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

TY - JOUR

T1 - Glucocorticoids prime the inflammatory response of human hippocampal cells through up-regulation of inflammatory pathways

AU - Horowitz, Mark A.

AU - Cattaneo, Annamaria

AU - Cattane, Nadia

AU - Lopizzo, Nicola

AU - Tojo, Luis

AU - Bakunina, Natalia

AU - Musaelyan, Ksenia

AU - Borsini, Alessandra

AU - Zunszain, Particia A.

AU - Pariante, Carmine M.

PY - 2020/7/1

Y1 - 2020/7/1

N2 - 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.

AB - 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.

KW - Chemokines

KW - Cytokines

KW - Depression

KW - Dexamethasone

KW - Glucocorticoid resistance

KW - Glucocorticoids

KW - Hippocampal progenitor cells

KW - Inflammation

KW - NLRP6

KW - NOD-like receptor

KW - Pro-inflammatory

UR - http://www.scopus.com/inward/record.url?scp=85082867528&partnerID=8YFLogxK

U2 - 10.1016/j.bbi.2020.03.012

DO - 10.1016/j.bbi.2020.03.012

M3 - Article

C2 - 32194233

AN - SCOPUS:85082867528

SN - 0889-1591

VL - 87

SP - 777

EP - 794

JO - Brain, Behavior, and Immunity

JF - Brain, Behavior, and Immunity

IS - 0

ER -