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Brief Report: Drugs Implicated in Systemic Autoimmunity Modulate Neutrophil Extracellular Trap Formation
Author(s) -
IrizarryCaro Jorge A.,
CarmonaRivera Carmelo,
Schwartz Daniella M.,
Khaznadar Sami S.,
Kaplan Mariana J.,
Grayson Peter C.
Publication year - 2018
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.40372
Subject(s) - neutrophil extracellular traps , pharmacology , autoimmunity , hydralazine , drug , chemistry , intracellular , procainamide , inflammation , immunology , medicine , biochemistry , immune system , blood pressure
Objective Aberrant neutrophil extracellular trap ( NET ) formation has been implicated as a mechanism to induce autoreactivity in individuals at risk of autoimmune diseases. The objective of this study was to assess whether medications implicated in cases of drug‐induced autoimmunity (hydralazine and procainamide) and medications less commonly associated with drug‐induced autoimmunity (minocycline and clozapine) induce NET formation and/or prevent NET degradation. Methods Human neutrophils were incubated with the drugs of interest and resultant NET formation was quantified by fluorescent microscopy. The ability of these drugs to interfere with NET degradation by serum nuclei was assessed. Pathways of drug‐induced NET formation were studied with pharmacologic inhibitors of reactive oxygen species ( ROS ), peptidylarginine deiminases ( PAD s), and muscarinic receptors, and by assessment of intracellular calcium levels by flow cytometry. To determine if NET protein cargo varies by drug stimulus and/or neutrophil source, proteomic analysis of NET lysates induced by specific medications was compared using neutrophils from healthy donors and from patients with autoimmune diseases. Results Hydralazine and procainamide significantly induced NET formation while minocycline and clozapine did not. None of the medications significantly impaired NET degradation. NET osis induced by these drugs required NADPH oxidase and PAD 4 activation. Procainamide triggered NET s via muscarinic receptor engagement on neutrophils, while hydralazine modulated calcium release from intracellular stores. Differences in protein cargo, particularly histone content, were observed in NET s induced by hydralazine and procainamide. Conclusion Medications commonly implicated in drug‐induced autoimmunity trigger NET formation displaying distinct protein cargo, via common and specific pathways. NET osis may play a role in the pathogenesis of drug‐induced autoimmunity.