dysregulation

AbstractCOVID-19, caused by the virus SARS-CoV-2, has infected millions worldwide. This pandemic overlaps with the ongoing epidemics of cigarette smoking and electronic cigarette (e-cig) vaping, with over 1 billion smokers and vapers worldwide. However, there is scarce data relating COVID-19 risks and outcome with cigarette or e-cig use. In this study, we mined 3 independent RNA expression datasets from smokers and vapers to understand the potential relationship between vaping/smoking and the dysregulation of key genes and pathways related to COVID-19. We found that smoking, but not vaping, upregulates ACE2, the cellular receptor that SARS-CoV-2 requires for infection. Both smoking and use of nicotine and flavor-containing e-cig led to upregulations of pro-inflammatory cytokine production and expression of genes related to inflammasomes. Vaping flavor-less and nicotine-less e-cig, however, did not lead to significant cytokine dysregulation and inflammasome activation. Release of inflammasome products, such as IL-1B, and cytokine storms are hallmarks of COVID-19 infection, especially in severe cases. Therefore, our findings demonstrated that smoking or vaping, specifically use of flavored or nicotine-containing e-cigs, may critically exacerbate COVID-19-related inflammation or increase susceptibility to the disease. Further scientific and public health investigations should be undertaken to address these concerning links between COVID-19 and e-cig/smoking.

scholarly journals Myeloid-derived NF-κB negative regulation of PU.1 and c/EBP-β-driven pro-inflammatory cytokine production restrains LPS-induced shock

2016 ◽  
Vol 23 (2) ◽  
pp. 175-187 ◽  
Author(s):  
Simone Vanoni ◽  
Yi-Ting Tsai ◽  
Amanda Waddell ◽  
Lisa Waggoner ◽  
Jared Klarquist ◽  
...  
Keyword(s):  
Inflammatory Cytokine ◽  
Cell Activation ◽  
Cytokine Production ◽  
Endotoxic Shock ◽  
Elevated Serum ◽  
Experimental Studies ◽  
Negative Regulation ◽  
Dendritic Cell Activation ◽  
Inflammatory Cytokine Production ◽  
Lps Challenge

Sepsis is a life-threatening event predominantly caused by Gram-negative bacteria. Bacterial infection causes a pronounced macrophage (MΦ) and dendritic cell activation that leads to excessive pro-inflammatory cytokine IL-1β, IL-6 and TNF-α production (cytokine storm), resulting in endotoxic shock. Previous experimental studies have revealed that inhibiting NF-κB signaling ameliorates disease symptoms; however, the contribution of myeloid p65 in endotoxic shock remains elusive. In this study, we demonstrate increased mortality in mice lacking p65 in the myeloid lineage (p65Δmye) compared with wild type mice upon ultra-pure LPS challenge. We show that increased susceptibility to LPS-induced shock was associated with elevated serum level of IL-1β and IL-6. Mechanistic analyses revealed that LPS-induced pro-inflammatory cytokine production was ameliorated in p65-deficient bone marrow-derived MΦs; however, p65-deficient ‘activated’ peritoneal MΦs exhibited elevated IL-1β and IL-6. We show that the elevated pro-inflammatory cytokine secretion was due, in part, to increased accumulation of IL-1β mRNA and protein in activated inflammatory MΦs. The increased IL-1β was linked with heightened binding of PU.1 and CCAAT/enhancer binding protein-β to Il1b and Il6 promoters in activated inflammatory MΦs. Our data provide insight into a role for NF-κB in the negative regulation of pro-inflammatory cytokines in myeloid cells.

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