APPA (apocynin and paeonol) modulates pathological aspects of human neutrophil function, without supressing antimicrobia
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Inflammopharmacology
ORIGINAL ARTICLE
APPA (apocynin and paeonol) modulates pathological aspects of human neutrophil function, without supressing antimicrobial ability, and inhibits TNFα expression and signalling A. L. Cross1 · J. Hawkes1 · H. L. Wright1 · R. J. Moots1 · S. W. Edwards2,3 Received: 1 April 2020 / Accepted: 24 April 2020 © The Author(s) 2020
Abstract Neutrophils are key players in the pathophysiological process underlying inflammatory conditions not only by release of tissue-damaging cytotoxic enzymes, reactive oxygen species (ROS) but also by secretion of important immunomodulatory chemokines and cytokines. Here, we report the effects of the novel agent APPA, undergoing formal clinical development for treatment of osteoarthritis, and its constituent components, apocynin (AP) and paeonol (PA) on a number of neutrophil functions, including effects on TNFα- expression and signalling. Neutrophils were treated with APPA (10–1000 µg/mL) prior to the measurement of cell functions, including ROS production, chemotaxis, apoptosis and surface receptor expression. Expression levels of several key genes and proteins were measured after incubation with APPA and the chromatin remodelling agent, R848. APPA did not significantly affect phagocytosis, bacterial killing or expression of surface receptors, while chemotactic migration was affected only at the highest concentrations. However, APPA down-regulated neutrophil degranulation and ROS levels, and decreased the formation of neutrophil extracellular traps. APPA also decreased cytokinestimulated gene expression, inhibiting both TNFα- and GM-CSF-induced cell signalling. APPA was as effective as infliximab in down-regulating chemokine and IL-6 expression following incubation with R848. Whilst APPA does not interfere with neutrophil host defence against infections, it does inhibit neutrophil degranulation, and cytokine-driven signalling pathways (e.g. autocrine signalling and NF-κB activation), processes that are associated with inflammation. These observations may explain the mechanisms by which APPA exerts anti-inflammatory effects and suggests a potential therapeutic role in inflammatory diseases in which neutrophils and TNFα signalling are important in pathology, such as rheumatoid arthritis. Keywords Neutrophil · APPA · Paeonol · Apocynin · NFκB · Rheumatoid arthritis
Introduction Advances in identifying the pathophysiological processes underlying systemic inflammatory disease such as rheumatoid arthritis (RA) have led to the development of targeted therapies and enhanced outcomes for many patients (Nikiphorou et al. 2017). However, no single drug is effective * S. W. Edwards [email protected] 1
Institute of Ageing and Chronic Disease, Aintree University Hospital, Longmoor Lane, Liverpool L9 7AL, UK
2
Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK
3
Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK
for all patients and each is associated with sig
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