AKIRIN1: A Potential New Reference Gene in Human Natural Killer Cells and Granulocytes in Sepsis

Coulibaly, Anna; Velásquez, Sonia Y.; Sticht, Carsten; Figueiredo, Ana Sofia; Himmelhan, Bianca S; Schulte, Jutta; Sturm, Timo; Centner, Franz-Simon; Schöttler, Jochen J; Thiel, Manfred; Lindner, Holger A.

doi:10.3390/ijms20092290

Cited by 14 publications

(16 citation statements)

References 66 publications

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“…Previous studies consistently suggested that specific changes in neutrophil function occur in patients with sepsis; some of these are associated with poor clinical outcome [ 11 ]. A microarray analysis indicated the suppression of neutrophil immune and inflammatory function in patients with sepsis 24 h after admission [ 12 ]. Neutrophils may also have reduced antimicrobial function and impaired ability to inhibit adaptive immunity in vitro [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Immune effects of PI3K/Akt/HIF-1α-regulated glycolysis in polymorphonuclear neutrophils during sepsis

et al. 2022

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Background Effective removal of pathogenic bacteria is key to improving the prognosis of sepsis. Polymorphonuclear neutrophils (PMNs) are the most important components of innate cellular immunity and play vital roles in clearing pathogenic bacteria. However, the metabolic characteristics and immunomodulatory pathways of PMNs during sepsis have not been investigated. In the present study, we explored the immune metabolism characteristics of PMNs and the mechanism by which neutrophilic glycolysis is regulated during sepsis. Methods Metabolomics analysis was performed on PMNs isolated from 14 septic patients, 26 patients with acute appendicitis, and 19 healthy volunteers. Transcriptome analysis was performed on the PMNs isolated from the healthy volunteers and the patients with sepsis to assess glycolysis and investigate its mechanism. Lipopolysaccharide (LPS) was used to stimulate the neutrophils isolated from the healthy volunteers at different time intervals to build an LPS-tolerant model. Chemotaxis, phagocytosis, lactate production, oxygen consumption rate (OCR), and extracellular acidification rate (ECAR) were evaluated. Results Transcriptomics showed significant changes in glycolysis and the mTOR/HIF-1α signaling pathway during sepsis. Metabolomics revealed that the Warburg effect was significantly altered in the patients with sepsis. We discovered that glycolysis regulated PMNs’ chemotaxis and phagocytosis functions during sepsis. Lactate dehydrogenase A (LDHA) downregulation was a key factor in the inhibition of glycolysis in PMNs. This study confirmed that the PI3K/Akt-HIF-1α pathway was involved in the LDHA expression level and also influenced PMNs’ chemotaxis and phagocytosis functions. Conclusions The inhibition of glycolysis contributed to neutrophil immunosuppression during sepsis and might be controlled by PI3K/Akt-HIF-1α pathway-mediated LDHA downregulation. Our study provides a scientific theoretical basis for the management and treatment of patients with sepsis and promotes to identify therapeutic target for the improvement of immune function in sepsis.

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Section: Introductionmentioning

confidence: 99%

Immune effects of PI3K/Akt/HIF-1α-regulated glycolysis in polymorphonuclear neutrophils during sepsis

et al. 2022

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“…In whole blood, nongranulocytic cells may also contribute to elevated expression of granule signature genes such as PLAC8 expressing MS1 monocytes (13). A caveat consists of the higher SOFA scores in sepsis compared to controls on ICU admission in our (32) as well as other (56,57) cohorts. Severe organ dysfunction in sepsis can also induce granulopoiesis and thus alter gene expression in the whole blood.…”

Section: Discussionmentioning

confidence: 88%

“…Transcriptional analyses were based on two historical monocenter prospective cohorts of adults admitted to the interdisciplinary surgical ICU of a tertiary care hospital (University Medical Center Mannheim) with a recent diagnosis of SIRS or sepsis for discovery (2012–2014) ( 31 , 32 ) and validation (2016–2017) ( 32 ). Samples for flow cytometric determination of CD15 blood cell counts included samples from an extended recruitment period (2018–2020) of the validation cohort.…”

Section: Methodsmentioning

confidence: 99%

“…Samples for flow cytometric determination of CD15 blood cell counts included samples from an extended recruitment period (2018–2020) of the validation cohort. The criteria for inclusion and exclusion were detailed before ( 31 , 32 ). In addition to demographic and clinical characteristics on admission ( 32 ), data on clinical phenotypes close to the time of blood sampling were retrieved from the medical records ( Supplementary Text 1 ) and are summarized in Tables 1 , 2 .…”

