scholarly journals Neutrophil Profiles of Pediatric COVID-19 and Multisystem Inflammatory Syndrome in Children

2021 ◽  
Author(s):  
Brittany Phatana Boribong ◽  
Thomas James LaSalle ◽  
Yannic C Bartsch ◽  
Felix Ellett ◽  
Maggie Elizabeth Loiselle ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Inflammatory Responses ◽  
Suppressor Cell ◽  
Neutrophil Activation ◽  
Neutrophil Extracellular Trap ◽  
Myeloid Derived Suppressor Cell ◽  
Altered Metabolism ◽  
Inflammatory Syndrome ◽  
Net Release

Multisystem Inflammatory Syndrome in Children (MIS-C) is a delayed-onset, COVID-19-related hyperinflammatory systemic illness characterized by SARS-CoV-2 antigenemia, cytokine storm and immune dysregulation; however, the role of the neutrophil has yet to be defined. In adults with severe COVID-19, neutrophil activation has been shown to be central to overactive inflammatory responses and complications. Thus, we sought to define neutrophil activation in children with MIS-C and acute COVID-19. We collected samples from 141 children: 31 cases of MIS-C, 43 cases of acute pediatric COVID-19, and 67 pediatric controls. We found that MIS-C neutrophils display a granulocytic myeloid-derived suppressor cell (G-MDSC) signature with highly altered metabolism, which is markedly different than the neutrophil interferon-stimulated gene (ISG) response observed in pediatric patients during acute SARS-CoV-2 infection. Moreover, we identified signatures of neutrophil activation and degranulation with high levels of spontaneous neutrophil extracellular trap (NET) formation in neutrophils isolated from fresh whole blood of MIS-C patients. Mechanistically, we determined that SARS-CoV-2 immune complexes are sufficient to trigger NETosis. Overall, our findings suggest that the hyperinflammatory presentation of MIS-C could be mechanistically linked to persistent SARS-CoV-2 antigenemia through uncontrolled neutrophil activation and NET release in the vasculature.

scholarly journals Potentiation of NETs release is novel characteristic of TREM-1 activation and the pharmacological inhibition of TREM-1 could prevent from the deleterious consequences of NETs release in sepsis

2021 ◽  
Author(s):  
Amir Boufenzer ◽  
Kevin Carrasco ◽  
Lucie Jolly ◽  
Benjamin Brustolin ◽  
Elisa Di-Pillo ◽  
...  
Keyword(s):  
Vascular Reactivity ◽  
Myeloid Cell ◽  
Neutrophil Extracellular Trap ◽  
Toll Like Receptor 4 ◽  
Genetic Ablation ◽  
Experimental Septic Shock ◽  
Net Release

AbstractDuring sepsis, neutrophil activation induces endothelial cell (EC) dysfunction partly through neutrophil extracellular trap (NET) release. The triggering receptor expressed on myeloid cell-1 (TREM-1) is an orphan immune receptor that amplifies the inflammatory response mediated by Toll-like receptor-4 (TLR4) engagement. Although the key role of TLR4 signaling in NETosis is known, the role of TREM-1 in this process has not yet been investigated. Here, we report that TREM-1 potentiates NET release by human and murine neutrophils and is a component of the NET structure. In contrast, pharmacologic inhibition or genetic ablation of TREM-1 decreased NETosis in vitro and during experimental septic shock in vivo. Moreover, isolated NETs were able to activate ECs and impair vascular reactivity, and these deleterious effects were dampened by TREM-1 inhibition. TREM-1 may, therefore, constitute a new therapeutic target to prevent NETosis and associated endothelial dysfunction.

scholarly journals Liver Damage in Pediatric Critically Ill COVID-19 Patients: Brazilian Case-Series

2020 ◽  
pp. 1-6
Author(s):  
Michele Luglio ◽  
Uenis Tannuri ◽  
Werther Brunow de Carvalho ◽  
Maria Fernanda Badue Pereira ◽  
Isadora Souza Rodrigues ◽  
...  
Keyword(s):  
Critical Care ◽  
Inflammatory Response ◽  
Critically Ill ◽  
Liver Damage ◽  
Pediatric Patients ◽  
Case Series ◽  
Critical Care Admission ◽  
Inflammatory Syndrome ◽  
Brazilian Case

