Evaluation of Toll-like, chemokine, and integrin receptors on monocytes and neutrophils from peripheral blood of septic patients and their correlation with clinical outcomes

Silva, Selma Cristina da; Baggio-Zappia, Giovana Lotici; Brunialti, Milena Karina Coló; Assunção, Murilo; Azevedo, Luciano César Pontes; Machado, Flávia Ribeiro; Salomão, Reinaldo

doi:10.1590/1414-431x20143190

Cited by 14 publications

(17 citation statements)

References 41 publications

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“…Thus, these important membrane and cytosolic sensors of flagellin are up-regulated similar to NLRP3 and may contribute to the conversion of IL-1b and IL-18 into mature proteins and to pyroptosis. The increased TLR5 gene expression was supported by a previous work in which we found that TLR-5 detection on the cell surface was higher among septic patients than healthy volunteers [29]. Interestingly, pretreatment of monocytes from human volunteers with lipopolysaccharide (LPS)-induced tolerance to LPS and macrophage-activating lipopeptide-2 (MALP-2) (a TLR-2/6 agonist), but did not change the intracellular detection of IL-6 after challenge with flagellin.…”

Section: Discussionsupporting

confidence: 76%

Inflammasome gene profile is modulated in septic patients, with a greater magnitude in non-survivors

Esquerdo

Sharma

Brunialti

et al. 2017

Clinical and Experimental Immunology

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Inflammasome signalling induces the processing and secretion of interleukin (IL)-1β and IL-18 which, coupled with pyroptosis, activate further the inflammatory response. In the present study we evaluated the expression of genes involved in inflammasome signalling pathways in septic patients, their interaction networks and the predicted functions modulated in survivors and non-survivors. Twenty-seven patients with sepsis secondary to community-acquired pneumonia admitted to intensive care units from three general hospitals in São Paulo were included into the study. We performed a polymerase chain reaction (PCR) array encompassing 35 genes related to the nucleotide-binding oligomerization domain and leucine-rich repeat-containing (NLR)-inflammasome in peripheral blood mononuclear cells obtained at admission and after 7 days of follow-up. Eleven healthy volunteers were used as the reference group. Increased NLRC4 and NLRP3 and decreased nucleotide-binding oligomerization domain (NOD1), and NLRP1 expression was observed in septic patients compared to healthy individuals; the IL-1β and IL-18 expression levels were also high in the patients. The gene expression changes followed the same patterns in surviving and non-surviving patients, with higher magnitudes observed in non-survivors. Functional analyses revealed, however, that activation and inhibition intensity for representing functions were different in survivors and non-survivors, as for production of reactive oxygen species, synthesis of nitric oxide and for the control of bacterial infections. Our results showed that the genes involved in the activation of the NLR-inflammasome cascades were altered substantially in septic patients, with a higher number of altered genes and a higher intensity in the disturbance of gene expression found among patients dying of sepsis.

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Section: Discussionsupporting

confidence: 76%

Inflammasome gene profile is modulated in septic patients, with a greater magnitude in non-survivors

Esquerdo

Sharma

Brunialti

et al. 2017

Clinical and Experimental Immunology

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“…In mouse burn wound models of sepsis, the administration of flagellin can enhance the antibacterial activities of neutrophils and the delivery of antiflagellin antibodies can promote host survival ( 80 , 81 ). In both our zebrafish model and human patients with sepsis-like syndromes, the flagellin receptor TLR5 is among the most highly induced pattern recognition receptors ( 56 , 58 , 82 ). Allelic variants of TLR5 may predispose infants to sepsis, and high-level expression of TLR5 in septic individuals is positively linked with more severe disease ( 82 – 84 ).…”

Section: Discussionmentioning

confidence: 99%

“…In both our zebrafish model and human patients with sepsis-like syndromes, the flagellin receptor TLR5 is among the most highly induced pattern recognition receptors ( 56 , 58 , 82 ). Allelic variants of TLR5 may predispose infants to sepsis, and high-level expression of TLR5 in septic individuals is positively linked with more severe disease ( 82 – 84 ).…”

