PAD4 has been strongly implicated in the pathogenesis of autoimmune, cardiovascular and oncological diseases through clinical genetics and gene disruption in mice. New selective PAD4 inhibitors binding a calcium-deficient form of the PAD4 enzyme have validated the critical enzymatic role of human and mouse PAD4 in both histone citrullination and neutrophil extracellular trap formation for, to our knowledge, the first time. The therapeutic potential of PAD4 inhibitors can now be explored.
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http://dx.doi.org/10.1038/nchembio.1735 | DOI Listing |
FASEB J
January 2025
Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Neutrophils are peripheral blood-circulating leukocytes that play a pivotal role in host defense against bacterial pathogens which upon activation, they release web-like chromatin structures called neutrophil extracellular traps (NETs). Here, we analyzed and compared the importance of myeloid differentiation factor 88 (MYD88), peptidyl arginine deiminase 4 (PAD4), and gasdermin D (GSDMD) for NET formation in vivo following sepsis and neutrophilia challenge. Injection of lipopolysaccharide (LPS)/E.
View Article and Find Full Text PDFLife Sci
January 2025
Department of Biological Sciences (Regulatory Toxicology), National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, TS 500037, India. Electronic address:
Pulmonary fibrosis (PF) arises from dysregulated wound healing, leading to excessive extracellular matrix (ECM) deposition and impaired lung function. Macrophages exhibit high plasticity, polarizing to pro-inflammatory M1 during early inflammation and anti-inflammatory, fibrosis-inducing M2 during later stages of PF. Additionally, neutrophils and neutrophil extracellular traps (NETs) release mediated by peptidyl arginine deiminase (PAD-4), also play a key role in PF progression.
View Article and Find Full Text PDFNan Fang Yi Ke Da Xue Xue Bao
December 2024
Department of Emergency Medicine, Affiliated Changsha Hospital of Xiangya School of Medicine, Central South University (Changsha First Hospital), Changsha 410005, China.
Objectives: To investigate the inhibitory effect of GSK484, a PAD4 inhibitor, on H3Cit expression following sepsis and its effects for improving sepsis-induced endothelial dysfunction.
Methods: Eighteen C57BL/6 mice were randomized into sham-operated group, sepsis model group and GSK484 treatment group (6), and in the latter two groups, models of sepsis were established by cecal ligation and puncture (CLP). The mice in GSK484 treatment group were given an intraperitoneal injection of GSK484 (4 mg/kg) on the second day following the surgery.
Commun Chem
December 2024
Protein-Protein Interaction Laboratory, The Francis Crick Institute, London, UK.
Covalent drugs can achieve high potency with long dosing intervals. However, concerns remain about side-effects associated with off-target reactivity. Combining macrocyclic peptides with covalent warheads provides a solution to minimise off-target reactivity: the peptide enables highly specific target binding, positioning a weakly reactive warhead proximal to a suitable residue in the target.
View Article and Find Full Text PDFThe microenvironment plays an important role in promoting tumor cell chemoresistance, but the mechanisms responsible for this effect are not clear. Here, using models of multiple myeloma (MM) and solid cancers, we demonstrate a novel mechanism mediated by neutrophils, a major cell population in the bone marrow (BM), that protects cancer cells from chemotherapeutics. We show that in response to tumor-derived soluble factors, BM neutrophils release their DNA in the form of neutrophil extracellular traps (NETs).
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