Coronavirus disease 2019 (COVID-19) has become an important cause critical care admission worldwide. In the context of newly described multisystem inflammatory syndrome temporally related to SARS-CoV-2 (PIM-TS), the question of liver compromise came into evidence. Our group summarized a case series of 6 critically ill COVID-19 pediatric patients that presented some degree of liver damage, as demonstrated by liver and/or canalicular enzymes elevation, a yet not fully explored characteristic of the infection in the pediatric patient, that may indicate a more severe progression. Observations regarding the role of systemic inflammatory response can be taken from the described cases.

scholarly journals Hepatic acute-phase proteins control innate immune responses during infection by promoting myeloid-derived suppressor cell function

2010 ◽  
Vol 207 (7) ◽  
pp. 1453-1464 ◽  
Author(s):  
Leif E. Sander ◽  
Sara Dutton Sackett ◽  
Uta Dierssen ◽  
Naiara Beraza ◽  
Reinhold P. Linke ◽  
...  
Keyword(s):  
Acute Phase ◽  
Cell Function ◽  
Inflammatory Responses ◽  
Acute Phase Proteins ◽  
Suppressor Cells ◽  
Suppressor Cell ◽  
Amyloid A ◽  
Myeloid Derived Suppressor Cell ◽  
Infection And Inflammation ◽  
Deficient Mice

Acute-phase proteins (APPs) are an evolutionarily conserved family of proteins produced mainly in the liver in response to infection and inflammation. Despite vast pro- and antiinflammatory properties ascribed to individual APPs, their collective function during infections remains poorly defined. Using a mouse model of polymicrobial sepsis, we show that abrogation of APP production by hepatocyte-specific gp130 deletion, the signaling receptor shared by IL-6 family cytokines, strongly increased mortality despite normal bacterial clearance. Hepatic gp130 signaling through STAT3 was required to control systemic inflammation. Notably, hepatic gp130–STAT3 activation was also essential for mobilization and tissue accumulation of myeloid-derived suppressor cells (MDSCs), a cell population mainly known for antiinflammatory properties in cancer. MDSCs were critical to regulate innate inflammation, and their adoptive transfer efficiently protected gp130-deficient mice from sepsis-associated mortality. The hepatic APPs serum amyloid A and Cxcl1/KC cooperatively promoted MDSC mobilization, accumulation, and survival, and reversed dysregulated inflammation and restored survival of gp130-deficient mice. Thus, gp130-dependent communication between the liver and MDSCs through APPs controls inflammatory responses during infection.

scholarly journals Characteristics of immune and inflammatory responses among different age groups of pediatric patients with COVID-19 in China

2021 ◽  
Author(s):  
Su-Qiong Ji ◽  
Min Zhang ◽  
Yong Zhang ◽  
Kun Xia ◽  
Yuan Chen ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Inflammatory Responses ◽  
Clinical Stage ◽  
Age Groups ◽  
Stage Disease ◽  
Long Course ◽  
Cell Proportion ◽  
Lower Production ◽  
Necrosis Factor

