Physiological Stimuli Induce PAD4-Dependent, ROS-Independent NETosis, With Early and Late Events Controlled by Discrete Signaling Pathways.

Abstract:

:Neutrophils are known to extrude decondensed chromatin, thus forming NETs (neutrophil extracellular traps). These structures immobilize pathogens, thereby preventing their spreading, and are also adorned with antimicrobial molecules. NETs can also influence pathogenesis in chronic inflammation, autoimmunity, and cancer. Despite the importance of NETs, the molecular mechanisms underlying their formation, as well as the upstream signaling pathways involved, are only partially understood. Likewise, current methodological approaches to quantify NETs suffer from significant drawbacks, not the least being the inclusion of a significant non-specific signal. In this study, we used novel, fluorescent polymers that only bind extruded chromatin, allowing a specific and standardized quantification of NETosis. This allowed us to reliably rank the relative potency of various physiologic NET inducers. In neutrophils activated with such stimuli, inhibition of the Syk or PI3K pathways blocked NETosis by acting upon late events in NET formation. Inhibition of the TAK1, p38 MAPK, or MEK pathways also hindered NETosis, but by acting on early events. By contrast, inhibiting PKC, Src family kinases, or JNK failed to prevent NETosis; cycloheximide or actinomycin D were also ineffective. Expectedly, NET formation was deeply compromised following inhibition of the NADPH oxidase in PMA-activated neutrophils, but was found to be ROS-independent in response to physiological agonists. Conversely, we show for the first time in human neutrophils that selective inhibition of PAD4 potently prevents NETosis by all stimuli tested. Our data substantially extends current knowledge of the signaling pathways controlling NETosis, and reveals how they affect early or late stages of the phenomenon. In view of the involvement of NETs in several pathologies, our findings also identify molecular targets that could be exploited for therapeutic intervention.

journal_name

Front Immunol

journal_title

Frontiers in immunology

authors

Tatsiy O,McDonald PP

doi

10.3389/fimmu.2018.02036

subject

Has Abstract

pub_date

2018-09-18 00:00:00

pages

2036

issn

1664-3224

journal_volume

9

pub_type

杂志文章
  • Follicular Helper T Cells in DiGeorge Syndrome.

    abstract::DiGeorge syndrome is an immunodeficiency characterized by thymic dysplasia resulting in T cell lymphopenia. Most patients suffer from increased susceptibility to infections and heightened prevalence of autoimmune disorders, such as autoimmune thrombocytopenia. B cells in DiGeorge syndrome show impaired maturation, wit...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2018.01730

    authors: Klocperk A,Paračková Z,Bloomfield M,Rataj M,Pokorný J,Unger S,Warnatz K,Šedivá A

    更新日期:2018-07-23 00:00:00

  • Tuftsin Combines With Remyelinating Therapy and Improves Outcomes in Models of CNS Demyelinating Disease.

    abstract::Though promoting remyelination in multiple sclerosis (MS) has emerged as a promising therapeutic strategy, it does not address inflammatory signals that continue to induce neuronal damage and inhibit effectiveness of repair mechanisms. Our lab has previously characterized the immunomodulatory tetrapeptide, tuftsin, wh...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2018.02784

    authors: Thompson KK,Nissen JC,Pretory A,Tsirka SE

    更新日期:2018-11-28 00:00:00

  • Activation of the Immune-Metabolic Receptor GPR84 Enhances Inflammation and Phagocytosis in Macrophages.

    abstract::GPR84 is a member of the metabolic G protein-coupled receptor family, and its expression has been described predominantly in immune cells. GPR84 activation is involved in the inflammatory response, but the mechanisms by which it modulates inflammation have been incompletely described. In this study, we investigated GP...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2018.01419

    authors: Recio C,Lucy D,Purvis GSD,Iveson P,Zeboudj L,Iqbal AJ,Lin D,O'Callaghan C,Davison L,Griesbach E,Russell AJ,Wynne GM,Dib L,Monaco C,Greaves DR

    更新日期:2018-06-20 00:00:00

  • CAR T Cells Targeting the Tumor MUC1 Glycoprotein Reduce Triple-Negative Breast Cancer Growth.

