Dataset Information

Inflammatory and glycolytic programs underpin a primed blood neutrophil state in patients with pneumonia.

ABSTRACT: Neutrophils are potent immune cells with key antimicrobial functions. Previous in vitro work has shown that neutrophil effector functions are mainly fueled by intracellular glycolysis. Little is known about the state of neutrophils still in the circulation in patients during infection. Here, we combined flow cytometry, stimulation assays, transcriptomics, and metabolomics to investigate the link between inflammatory and metabolic pathways in blood neutrophils of patients with community-acquired pneumonia. Patients' neutrophils, relative to neutrophils from age- and sex- matched controls, showed increased degranulation upon ex vivo stimulation, and portrayed distinct upregulation of inflammatory transcriptional programs. This neutrophil phenotype was accompanied by a high-energy state with increased intracellular ATP content, and transcriptomic and metabolic upregulation of glycolysis and glycogenolysis. One month after hospital admission, these metabolic and transcriptomic changes were largely normalized. These data elucidate the molecular programs that underpin a balanced, yet primed state of blood neutrophils during pneumonia.

SUBMITTER: Schuurman AR

PROVIDER: S-EPMC10366455 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Inflammatory and glycolytic programs underpin a primed blood neutrophil state in patients with pneumonia.

Schuurman Alex R AR Butler Joe M JM Michels Erik H A EHA Otto Natasja A NA Brands Xanthe X Haak Bastiaan W BW Uhel Fabrice F Klarenbeek Augustijn M AM Faber Daniël R DR Schomakers Bauke V BV van Weeghel Michel M de Vos Alex F AF Scicluna Brendon P BP Houtkooper Riekelt H RH Wiersinga W Joost WJ van der Poll Tom T

iScience 20230619 7

Neutrophils are potent immune cells with key antimicrobial functions. Previous <i>in vitro</i> work has shown that neutrophil effector functions are mainly fueled by intracellular glycolysis. Little is known about the state of neutrophils still in the circulation in patients during infection. Here, we combined flow cytometry, stimulation assays, transcriptomics, and metabolomics to investigate the link between inflammatory and metabolic pathways in blood neutrophils of patients with community-ac ...[more]

PMID: 37496676

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Project description:Hirschsprung disease (HSCR) is a rare congenital anomaly characterized by the absence of enteric ganglia in the distal intestinal tract. While classified as a multigenic disorder, the altered function of the RET tyrosine kinase receptor is responsible for the majority of the pathogenesis of HSCR. Recent evidence demonstrate a strong association between RET and the homeostasis of immune system. Here, we utilize a unique cohort of fifty HSCR patients to fully characterize the expression of RET receptor on both innate (monocytes and Natural Killer lymphocytes) and adaptive (B and T lymphocytes) human peripheral blood mononuclear cells (PBMCs) and to explore the role of RET signaling in the immune system. We show that the increased expression of RET receptor on immune cell subsets from HSCR individuals correlates with the presence of loss-of-function RET mutations. Moreover, we demonstrate that the engagement of RET on PBMCs induces the modulation of several inflammatory genes. In particular, RET stimulation with glial-cell line derived neurotrophic factor family (GDNF) and glycosyl-phosphatidylinositol membrane anchored co-receptor ?1 (GFR?1) trigger the up-modulation of genes encoding either for chemokines (CCL20, CCL2, CCL3, CCL4, CCL7, CXCL1) and cytokines (IL-1?, IL-6 and IL-8) and the down-regulation of chemokine/cytokine receptors (CCR2 and IL8-R?). Although at different levels, the modulation of these "RET-dependent genes" occurs in both healthy donors and HSCR patients. We also describe another set of genes that, independently from RET stimulation, are differently regulated in healthy donors versus HSCR patients. Among these "RET-independent genes", there are CSF-1R, IL1-R1, IL1-R2 and TGF?-1, whose levels of transcripts were lower in HSCR patients compared to healthy donors, thus suggesting aberrancies of inflammatory responses at mucosal level. Overall our results demonstrate that immune system actively participates in the physiopathology of HSCR disease by modulating inflammatory programs that are either dependent or independent from RET signaling.

Dataset Information

Inflammatory and glycolytic programs underpin a primed blood neutrophil state in patients with pneumonia.

Publications

Inflammatory and glycolytic programs underpin a primed blood neutrophil state in patients with pneumonia.

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