Dehydroepiandrosterone (DHEA) Counteracts <i>Leishmania donovani</i> -Induced Cortisol-Glucocorticoid Receptor Signaling-Mediated Immunosuppression and Anti-inflammatory Bias

Imbalance of cortisol and dehydroepiandrosterone (DHEA) levels have been observed in several infectious diseases, and high plasma cortisol levels have also been found in human visceral leishmaniasis. However, the mechanism remains ambiguous. In Leishmania donovani-infected BALB/c mice, we observe increased cortisol versus decreased DHEA levels coinciding with high organ parasite burden and anti-inflammatory cytokines, along with increased 11β-hydroxysteroid dehydrogenase (11βHSD1) expression. DHEA treatment in J774 and THP-1-derived macrophages restrains L. donovani-induced cortisol levels by inhibiting 11βHSD1 expression, which increases proinflammatory and decreases anti-inflammatory mediators, thereby lowering intracellular parasitemia. In infected THP-1-derived macrophages, DHEA reciprocally regulates glucocorticoid receptors α and β (GRα and GRβ) expression, increasing GRα/GRβ heterodimers, which antagonize GRα homodimer binding on IL10, DUSP1, and NFKBIA promoters. Finally, L. donovani induces PPAR-γ binding on the 11βHSD1 promoter by lipophosphoglycan, which drives cortisol production. Collectively, our observations identify DHEA as a potent immunomodulator that inhibits cortisol-mediated immunosuppression and GRβ induction to counteract GRα anti-inflammatory signaling.