Glucocorticoids prime the inflammatory response of human hippocampal cells through up-regulation of inflammatory pathways

Mark A. Horowitz, Annamaria Cattaneo, Nadia Cattane, Nicola Lopizzo, Luis Tojo, Natalia Bakunina, Ksenia Musaelyan, Alessandra Borsini, Particia A. Zunszain, Carmine M. Pariante

Research output: Contribution to journalArticlepeer-review

Abstract

Increased pro-inflammatory cytokines and an overactive hypothalamic-pituitary-adrenal (HPA) axis have both been implicated in the pathogenesis of depression. However, these explanations appear contradictory because glucocorticoids are well recognised for their anti-inflammatory effects. Two hypotheses exist to resolve this paradox: the mediating presence of glucocorticoid receptor resistance, or the possibility that glucocorticoids can potentiate inflammatory processes in some circumstances. We sought to investigate these hypotheses in a cell model with significant relevance to depression: human hippocampal progenitor cells. We demonstrated that dexamethasone in vitro given for 24 hours and followed by a 24 hours rest interval before an immune challenge potentiates inflammatory effects in these neural cells, that is, increases the IL-6 protein secretion induced by stimulation with IL-1β (10 ng/mL for 24 hours) by + 49% (P < 0.05) at a concentration of 100 nM and by + 70% (P < 0.01) for 1 μM. These effects are time- and dose-dependent and require activation of the glucocorticoid receptor. Gene expression microarray assays using Human Gene 2.1st Array Strips demonstrated that glucocorticoid treatment up-regulated several innate immune genes, including chemokines and Nod-like receptor, NLRP6; using transcription factor binding motifs we found limited evidence that glucocorticoid resistance was induced in the cells. Our data suggests a mechanism by which stress may prime the immune system for increased inflammation and suggests that stress and inflammation may be synergistic in the pathogenesis of depression.

Original languageEnglish
Pages (from-to)777-794
Number of pages18
JournalBrain, Behavior, and Immunity
Volume87
DOIs
Publication statusPublished - Jul 2020

Keywords

  • Chemokines
  • Cytokines
  • Depression
  • Dexamethasone
  • Glucocorticoid resistance
  • Glucocorticoids
  • Hippocampal progenitor cells
  • Inflammation
  • NLRP6
  • NOD-like receptor
  • Pro-inflammatory

ASJC Scopus subject areas

  • Immunology
  • Endocrine and Autonomic Systems
  • Behavioral Neuroscience

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