Section: Methodsmentioning

confidence: 99%

“…The criteria for inclusion and exclusion were detailed before ( 31 , 32 ). In addition to demographic and clinical characteristics on admission ( 32 ), data on clinical phenotypes close to the time of blood sampling were retrieved from the medical records ( Supplementary Text 1 ) and are summarized in Tables 1 , 2 . Cells were selected from whole blood using CD15 MicroBeads (iltenyi Biotec, Bergisch Gladbach, Germany), preserving all stages of terminal granulocytic differentiation ( 32 ).…”

Section: Methodsmentioning

confidence: 99%

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Key Signature Genes of Early Terminal Granulocytic Differentiation Distinguish Sepsis From Systemic Inflammatory Response Syndrome on Intensive Care Unit Admission

et al. 2022

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Infection can induce granulopoiesis. This process potentially contributes to blood gene classifiers of sepsis in systemic inflammatory response syndrome (SIRS) patients. This study aimed to identify signature genes of blood granulocytes from patients with sepsis and SIRS on intensive care unit (ICU) admission. CD15+ cells encompassing all stages of terminal granulocytic differentiation were analyzed. CD15 transcriptomes from patients with sepsis and SIRS on ICU admission and presurgical controls (discovery cohort) were subjected to differential gene expression and pathway enrichment analyses. Differential gene expression was validated by bead array in independent sepsis and SIRS patients (validation cohort). Blood counts of granulocyte precursors were determined by flow cytometry in an extension of the validation cohort. Despite similar transcriptional CD15 responses in sepsis and SIRS, enrichment of canonical pathways known to decline at the metamyelocyte stage (mitochondrial, lysosome, cell cycle, and proteasome) was associated with sepsis but not SIRS. Twelve of 30 validated genes, from 100 selected for changes in response to sepsis rather than SIRS, were endo-lysosomal. Revisiting the discovery transcriptomes revealed an elevated expression of promyelocyte-restricted azurophilic granule genes in sepsis and myelocyte-restricted specific granule genes in sepsis followed by SIRS. Blood counts of promyelocytes and myelocytes were higher in sepsis than in SIRS. Sepsis-induced granulopoiesis and signature genes of early terminal granulocytic differentiation thus provide a rationale for classifiers of sepsis in patients with SIRS on ICU admission. Yet, the distinction of this process from noninfectious tissue injury-induced granulopoiesis remains to be investigated.

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Akirin proteins in development and disease: critical roles and mechanisms of action

Bösch

Peek

Smolikove

et al. 2020

Cell. Mol. Life Sci.

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The Akirin genes, which encode small, nuclear proteins, were first characterized in 2008 in Drosophila and rodents. Early studies demonstrated important roles in immune responses and tumorigenesis, which subsequent work found to be highly conserved. More recently, a multiplicity of Akirin functions, and the associated molecular mechanisms involved, have been uncovered. Here, we comprehensively review what is known about invertebrate Akirin and its two vertebrate homologues Akirin1 and Akirin2, highlighting their role in regulating gene expression changes across a number of biological systems. We detail essential roles for Akirin family proteins in the development of the brain, limb, and muscle, in meiosis, and in tumorigenesis, emphasizing associated signaling pathways. We describe data supporting the hypothesis that Akirins act as a "bridge" between a variety of transcription factors and major chromatin remodeling complexes, and discuss several important questions remaining to be addressed. In little more than a decade, Akirin proteins have gone from being completely unknown to being increasingly recognized as evolutionarily conserved mediators of gene expression programs essential for the formation and function of animals.Terms of use and reuse: academic research for non-commercial purposes, see here for full terms. https://www.springer.com/aamterms-v1

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AKIRIN1: A Potential New Reference Gene in Human Natural Killer Cells and Granulocytes in Sepsis

Cited by 14 publications

References 66 publications

Immune effects of PI3K/Akt/HIF-1α-regulated glycolysis in polymorphonuclear neutrophils during sepsis

Immune effects of PI3K/Akt/HIF-1α-regulated glycolysis in polymorphonuclear neutrophils during sepsis

Key Signature Genes of Early Terminal Granulocytic Differentiation Distinguish Sepsis From Systemic Inflammatory Response Syndrome on Intensive Care Unit Admission

Akirin proteins in development and disease: critical roles and mechanisms of action

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