Therapeutic ACPA inhibits NET formation: a potential therapy for neutrophil-mediated inflammatory diseases.

08:00 EDT 20th March 2020 | BioPortfolio

Summary of "Therapeutic ACPA inhibits NET formation: a potential therapy for neutrophil-mediated inflammatory diseases."

Excessive release of neutrophil extracellular traps (NETs) is associated with disease severity and contributes to tissue injury, followed by severe organ damage. Pharmacological or genetic inhibition of NET release reduces pathology in multiple inflammatory disease models, indicating that NETs are potential therapeutic targets. Here, we demonstrate using a preclinical basket approach that our therapeutic anti-citrullinated protein antibody (tACPA) has broad therapeutic potential. Treatment with tACPA prevents disease symptoms in various mouse models with plausible NET-mediated pathology, including inflammatory arthritis (IA), pulmonary fibrosis, inflammatory bowel disease and sepsis. We show that citrulline residues in the N-termini of histones 2A and 4 are specific targets for therapeutic intervention, whereas antibodies against other N-terminal post-translational histone modifications have no therapeutic effects. Because citrullinated histones are generated during NET release, we investigated the ability of tACPA to inhibit NET formation. tACPA suppressed NET release from human neutrophils triggered with physiologically relevant human disease-related stimuli. Moreover, tACPA diminished NET release and potentially initiated NET uptake by macrophages in vivo, which was associated with reduced tissue damage in the joints of a chronic arthritis mouse model of IA. To our knowledge, we are the first to describe an antibody with NET-inhibiting properties and thereby propose tACPA as a drug candidate for NET-mediated inflammatory diseases, as it eliminates the noxious triggers that lead to continued inflammation and tissue damage in a multidimensional manner.


Journal Details

This article was published in the following journal.

Name: Cellular & molecular immunology
ISSN: 2042-0226


DeepDyve research library

PubMed Articles [32665 Associated PubMed Articles listed on BioPortfolio]

Mechanism of pulmonary immunosuppression: extrapulmonary burn injury suppresses bacterial endotoxin-induced pulmonary neutrophil recruitment and neutrophil extracellular trap (NET) formation.

Pulmonary immunosuppression often occurs after burn injury (BI). However, the reasons for BI-induced pulmonary immunosuppression are not clearly understood. Neutrophil recruitment and neutrophil extra...

Neutrophils in the Tumor Microenvironment.

Neutrophils are the first responders to inflammation, infection, and injury. As one of the most abundant leukocytes in the immune system, neutrophils play an essential role in cancer progression, thro...

ACPA-positive versus ACPA-negative rheumatoid arthritis: two distinct erosive disease entities on radiography and ultrasonography.

The objective of this study is to assess the prevalence, localization, and severity of bone erosions on radiography (RX) and ultrasonography (US) according to ACPA status in patients with rheumatoid a...

Inhibition of neutrophil elastase prevents neutrophil extracellular trap formation and rescues mice from endotoxic shock.

Neutrophil elastase (NE) is a serine protease stored in the azurophilic granules of neutrophils and released into the extracellular milieu during inflammatory response or formation of neutrophil extra...

LncRNA625 inhibits STAT1-mediated transactivation potential in esophageal cancer cells.

Although Signal transducer and activator of transcription 1 (STAT1)-mediated transactivation potential is inhibited in cancer cells, the mechanism is poorly understood. In the present study, we implic...

Clinical Trials [10146 Associated Clinical Trials listed on BioPortfolio]

Alloimmune Response to Citrullinated Shared Epitope Sequence in Patients With Rheumatoid Arthritis

Rheumatoid arthritis (RA) is an autoimmune and sistemic disease,characterized by joint sinovitis and the production of autoantibodies (Ab). The Ab against citrullinated peptides (ACPA) are...

Neutrophil Extracellular Trap Formation in Newborn Infants at Risk for Necrotizing Enterocolitis

The purpose of this study is to characterize the time to maturation of neutrophil extracellular trap(NET) formation capability in polymorphonuclear leukocytes(PMNs) isolated from newborn p...

Impact of Neutrophil Activation in Acute Ischemic Stroke Patients Treated With Endovascular Therapy

Clinical and experimental data suggest that neutrophil activation and extravasation are deleterious in acute ischemic stroke (AIS) involving an increased risk of unfavorable outcome and he...

TOLERA: Tolerance Enhancement in RA

Although anti-citrullinated protein antibodies (ACPA) including anti-CCP2 antibodies are known to promote inflammation and joint destruction in patients suffering from ACPA-positive rheuma...

Neutrophil Extracellular Traps and Neonatal (PV4991) & Pediatric Sepsis (PV5063)

This study is designed to assess the role of neutrophil extracellular traps (NETs) in neonatal and pediatric sepsis as well as to evaluate markers of NETs formation as early predictors of ...

Medical and Biotech [MESH] Definitions

The process in which the neutrophil is stimulated by diverse substances, resulting in degranulation and/or generation of reactive oxygen products, and culminating in the destruction of invading pathogens. The stimulatory substances, including opsonized particles, immune complexes, and chemotactic factors, bind to specific cell-surface receptors on the neutrophil.

A therapeutic approach, involving chemotherapy, radiation therapy, or surgery, after initial regimens have failed to lead to improvement in a patient's condition. Salvage therapy is most often used for neoplastic diseases.

Plasma glycoprotein member of the serpin superfamily which inhibits TRYPSIN; NEUTROPHIL ELASTASE; and other PROTEOLYTIC ENZYMES.

A non-steroidal anti-inflammatory agent (NSAID) that inhibits the enzyme cyclooxygenase necessary for the formation of prostaglandins and other autacoids. It also inhibits the motility of polymorphonuclear leukocytes.

Treatment using irradiation with LASER light of low power intensity so that the effects are not due to heat, as in LASER THERAPY. These non-thermal effects are thought to be mediated by a photochemical reaction that alters CELL MEMBRANE PERMEABILITY, leading to increased mRNA synthesis and CELL PROLIFERATION. Low-level laser therapy has been used for a wide variety of conditions, but most frequently for wound healing and pain control.

Quick Search

DeepDyve research library

Relevant Topics

An antibody is a protein produced by the body's immune system when it detects harmful substances, called antigens. Examples of antigens include microorganisms (such as bacteria, fungi, parasites, and viruses) and chemicals. Antibodies may be produc...

Joint Disorders
A joint is where two or more bones come together, like the knee, hip, elbow, or shoulder. Joints can be damaged by many types of injuries or diseases, including Arthritis - inflammation of a joint causes pain, stiffness, and swelling with ...

Searches Linking to this Article