    abstract::Antibody-derived chimeric antigen receptor (CAR) T cell therapy has achieved gratifying breakthrough in hematologic malignancies but has shown limited success in solid tumor immunotherapy. Monoclonal antibody, TAB004, specifically recognizes the aberrantly glycosylated tumor form of MUC1 (tMUC1) in all subtypes of bre...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2019.01149

    authors: Zhou R,Yazdanifar M,Roy LD,Whilding LM,Gavrill A,Maher J,Mukherjee P

    更新日期:2019-05-24 00:00:00

  • The Role of Complement Activating Collectins and Associated Serine Proteases in Patients With Hematological Malignancies, Receiving High-Dose Chemotherapy, and Autologous Hematopoietic Stem Cell Transplantations (Auto-HSCT).

    abstract::We conducted a prospective study of 312 patients (194 with multiple myeloma, 118 with lymphomas) receiving high-dose conditioning chemotherapy and autologous hematopoietic stem cell transplantation (auto-HSCT). Polymorphisms of MBL2 and MASP2 genes were investigated and serial measurements of serum concentrations of m...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2018.02153

    authors: Świerzko AS,Michalski M,Sokołowska A,Nowicki M,Eppa Ł,Szala-Poździej A,Mitrus I,Szmigielska-Kapłon A,Sobczyk-Kruszelnicka M,Michalak K,Gołos A,Wierzbowska A,Giebel S,Jamroziak K,Kowalski ML,Brzezińska O,Thiel S,Jenseniu

    更新日期:2018-09-20 00:00:00

  • A Novel Synthetic Dual Agonistic Liposomal TLR4/7 Adjuvant Promotes Broad Immune Responses in an Influenza Vaccine With Minimal Reactogenicity.

    abstract::The limited efficacy of seasonal influenza vaccines is usually attributed to ongoing variation in the major antigenic targets for protective antibody responses including hemagglutinin (HA) and neuraminidase (NA). Hence, vaccine development has largely focused on broadening antigenic epitopes to generate cross-reactive...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2020.01207

    authors: Sato-Kaneko F,Yao S,Lao FS,Shpigelman J,Messer K,Pu M,Shukla NM,Cottam HB,Chan M,Chu PJ,Burkhart D,Schoener R,Matsutani T,Carson DA,Corr M,Hayashi T

    更新日期:2020-06-19 00:00:00

  • Betaine Inhibits Interleukin-1β Production and Release: Potential Mechanisms.

    abstract::Betaine is a critical nutrient for mammal health, and has been found to alleviate inflammation by lowering interleukin (IL)-1β secretion; however, the underlying mechanisms by which betaine inhibits IL-1β secretion remain to be uncovered. In this review, we summarize the current understanding about the mechanisms of b...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审

    doi:10.3389/fimmu.2018.02670

    authors: Xia Y,Chen S,Zhu G,Huang R,Yin Y,Ren W

    更新日期:2018-11-20 00:00:00

  • Corticosterone Preexposure Increases NF-κB Translocation and Sensitizes IL-1β Responses in BV2 Microglia-Like Cells.

    abstract::Corticosterone (CORT), a critical mediator of the hypothalamus pituitary adrenal axis in rodents, is a stress hormone that is classically viewed as possessing immune-suppressive properties. CORT is now appreciated to also mediate the neuroimmune-priming effect of stress to innate-immune stimulation, and hence serves a...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2018.00003

    authors: Liu J,Mustafa S,Barratt DT,Hutchinson MR

    更新日期:2018-01-22 00:00:00

  • Our Evolving Understanding of Kawasaki Disease Pathogenesis: Role of the Gut Microbiota.

    abstract::Kawasaki disease (KD) was first described by Dr. Tomisaku Kawasaki in 1967. The etiology of KD has been studied comprehensively but remains largely unknown. The disease seems to result from the interplay of genetic and environmental susceptibility factors with infectious triggers, followed by a subsequent abnormal imm...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2020.01616

    authors: Kaneko K,Akagawa S,Akagawa Y,Kimata T,Tsuji S

    更新日期:2020-07-24 00:00:00

  • Abrogation of Endogenous Glycolipid Antigen Presentation on Myelin-Laden Macrophages by D-Sphingosine Ameliorates the Pathogenesis of Experimental Autoimmune Encephalomyelitis.

