Immunosuppression Affects Neutrophil Functions: Does Calcineurin-NFAT Signaling Matter?

Vymazal, Ondřej; Bendíčková, Kamila; Zuani, Marco De; Vlková, Marcela; Hortová-Kohoutková, Marcela; Frič, Jan

doi:10.3389/fimmu.2021.770515

Cited by 8 publications

(2 citation statements)

References 105 publications

(142 reference statements)

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“…In addition, we have shown that the calcineurin phosphatase (CN)/NFAT transcription factor signaling pathway, a key player in neutrophil activation during the immune responses ( 26 ), is also activated in an IgE-dependent manner ( 27 ).…”

Section: Resultsmentioning

confidence: 99%

Regulation and directed inhibition of ECP production by human neutrophils

et al. 2022

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BackgroundNeutrophils are involved in the pathophysiology of allergic asthma, where the Eosinophil Cationic Protein (ECP) is a critical inflammatory mediator. Although ECP production is attributed to eosinophils, we reported that ECP is also present in neutrophils from allergic patients where, in contrast to eosinophils, it is produced in an IgE-dependent manner. Given the key role of ECP in asthma, we investigated the molecular mechanisms involved in ECP production as well as the effects induced by agonists and widely used clinical approaches. We also analyzed the correlation between ECP production and lung function.MethodsNeutrophils from allergic asthmatic patients were challenged with allergens, alone or in combination with cytokines, in the presence of cell-signaling inhibitors and clinical drugs. We analyzed ECP levels by ELISA and confocal microscopy. Lung function was assessed by spirometry.ResultsIgE-mediated ECP release is dependent on phosphoinositide 3-kinase, the extracellular signal-regulated kinase (ERK1/2) and the production of reactive oxygen species by NADPH-oxidase. Calcineurin phosphatase and the transcription factor NFAT are also involved. ECP release is enhanced by the cytokines interleukin (IL)-5 and granulocyte macrophage-colony stimulating factor, and inhibited by interferon-γ, IL-10, clinical drugs (formoterol, tiotropium and budesonide) and allergen-specific IT. We also found an inverse correlation between asthma severity and ECP levels.ConclusionsOur results suggest the molecular pathways involved in ECP production and potential therapeutic targets. We also provide a new method to evaluate disease severity in asthmatic patients based on the quantification of in vitro ECP production by peripheral neutrophils.

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Section: Resultsmentioning

confidence: 99%

Regulation and directed inhibition of ECP production by human neutrophils

et al. 2022

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“…Steroids, commonly used to treat autoimmune diseases, signi cantly affect neutrophil recruitment from the bone marrow 14 . In addition, immunosuppressive drugs often reduce the number and function of peripheral neutrophils 15 . Therefore, it is essential to analyze patient samples prior to therapeutic intervention to accurately capture neutrophil behavior.…”

Section: Introductionmentioning

confidence: 99%

Neutrophil single-cell analysis identifies a uniquely primed subset and provides insights into predicting relapse of autoimmune small vessel vasculitis

Nishide,

Nishimura,

Matsushita

et al. 2024

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Single cell analysis in autoimmune disease has largely focused on mononuclear cells and diseased tissues, leaving the diversity of neutrophils poorly understood. To identify the dynamics of neutrophil autoimmunity, we focus on an autoimmune disease characterized by abnormal neutrophil activation, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Single-cell transcriptome and surface proteome analyses are performed on 179,664 peripheral white blood cells from treatment-naïve patients with new-onset microscopic polyangiitis (MPA) and healthy donors. Neutrophils are classified into seven subsets, two of which are significantly increased in MPA patients: immature neutrophils (Neu_Immature) and neutrophils characterized by type II interferon signature genes (Neu_T2ISG). The Neu_T2ISG subset shows increased expression of interferon (IFN)-γ response genes, many of which are identified as differentially expressed genes in neutrophils from MPA patients compared to those from healthy donors. Trajectory and cell–cell interaction analyses identify Neu_T2ISG as a uniquely primed subset that differentiates from mature neutrophils upon stimulation with IFN-γ and tumor necrosis factor (TNF)-α. The combined effect of these cytokines simultaneously exposes myeloperoxidase and Fcγ receptors on the neutrophil cell surface and promotes ANCA–induced neutrophil extracellular trap formation. Case-by-case analysis indicates that patients with a high proportion of the Neu_T2ISG subset are associated with persistent vasculitis symptoms. In a larger cohort using stored sera, serum IFN-γ levels at disease onset significantly correlate with susceptibility to disease relapse. Our findings identify neutrophil diversity at the single cell level and bridge the data to a clinically applicable biomarker for predicting relapse in small vessel vasculitis.

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