Transcriptional Response in a Sepsis Mouse Model Reflects Transcriptional Response in Sepsis Patients

Rosier, Florian; Nuñez, Nicolas Fernandez; Torres, Magali; Loriod, Béatrice; Rihet, Pascal; Pradel, Lydie

doi:10.3390/ijms23020821

Cited by 11 publications

(10 citation statements)

References 47 publications

(85 reference statements)

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“…As recently described, LPS administration in these settings results in the upregulation of the serum levels of TNFα and IL-6 [ 19 ]. The corresponding mRNA levels of TNF, IL-1b and IL-6 in the liver, spleen and lung tissues were also found to be increased ( Figure S2 ), as previously shown [ 20 ]. Normal saline alone was administered to littermate mice; the survival and health status of mice were monitored every 4 h during the light period.…”

Section: Resultssupporting

confidence: 85%

Autotaxin Has a Negative Role in Systemic Inflammation

Nikitopoulou

Katsifa

Kanellopoulou

et al. 2022

IJMS

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The pathogenesis of sepsis involves complex interactions and a systemic inflammatory response leading eventually to multiorgan failure. Autotaxin (ATX, ENPP2) is a secreted glycoprotein largely responsible for the extracellular production of lysophosphatidic acid (LPA), which exerts multiple effects in almost all cell types through its at least six G-protein-coupled LPA receptors (LPARs). Here, we investigated a possible role of the ATX/LPA axis in sepsis in an animal model of endotoxemia as well as in septic patients. Mice with 50% reduced serum ATX levels showed improved survival upon lipopolysaccharide (LPS) stimulation compared to their littermate controls. Similarly, mice bearing the inducible inactivation of ATX and presenting with >70% decreased ATX levels were even more protected against LPS-induced endotoxemia; however, no significant effects were observed upon the chronic and systemic transgenic overexpression of ATX. Moreover, the genetic deletion of LPA receptors 1 and 2 did not significantly affect the severity of the modelled disease, suggesting that alternative receptors may mediate LPA effects upon sepsis. In translation, ATX levels were found to be elevated in the sera of critically ill patients with sepsis in comparison with their baseline levels upon ICU admission. Therefore, the results indicate a role for ATX in LPS-induced sepsis and suggest possible therapeutic benefits of pharmacologically targeting ATX in severe, systemic inflammatory disorders.

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Section: Resultssupporting

confidence: 85%

Autotaxin Has a Negative Role in Systemic Inflammation

Nikitopoulou

Katsifa

Kanellopoulou

et al. 2022

IJMS

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“…Plk3 has been connected to inflammatory cell function as Plk3 mRNA and protein expression is enhanced in human macrophages as they transition from peripheral monocytes to attached macrophages 12 . Similarly, Plk3 mRNA expression is quickly elevated in LPS-treated mouse peritoneal cells 13 . These data suggest that Plk3 expression is enhanced during infection or the early stages of sepsis in both mouse and human.…”

Section: Discussionmentioning

confidence: 94%

Plk3 Regulates Bacteremia and Supports Sepsis

Kostyak,

Sarojini,

Naik

et al. 2024

Preprint

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ObjectiveSepsis, which is the body’s response to overwhelming infection, can lead to septic shock, characterized by thrombocytopenia, hypotension, and organ damage. Polo-like kinase 3 (Plk3) is a ubiquitously expressed serine/threonine kinase, but its exact role in immune function is unknown.Approach and ResultsWe usedPlk3−/−and WT mice to evaluate the function of Plk3 in several models of severe sepsis. We found that WT mice die within 48 hours of 100% cecal ligation and puncture (CLP), whilePlk3−/−mice survive. Survival following cecal slurry (CS) injection mirrored that of CLP as recipient WT mice succumbed, while recipientPlk3−/−mice survived. Analysis of bacterial load 24 hours after CLP revealed that WT blood and peritonea were loaded with bacteria, but bacteria were virtually undetectable in the peritonea or blood ofPlk3−/−mice. To determine if bacteria infiltrate the blood ofPlk3−/−mice shortly after infection, we measured bacteria 1 and 3 hours after CS injection. We found a time-dependent increase in bacteria in the blood of WT mice that was not observed inPlk3−/−mice. To determine if the lack of bacteria in the blood ofPlk3−/−mice is due to enhanced clearance, we injectedE. coliIV into WT andPlk3−/−mice. We found 75% mortality for both WT andPlk3−/−mice within 72 hours following IV injection suggesting that survival ofPlk3−/−mice following enteric infection is likely due to reduced bacteremia.ConclusionCollectively our data suggest that Plk3 supports the systemic dissemination of bacteria and subsequent sepsis following enteric infection.

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“…Two studies of the effect of LPS stimulation in vivo in mice have recently also shown strong effects on both mRNA levels in inflammatory cytokines and chemokines and on protein levels in the serum of IL-6, TNF-α, IL-1β and IL-8 when using levels of LPS comparable or higher than what we use in vitro [ 26 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

The Human Monocyte—A Circulating Sensor of Infection and a Potent and Rapid Inducer of Inflammation

Lara

Akula

et al. 2022

IJMS

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Monocytes were previously thought to be the precursors of all tissue macrophages but have recently been found to represent a unique population of cells, distinct from the majority of tissue macrophages. Monocytes and intestinal macrophages seem now to be the only monocyte/macrophage populations that originate primarily from adult bone marrow. To obtain a better view of the biological function of monocytes and how they differ from tissue macrophages, we have performed a quantitative analysis of its transcriptome in vivo and after in vitro stimulation with E. coli LPS. The monocytes rapidly responded to LPS by producing extremely high amounts of mRNA for the classical inflammatory cytokines, IL-1α, IL-1β, IL-6 and TNF-α, but almost undetectable amounts of other cytokines. IL-6 was upregulated 58,000 times, from almost undetectable levels at baseline to become one of the major transcripts already after a few hours of cultivation. The cells also showed very strong upregulation of a number of chemokines, primarily IL-8, Ccl2, Ccl3, Ccl3L3, Ccl20, Cxcl2, Cxcl3 and Cxcl4. IL-8 became the most highly expressed transcript in the monocytes already after four hours of in vitro culture in the presence of LPS. A high baseline level of MHC class II chains and marked upregulation of super oxide dismutase (SOD2), complement factor B, complement factor C3 and coagulation factor 3 (F3; tissue factor) at four hours of in vitro culture were also observed. This indicates a rapid protective response to high production of oxygen radicals, to increase complement activation and possibly also be an inducer of local coagulation. Overall, these findings give strong support for monocytes acting primarily as potent mobile sensors of infection and rapid activators of a strong inflammatory response.

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Transcriptional Response in a Sepsis Mouse Model Reflects Transcriptional Response in Sepsis Patients

Cited by 11 publications

References 47 publications

Autotaxin Has a Negative Role in Systemic Inflammation

Autotaxin Has a Negative Role in Systemic Inflammation

Plk3 Regulates Bacteremia and Supports Sepsis

The Human Monocyte—A Circulating Sensor of Infection and a Potent and Rapid Inducer of Inflammation

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