    abstract::Background: Although myelin is composed of mostly lipids, the pathological role of myelin lipids in demyelinating diseases remains elusive. The principal lipid of the myelin sheath is β-galactosylceramide (β-Galcer). Its α-anomer (α-Galcer) has been demonstrated to be antigenically presented by macrophages via CD1d, a...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2019.00404

    authors: Ban Y,Dong W,Zhang L,Zhou T,Altiti AS,Ali K,Mootoo DR,Blaho VA,Hla T,Ren Y,Ma X

    更新日期:2019-03-19 00:00:00

  • Hepatic Localization of Macrophage Phenotypes during Fibrogenesis and Resolution of Fibrosis in Mice and Humans.

    abstract::Macrophages have been found to both promote liver fibrosis and contribute to its resolution by acquiring different phenotypes based on signals from the micro-environment. The best-characterized phenotypes in the macrophage spectrum are labeled M1 (classically activated) and M2 (alternatively activated). Until now the ...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2014.00430

    authors: Beljaars L,Schippers M,Reker-Smit C,Martinez FO,Helming L,Poelstra K,Melgert BN

    更新日期:2014-09-08 00:00:00

  • Protective Effects of Aryl Hydrocarbon Receptor Signaling in Celiac Disease Mucosa and in Poly I:C-Induced Small Intestinal Atrophy Mouse Model.

    abstract::Aryl hydrocarbon receptor (AhR), a transcription factor activated by a large number of natural and synthetic agents, modulates the activity of immune cells in the gut and represents an important link between the environment and immune-mediated pathologies. In this study, we investigated the role of AhR in celiac disea...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2019.00091

    authors: Dinallo V,Marafini I,Di Fusco D,Di Grazia A,Laudisi F,Dwairi R,Paoluzi OA,Monteleone G,Monteleone I

    更新日期:2019-02-04 00:00:00

  • Checkpoint Blockade Toxicity and Immune Homeostasis in the Gastrointestinal Tract.

    abstract::Monoclonal antibodies targeting the regulatory immune "checkpoint" receptors CTLA-4, PD-1, and PD-L1 are now standard therapy for diverse malignancies including melanoma, lung cancer, and renal cell carcinoma. Although effective in many patients and able to induce cures in some, targeting these regulatory pathways has...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审

    doi:10.3389/fimmu.2017.01547

    authors: Dougan M

    更新日期:2017-11-15 00:00:00

  • Cytokine-Based Generation of CD49a+Eomes-/+ Natural Killer Cell Subsets.

    abstract::Recent studies have identified CD49a+Eomes- and CD49a+Eomes+ subsets of tissue-resident NK (trNK) cells in different organs of the mouse. However, the characteristics of CD49a+Eomes-/+ NK cell development and the regulation of Eomes expression in NK cells remain unclear. Here, we established an in vitro cytokine-based...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2018.02126

    authors: Ni X,Fu B,Zhang J,Sun R,Tian Z,Wei H

    更新日期:2018-09-25 00:00:00

  • Higher Serum Immunoglobulin G3 Levels May Predict the Development of Multiple Sclerosis in Individuals With Clinically Isolated Syndrome.

    abstract::Clinically isolated syndrome (CIS) is a first episode of neurological symptoms that may precede a diagnosis of multiple sclerosis (MS). Therefore, studying individuals with CIS may lead to breakthroughs in understanding the development and pathogenesis of MS. In this study, serum levels of immunoglobulin (Ig)G, IgA, I...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2018.01590

    authors: Trend S,Jones AP,Cha L,Byrne SN,Geldenhuys S,Fabis-Pedrini MJ,Carroll WM,Cole JM,Booth DR,Lucas RM,Kermode AG,French MA,Hart PH

    更新日期:2018-07-13 00:00:00

  • Costimulatory Molecules and Immune Checkpoints Are Differentially Expressed on Different Subsets of Dendritic Cells.

    abstract::Dendritic cells (DCs) play a crucial role in initiating and shaping immune responses. The effects of DCs on adaptive immune responses depend partly on functional specialization of distinct DC subsets, and partly on the activation state of DCs, which is largely dictated by environmental signals. Fully activated immunos...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2019.01325

    authors: Carenza C,Calcaterra F,Oriolo F,Di Vito C,Ubezio M,Della Porta MG,Mavilio D,Della Bella S