Abstract Background Severe cases of coronavirus disease 2019 (COVID-19) among pediatric patients are more common in children less than 1 year of age. Our aim is to address the underlying role of immunity and inflammation conditions among different age groups of pediatric patients. Methods We recruited pediatric patients confirmed of moderate COVID-19 symptoms, admitted to Wuhan Children's Hospital from January 28th to April 1st in 2020. Patients were divided into four age groups (≤ 1, 1–6, 7–10, and 11–15 years). Demographic information, clinical characteristics, laboratory results of lymphocyte subsets test, immune and inflammation related markers were all evaluated. Results Analysis included 217/241 (90.0%) of patients with moderate clinical stage disease. Average recovery time of children more than 6 years old was significantly shorter than of children younger than 6 years (P = 0.001). Reduced neutrophils and increased lymphocytes were significantly most observed among patients under 1 year old (P < 0.01). CD19+ B cells were the only significantly elevated immune cells, especially among patients under 1 year old (cell proportion: n = 12, 30.0%, P < 0.001; cell count: n = 13, 32.5%, P < 0.001). While, low levels of immune related makers, such as immunoglobulin (Ig) G (P < 0.001), IgA (P < 0.001), IgM (P < 0.001) and serum complement C3c (P < 0.001), were also mostly found among patients under 1 year old, together with elevated levels of inflammation related markers, such as tumor necrosis factor γ (P = 0.007), interleukin (IL)-10 (P = 0.011), IL-6 (P = 0.008), lactate dehydrogenase (P < 0.001), and procalcitonin (P = 0.007). Conclusion The higher rate of severe cases and long course of COVID-19 among children under 1 year old may be due to the lower production of antibodies and serum complements of in this age group.

P6396LDL cholesterol promotes neutrophil extracellular trap formation

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A S Ondracek ◽  
T M Hofbauer ◽  
P P Wadowski ◽  
A Mangold ◽  
T Gremmel ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Troponin T ◽  
Ex Vivo ◽  
Plasma Concentrations ◽  
Density Lipoprotein ◽  
Neutrophil Activation ◽  
Neutrophil Extracellular Trap ◽  
Dependent Manner ◽  
Activated Neutrophils

Abstract Background Pro-protein convertase subtilisin/kexin 9 (PCSK9) is a regulator of low density lipoprotein (LDL) receptor (LDLR) expression and has gained attention in the treatment of hyperlipidemia. Serum levels of LDL are correlated with numbers of activated neutrophils in the circulation of hyperlipidemic patients. Activated neutrophils can form neutrophil extracellular traps (NETs) by expelling their chromatin, and NETs have been recognized as important risk factors for acute myocardial infarction (AMI) and stroke. Purpose We analyzed the influence of serum LDL levels on neutrophil activation, their propensity to form NETs, and the correlation of NET surrogate markers with systemic inflammatory responses in AMI. Methods We recruited 249 consecutive patients with AMI (mean age 58 years, 20% females) and assessed laboratory parameters, inflammatory markers, and serum lipid profiles 72 h after primary percutaneous coronary intervention. Double-stranded DNA (dsDNA) and citrullinated histone H3 were determined from plasma as markers of in vivo NET formation. In a subset of patients (n=25), ex vivo NET formation in response to PCSK9 and ionomycin was analyzed, neutrophils were stained for CD11b, LDLR, and lectin-like oxidized LDLR (LOX-1) using flow cytometry at baseline and after activation with phorbol myristate acetate. PCSK9 levels were measured by ELISA. Results Patients with serum LDL levels above the median [median (IQR) LDL 111 mg/dl (87–141), mean ± SD LDL 115±41 mg/dl] had significantly higher concentrations of circulating dsDNA. Levels of dsDNA [median 121 ng/ml, IQR 101–156] were linked with levels of the specific NET marker citH3 [median (IQR) 252 ng/ml (655–1600), rs=0.157]. Plasma concentrations of dsDNA and citH3 correlated significantly with CRP (dsDNA rs=0.328; citH3 rs=0.209), proBNP (dsDNA rs=0.286; citH3 rs=0.192), troponin T (dsDNA rs=0.282; citH3 rs=0.197), and IL-6 (dsDNA rs=0.242; citH3 rs=0.216). In the subset of patients in whom neutrophils were characterized, pre-treatment of neutrophils with PCSK9 could significantly decrease ionomycin induced NET release in a dose-dependent manner. Levels of serum LDL were associated with spontaneous NET formation (r=0.504) ex vivo and activated CD11b on neutrophils (r=0.495). LOX-1 expression correlated significantly with LDLR expression (rs=0.670) and PCSK9 levels (r=0.520). Patient neutrophil stimulation in whole blood led to a significant decrease of the LDLR positive neutrophil population. This effect was greater when PCSK9 levels were higher. Conclusion Our data indicate a role for LDL in boosting neutrophil activation depending on PCSK9.

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