Glucocorticoids mobilize macrophages by transcriptionally up-regulating the exopeptidase DPP4

Diaz-Jimenez, David; Petrillo, Maria Grazia; Busada, Jonathan T.; Hermoso, Marcela A.; Cidlowski, John A.

Abstract

Glucocorticoids are potent endogenous anti-inflammatory molecules, and their cognate receptor, glucocorticoid receptor (GR), is expressed in nearly all immune cells. Macrophages are heterogeneous immune cells having a central role in both tissue homeostasis and inflammation and also play a role in the pathogenesis of some inflammatory diseases. Paradoxically, glucocorticoids have only a limited efficacy in controlling the resolution of these macrophage-related diseases. Here, we report that the transcriptomes of monocyte-like THP-1 cells and macrophage-like THP-1 cells (THP1-M?) have largely conserved gene expression patterns. In contrast, the differentiation to THP1-M? significantly altered the sensitivity of gene transcription to glucocorticoids. Among glucocorticoid-regulated genes, we identified the exopeptidase dipeptidyl peptidase-4 (DPP4) as a critical glucocorticoid-responsive gene in THP1-M?. We found that GR directly induces DPP4 gene expression by binding to two glucocorticoid-responsive elements (GREs) within the DPP4 promoter. Additionally, we show that glucocorticoid-induced DPP4 expression is blocked by the GR antagonist RU-486 and by GR siRNA transfection and that DPP4 enzyme activity is reduced by DPP4 inhibitors. Of note, glucocorticoids highly stimulated macrophage mobility; unexpectedly, DPP4 mediated the glucocorticoid-induced macrophage migration, and siRNA-mediated knockdowns of GR and DPP4 blocked dexamethasone-induced THP1-M? migration. Moreover, glucocorticoid-induced DPP4 activation was also observed in proinflammatory M1-polarized murine macrophages, as well as peritoneal macrophages, and was associated with increased macrophage migration. Our results indicate that glucocorticoids directly up-regulate DPP4 expression and thereby induce migration in macrophages, potentially explaining why glucocorticoid therapy is less effective in controlling macrophage-dominated inflammatory disorders.

Más información

Título según WOS: Glucocorticoids mobilize macrophages by transcriptionally up-regulating the exopeptidase DPP4
Título según SCOPUS: Glucocorticoids mobilize macrophages by transcriptionally up-regulating the exopeptidase DPP4
Volumen: 295
Número: 10
Fecha de publicación: 2020
Página de inicio: 3213
Página final: 3227
Idioma: English
DOI:

10.1074/jbc.RA119.010894

Notas: ISI, SCOPUS