Glucocorticoids mobilize macrophages by transcriptionally up-regulating the exopeptidase DPP4
Open accessAbstract
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-MΦ) have largely conserved gene expression patterns. In contrast, the differentiation to THP1-MΦ 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-MΦ. 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-MΦ 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.
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GR is expressed in macrophages but not in monocytes.
“As GR is expressed in macrophages but not in monocytes,62”
From Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy (2023) · cites this paper as [62]
The transcriptome-analysis section reports higher GR expression in macrophage-like THP-1 cells than in monocyte-like THP-1 cells, not an absence of GR in the latter. Its qRT-PCR and Western blot results compare GR levels in both cell types (Fig. 1C–D). (LLM, conf=0.90)
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Immune regulation by glucocorticoids
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Kleeman, S. O., Thakir, T. M., Demestichas, B., Mourikis, N., Loiero, D., Ferrer, M., Bankier, S., Riazat-Kesh, Y. J. R. A., Lee, H., Chantzichristos, D., et al. (2023) · Cell Genomics · doi:10.1016/j.xgen.2023.100347 · Cited by 37 · see citing works
- Authors
- Diaz-Jimenez, D., Petrillo, M. G., Busada, J. T., Hermoso, M. A., & Cidlowski, J. A.
- Affiliations
- National Institutes of Health (US)
- University of Chile (CL)
- Corresponding author
- Cidlowski, John A.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2020-03
- Volume
- 295
- Issue
- 10
- Pages
- 3213-3227
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC7062181
- OpenAlex
- W3004037465
- Cited by
- 37
- References
- 7
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 7 · 2023: 5 · 2022: 3 · 2021: 10 · 2020: 6
- FWCI
- 3.52
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Universidad de Chile (submittedVersion, cc-by-nc-nd)
- Funders
- HHS | NIH | National Institute of Environmental Health Sciences (Intramural Research Program of the NIEHS National Institutes of Health)
- Fondo Nacional de Desarrollo Científico y Tecnológico (1170648)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- glucocorticoids, glucocorticoid receptor, dipeptidyl peptidase IV, macrophage migration, macrophage mobilization, glucocorticoid response element, THP-1 cells, M1 macrophages, anti-inflammatory therapy, glucocorticoid resistance
- MeSH terms
- Sitagliptin Phosphate, Linagliptin, THP-1 Cells, Animals, Cell Differentiation, Cell Movement, Dexamethasone, Glucocorticoids, Humans, Macrophages, Monocytes, Promoter Regions, Genetic, Receptors, Glucocorticoid, Up-Regulation, Dipeptidyl Peptidase 4, RNA Interference, RNA, Small Interfering, Regulatory Elements, Transcriptional, Mice, Transcriptome
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