Section: Discussionmentioning

confidence: 99%

Similarly Lethal Strains of Extraintestinal Pathogenic Escherichia coli Trigger Markedly Diverse Host Responses in a Zebrafish Model of Sepsis

Barber

Fleming

Mulvey

2016

mSphere

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Sepsis is a life-threatening systemic inflammatory condition that is initiated by the presence of microorganisms in the bloodstream. In the United States, sepsis due to ExPEC and other pathogens kills well over a quarter of a million people each year and is associated with tremendous health care costs. A high degree of heterogeneity in the signs and symptomology of sepsis makes this disease notoriously difficult to effectively diagnose and manage. Here, using a zebrafish model of sepsis, we find that similarly lethal but genetically distinct ExPEC isolates can elicit notably disparate host responses. These variances are in part due to differences in the levels and types of flagellin that are expressed by the infecting ExPEC strains. A better understanding of the variable impact that bacterial factors like flagellin have on host responses during sepsis could lead to improved diagnostic and therapeutic approaches to these often deadly infections.

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“…This activity was likely associated with the ability of flagellin/entolimod to elicit early neutrophil mobilization (observed even in irradiated NHPs within 24 hours following entolimod treatment—see Fig 2C and 2D ; S1C and S1D Fig ) followed by neutrophil infiltration into tissues where they play an important role in local antibacterial responses [ 93 ]. Mobilization and tissue deposition of neutrophils (especially in the lung and the liver) can be explained by both entolimod-dependent induction of IL-8 [ 50 ] and by entolimod’s direct action on TLR5 expressed on the surface of neutrophils [ 97 , 98 ]. TLR5 activation also enhances the phagocytic capacity and the respiratory burst activity of airway neutrophils, which likely contributes to their antibacterial potency [ 99 ].…”

Section: Discussionmentioning

confidence: 99%

The Toll-Like Receptor 5 Agonist Entolimod Mitigates Lethal Acute Radiation Syndrome in Non-Human Primates

et al. 2015

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There are currently no approved medical radiation countermeasures (MRC) to reduce the lethality of high-dose total body ionizing irradiation expected in nuclear emergencies. An ideal MRC would be effective even when administered well after radiation exposure and would counteract the effects of irradiation on the hematopoietic system and gastrointestinal tract that contribute to its lethality. Entolimod is a Toll-like receptor 5 agonist with demonstrated radioprotective/mitigative activity in rodents and radioprotective activity in non-human primates. Here, we report data from several exploratory studies conducted in lethally irradiated non-human primates (rhesus macaques) treated with a single intramuscular injection of entolimod (in the absence of intensive individualized supportive care) administered in a mitigative regimen, 1–48 hours after irradiation. Following exposure to LD50-70/40 of radiation, injection of efficacious doses of entolimod administered as late as 25 hours thereafter reduced the risk of mortality 2-3-fold, providing a statistically significant (P<0.01) absolute survival advantage of 40–60% compared to vehicle treatment. Similar magnitude of survival improvement was also achieved with drug delivered 48 hours after irradiation. Improved survival was accompanied by predominantly significant (P<0.05) effects of entolimod administration on accelerated morphological recovery of hematopoietic and immune system organs, decreased severity and duration of thrombocytopenia, anemia and neutropenia, and increased clonogenic potential of the bone marrow compared to control irradiated animals. Entolimod treatment also led to reduced apoptosis and accelerated crypt regeneration in the gastrointestinal tract. Together, these data indicate that entolimod is a highly promising potential life-saving treatment for victims of radiation disasters.

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Evaluation of Toll-like, chemokine, and integrin receptors on monocytes and neutrophils from peripheral blood of septic patients and their correlation with clinical outcomes

Cited by 14 publications

References 41 publications

Inflammasome gene profile is modulated in septic patients, with a greater magnitude in non-survivors

Inflammasome gene profile is modulated in septic patients, with a greater magnitude in non-survivors

Similarly Lethal Strains of Extraintestinal Pathogenic Escherichia coli Trigger Markedly Diverse Host Responses in a Zebrafish Model of Sepsis

The Toll-Like Receptor 5 Agonist Entolimod Mitigates Lethal Acute Radiation Syndrome in Non-Human Primates

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