ArticleClinical and experimental immunology2023
Chloroquine reduces neutrophil extracellular trap (NET) formation through inhibition of peptidyl arginine deiminase 4 (PAD4).
Article in Clinical and experimental immunology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 31 citations in OpenAlex.
- Neutrophil extracellular traps in tumor progression: from mechanistic insights and regulatory factors to clinical detection and diagnosis.Journal of molecular medicine (Berlin, Germany) · 2026Review
- Regulated cell death in autoimmune diseases: molecular mechanisms and therapeutic opportunities.Molecular biology reports · 2026Review
- Neutrophil extracellular traps in thrombosis of hematologic malignancies: Underlying mechanisms and therapeutic opportunities (Review).International journal of molecular medicine · 2026Review
- Epigenetic Mechanisms in Perioperative Medicine: From Neuroinflammation and NETosis to Organ Dysfunction and Precision Therapeutics.Biomedicines · 2026Review
- A neutrophil-mesangial cell axis promotes glomerular injury in lupus nephritis.Annals of the rheumatic diseases · 2026Article
- Beyond PAD Inhibition: Emerging Avenues and Natural Products for Targeting Citrullination in Immune Diseases.Biomedicines · 2026Review
- Clinical and translational results from a phase 1 trial of gemcitabine/nab-paclitaxel with nivolumab/ipilimumab or hydroxychloroquine/ipilimumab in untreated metastatic pancreatic adenocarcinoma.Journal for immunotherapy of cancer · 2026Article
- Can Phagocytosis, Neutrophil Extracellular Traps, and IFN-α Production in Systemic Lupus Erythematosus Be Simultaneously Modulated? A Pharmacological Perspective.International journal of molecular sciences · 2026Review
- Altered neutrophil signalling linked to impaired chemotaxis and increased ROS and NET production in older people with frailty.Clinical and experimental immunology · 2026Article
- Neutrophil Extracellular Traps in Pancreatic Ductal Adenocarcinoma: A Vicious Cycle in the Tumor Microenvironment and Targeted Interventions.International journal of biological sciences · 2026Review
- Tumor-associated neutrophils in pancreatic ductal adenocarcinoma: mechanisms and therapeutic targeting.Frontiers in immunology · 2026Review
- Neutrophil extracellular traps in pregnancy complications.Frontiers in immunology · 2026Review
- Neutrophil Extracellular Traps in Diabetic Kidney Disease: Mechanisms of Pathogenesis and Emerging Therapeutic Strategies.Drug design, development and therapy · 2026Review
- Multifactorial pathogenesis of rheumatoid arthritis: interaction between inflammation, metabolic dysregulation, and tissue mechanics.Frontiers in immunology · 2026Review
- Tumor-immune metabolic tug-of-war: from immune escape to targeting metabolic rewiring in cancer therapy.Frontiers in cell and developmental biology · 2026Review
- Imaging Reactive Oxygen Species with L-012 Reveals Neutrophil Extracellular Trap Formation in Pancreatic Ductal Adenocarcinoma.Antioxidants (Basel, Switzerland) · 2025Article
- The science of tumor-infiltrating lymphocytes (TIL): perspectives from the SITC Surgery Committee.Journal for immunotherapy of cancer · 2025Review
- Neutrophil Extracellular Traps Modulate Recruitment and Immunosuppression of Macrophages in Pancreatic Adenocarcinoma.Cancer immunology research · 2025Article
- Hydroxychloroquine reduces metastatic tumor burden in pancreatic adenocarcinoma through myeloperoxidase inhibition.Journal of inflammation (London, England) · 2025Article
- The trap becomes the target: molecular basis for targeted inhibition of neutrophil extracellular traps in the pre-metastatic niche.Expert opinion on therapeutic targets · 2025Article
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
Neutrophil extracellular traps (NETs) occur when chromatin is decondensed and extruded from the cell, generating a web-like structure. NETs have been implicated in the pathogenesis of several sterile disease states and thus are a potential therapeutic target. Various pathways have been shown to induce NETs, including autophagy, with several key enzymes being activated like peptidyl arginine deiminase 4 (PAD4), an enzyme responsible for citrullination of histones, allowing for DNA unwinding and subsequent release from the cell. Pre-clinical studies have already demonstrated that chloroquine (CQ) and hydroxychloroquine (HCQ) are able to reduce NETs and slow disease progression. The exact mechanism as to how these drugs reduce NETs has yet to be elucidated. CQ and HCQ decrease NET formation from various NET activators, independent of their autophagy inhibitory function. CQ and HCQ were found to inhibit PAD4 exclusively, in a dose-dependent manner, confirmed with reduced CitH3+ NETs after CQ or HCQ treatment. Circulating CitH3 levels were reduced in pancreatic cancer patients after HCQ treatment. In silico screening of PAD4 protein structure identified a likely binding site interaction at Arg639 for CQ and Trp347, Ser468, and Glu580 for HCQ. SPR analysis confirmed the binding of HCQ and CQ with PAD4 with KD values of 54.1 µM (CQ) and 88.1 µM (HCQ). This data provide evidence of direct PAD4 inhibition as a mechanism for CQ/HCQ inhibition of NETs. We propose that these drugs likely reduce NET formation through multiple mechanisms; the previously established TLR9 and autophagy inhibitory mechanism and the novel PAD4 inhibitory mechanism.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.