    更新日期:2019-06-11 00:00:00

  • Endometriosis, a disease of the macrophage.

    abstract::Endometriosis, a common cause of pelvic pain and female infertility, depends on the growth of vascularized endometrial tissue at ectopic sites. Endometrial fragments reach the peritoneal cavity during the fertile years: local cues decide whether they yield endometriotic lesions. Macrophages are recruited at sites of h...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2013.00009

    authors: Capobianco A,Rovere-Querini P

    更新日期:2013-01-28 00:00:00

  • Pro-inflammatory Actions of Heme and Other Hemoglobin-Derived DAMPs.

    abstract::Damage associated molecular patterns (DAMPs) are endogenous molecules originate from damaged cells and tissues with the ability to trigger and/or modify innate immune responses. Upon hemolysis hemoglobin (Hb) is released from red blood cells (RBCs) to the circulation and give a rise to the production of different Hb r...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审

    doi:10.3389/fimmu.2020.01323

    authors: Bozza MT,Jeney V

    更新日期:2020-06-30 00:00:00

  • Challenges for the Newborn Following Influenza Virus Infection and Prospects for an Effective Vaccine.

    abstract::Newborns are at significantly increased risk of severe disease following infection with influenza virus. This is the collective result of their naïve status, altered immune responsiveness, and the lack of a vaccine that is effective in these individuals. Numerous studies have revealed impairments in both the innate an...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审

    doi:10.3389/fimmu.2020.568651

    authors: Alexander-Miller MA

    更新日期:2020-09-16 00:00:00

  • T Lymphocyte Migration: An Action Movie Starring the Actin and Associated Actors.

    abstract::The actin cytoskeleton is composed of a dynamic filament meshwork that builds the architecture of the cell to sustain its fundamental properties. This physical structure is characterized by a continuous remodeling, which allows cells to accomplish complex motility steps such as directed migration, crossing of biologic...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审

    doi:10.3389/fimmu.2015.00586

    authors: Dupré L,Houmadi R,Tang C,Rey-Barroso J

    更新日期:2015-11-18 00:00:00

  • Antibody Dependent Enhancement Due to Original Antigenic Sin and the Development of SARS.

    abstract::Human coronavirus (HCoV) is one of the most common causes of respiratory tract infections throughout the world. Two phenomena observed so far in the development of the SARS-CoV-2 pandemic deserve further attention. First, the relative absence of clinical signs of infections in children, second, the early appearance of...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2020.01120

    authors: Fierz W,Walz B

    更新日期:2020-06-05 00:00:00

  • Killed Whole-Cell Oral Cholera Vaccine Induces CCL20 Secretion by Human Intestinal Epithelial Cells in the Presence of the Short-Chain Fatty Acid, Butyrate.

    abstract::Short-chain fatty acids (SCFAs), such as acetate, butyrate, and propionate, modulate immune responses in the gut. However, the effect of SCFAs on mucosal vaccine-induced immune cell migration is poorly understood. Here, we investigated whether SCFAs modulate chemokine expression induced by the killed whole-cell oral c...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2018.00055

    authors: Sim JR,Kang SS,Lee D,Yun CH,Han SH

    更新日期:2018-01-29 00:00:00

  • Regulatory T-Cell-Mediated Suppression of Conventional T-Cells and Dendritic Cells by Different cAMP Intracellular Pathways.

    abstract::Regulatory T-cells (Tregs) mediate their suppressive action by acting directly on conventional T-cells (Tcons) or dendritic cells (DCs). One mechanism of Treg suppression is the increase of cyclic adenosine 3',5'-monophosphate (cAMP) levels in target cells. Tregs utilize cAMP to control Tcon responses, such as prolife...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审

    doi:10.3389/fimmu.2016.00216

    authors: Rueda CM,Jackson CM,Chougnet CA

    更新日期:2016-06-02 00:00:00

  • Antimicrobial Proteins and Peptides in Early Life: Ontogeny and Translational Opportunities.

