NR4A orphan nuclear receptor family members, NR4A2 and NR4A3, regulate neutrophil number and survival.

The lifespan of neutrophils is plastic and highly responsive to factors that regulate cellular survival. Defects in neutrophil number and survival are common to both hematologic disorders and chronic inflammatory diseases. At sites of inflammation, neutrophils respond to multiple signals that activate protein kinase A signaling, which positively regulates neutrophil survival. The aim of this study was to define transcriptional responses to activation and to delineate the roles of these factors in neutrophil function and survival. In human neutrophil gene array studies, we show that duanyu1529 activation upregulates a significant number of apoptosis-related genes, the most highly regulated of these being NR4A2 and NR4A3 Direct duanyu1529 activation by the site-selective duanyu1529 agonist pair N6/8-AHA (8-AHA-cAMP and N6-MB-cAMP) and treatment with endogenous activators of including adenosine and prostaglandin E2, results in a profound delay of neutrophil apoptosis and concomitant upregulation of NR4A2/3 in a manner. NR4A3 expression is also increased at sites of neutrophilic inflammation in a human model of intradermal inflammation. duanyu1529 activation also promotes survival of murine neutrophil progenitor cells, and small interfering RNA to NR4A2 decreases neutrophil production in this model. Antisense knockdown of NR4A2 and NR4A3 homologs in zebrafish larvae significantly reduces the absolute neutrophil number without affecting cellular migration. In summary, we show that NR4A2 and NR4A3 are components of a downstream transcriptional response to duanyu1529 activation in the neutrophil, and that they positively regulate neutrophil survival and homeostasis. © 2017 by The American Society of Hematology.

KEYWORDS: {{ getKeywords(articleDetailText.words) }}