Clozapine Induces an Acute Proinflammatory Response That Is Attenuated by Inhibition of Inflammasome Signaling: Implications for Idiosyncratic Drug-Induced Agranulocytosis

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作   者：

Sernoskie, Samantha Christine;  Lobach, Alexandra R.;  Kato, Ryuji;  Jee, Alison;  Weston, Joseph Kyle;  Uetrecht, Jack; 

作者机构：

Univ Toronto;  Fac Pharm;  Osaka Med & Pharmaceut Univ;  Temerty Fac Med; 

关键词：

OXIDATIVE STRESS;  ACTIVATION;  COVALENT BINDING;  caspase 1;  SCHIZOPHRENIA;  NECROSIS-FACTOR-ALPHA;  inflammasome activation;  INDUCED CARDIOTOXICITY;  innate immunity;  inflammation;  idiosyncratic drug-induced agranulocytosis;  clozapine;  NLRP3;  OLANZAPINE;  NEUTROPHILS IN-VITRO;  INDUCED HEPATOTOXICITY; 

期刊名称：

Toxicological sciences: An official journal of the Society of Toxicology

i s s n：

1096-6080

年卷期：

2022 年 186 卷 1 期

页   码：

70-82

页   码：

摘   要：

Although clozapine is a highly efficacious schizophrenia treatment, it is under-prescribed due to the risk of idiosyncratic drug-induced agranulocytosis (IDIAG). Clinical data indicate that most patients starting clozapine experience a transient immune response early in treatment and a similar response has been observed in clozapine-treated rats, but the mechanism by which clozapine triggers this transient inflammation remains unclear. Therefore, the aim of this study was to characterize the role of inflammasome activation during the early immune response to clozapine using in vitro and in vivo models. In both differentiated and nondifferentiated human monocytic THP-1 cells, clozapine, but not its structural analogues fluperlapine and olanzapine, caused inflammasome-dependent caspase-1 activation and IL-1 beta release that was inhibited using the caspase-1 inhibitor yVAD-cmk. In Sprague Dawley rats, a single dose of clozapine caused an increase in circulating neutrophils and a decrease in lymphocytes within hours of drug administration along with transient spikes in the proinflammatory mediators IL-1 beta, CXCL1, and TNF-alpha in the blood, spleen, and bone marrow. Blockade of inflammasome signaling using the caspase-1 inhibitor VX-765 or the IL-1 receptor antagonist anakinra attenuated this inflammatory response. These data indicate that caspase-1-dependent IL-1 beta production is fundamental for the induction of the early immune response to clozapine and, furthermore, support the general hypothesis that inflammasome activation is a common mechanism by which drugs associated with the risk of idiosyncratic reactions trigger early immune system activation. Ultimately, inhibition of inflammasome signaling may reduce the risk of IDIAG, enabling safer, more frequent use of clozapine in patients.