    abstract::While developing adaptive immune responses, young infants are especially vulnerable to serious infections, including sepsis, meningitis, and pneumonia. Antimicrobial proteins and peptides (APPs) are key effectors that function as broad-spectrum anti-infectives. This review seeks to summarize the clinically relevant fu...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审

    doi:10.3389/fimmu.2016.00309

    authors: Battersby AJ,Khara J,Wright VJ,Levy O,Kampmann B

    更新日期:2016-08-18 00:00:00

  • Sialylated Cervical Mucins Inhibit the Activation of Neutrophils to Form Neutrophil Extracellular Traps in Bovine in vitro Model.

    abstract::In order to combat invading pathogens neutrophils can release neutrophil extracellular traps (NETs). However, since NETs can also damage endogenous cells, several control mechanisms for the formation of NETs must work effectively. For instance, neutrophil activation is silenced within blood circulation by the binding ...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2019.02478

    authors: Bornhöfft KF,Rebl A,Gallagher ME,Viergutz T,Zlatina K,Reid C,Galuska SP

    更新日期:2019-11-06 00:00:00

  • Dynamics of Systemic Inflammation as a Function of Developmental Stage in Pediatric Acute Liver Failure.

    abstract::The Pediatric Acute Liver Failure (PALF) study is a multicenter, observational cohort study of infants and children diagnosed with this complex clinical syndrome. Outcomes in PALF reflect interactions among the child's clinical condition, response to supportive care, disease severity, potential for recovery, and, if n...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2020.610861

    authors: Vodovotz Y,Barclay D,Yin J,Squires RH,Zamora R

    更新日期:2021-01-15 00:00:00

  • Tolerogenic Dendritic Cells and T-Regulatory Cells at the Clinical Trials Crossroad for the Treatment of Autoimmune Disease; Emphasis on Type 1 Diabetes Therapy.

    abstract::Tolerogenic dendritic cells and T-regulatory cells are two immune cell populations with the potential to prevent the onset of clinical stage type 1 diabetes, and manage the beginning of underlying autoimmunity, at the time-at-onset and onwards. Initial phase I trials demonstrated that the administration of a number of...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审

    doi:10.3389/fimmu.2019.00148

    authors: Phillips BE,Garciafigueroa Y,Engman C,Trucco M,Giannoukakis N

    更新日期:2019-02-06 00:00:00

  • Controlling the Immune Suppressor: Transcription Factors and MicroRNAs Regulating CD73/NT5E.

    abstract::The NT5E (CD73) molecule represents an ecto-5'-nucleotidase expressed on the cell surface of various cell types. Hydrolyzing extracellular adenosine monophosphate into adenosine and inorganic phosphate, NT5E performs numerous homeostatic functions in healthy organs and tissues. Importantly, NT5E can act as inhibitory ...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章,评审

    doi:10.3389/fimmu.2018.00813

    authors: Kordaß T,Osen W,Eichmüller SB

    更新日期:2018-04-18 00:00:00

  • Leveraging Public Single-Cell and Bulk Transcriptomic Datasets to Delineate MAIT Cell Roles and Phenotypic Characteristics in Human Malignancies.

    abstract::Mucosa-associated invariant T (MAIT) cells are unconventional, innate-like T lymphocytes that recognize vitamin B metabolites of microbial origin among other antigens displayed by the monomorphic molecule MHC class I-related protein 1 (MR1). Abundant in human tissues, reactive to local inflammatory cues, and endowed w...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2020.01691

    authors: Yao T,Shooshtari P,Haeryfar SMM

    更新日期:2020-07-31 00:00:00

  • M1- and M2-Type Macrophage Responses Are Predictive of Adverse Outcomes in Human Atherosclerosis.

    abstract::Atherosclerosis is an inflammatory disease caused by endothelial injury, lipid deposition, and oxidative stress. This progressive disease can be converted into an acute clinical event by plaque rupture and thrombosis. In the context of atherosclerosis, the underlying cause of myocardial infarction and stroke, macropha...

    journal_title:Frontiers in immunology

    pub_type: 杂志文章

    doi:10.3389/fimmu.2016.00275

    authors: de Gaetano M,Crean D,Barry M,Belton O

    更新日期:2016-07-19 00:00:00