Rescue of IL-1β-induced reduction of human neurogenesis by omega-3 fatty acids and antidepressants

Abstract

Both increased inflammation and reduced neurogenesis have been associated with the pathophysiology of major depression. We have previously described how interleukin-1 (IL-1) β, a pro-inflammatory cytokine increased in depressed patients, decreases neurogenesis in human hippocampal progenitor cells. Here, using the same human in vitro model, we show how omega-3 (ω-3) polyunsaturated fatty acids and conventional antidepressants reverse this reduction in neurogenesis, while differentially affecting the kynurenine pathway. We allowed neural cells to proliferate for 3days and further differentiate for 7days in the presence of IL-1β (10ng/ml) and either the selective serotonin reuptake inhibitor sertraline (1µM), the serotonin and norepinephrine reuptake inhibitor venlafaxine (1µM), or the ω-3 fatty acids eicosapentaenoic acid (EPA, 10µM) or docosahexaenoic acid (DHA, 10µM). Co-incubation with each of these compounds reversed the IL-1β-induced reduction in neurogenesis (DCX- and MAP2-positive neurons), indicative of a protective effect. Moreover, EPA and DHA also reversed the IL-1β-induced increase in kynurenine, as well as mRNA levels of indolamine-2,3-dioxygenase (IDO); while DHA and sertraline reverted the IL-1β-induced increase in quinolinic acid and mRNA levels of kynurenine 3-monooxygenase (KMO). Our results show common effects of monoaminergic antidepressants and ω-3 fatty acids on the reduction of neurogenesis caused by IL-1β, but acting through both common and different kynurenine pathway-related mechanisms. Further characterization of their individual properties will be of benefit towards improving a future personalized medicine approach.

Keywords: Cytokines; Fish oil; IL-1 beta; Immune; Kynurenine-pathway; Neurogenic; PUFA; Sertraline; Venlafaxine.

Fig. 1

Simplified kynurenine pathway of tryptophan metabolism. ACMSD: aminocarboxymuconate semialdehyde decarboxylase, IDO: indolamine-2,3-dioxygenase, KAT: kynurenine aminotransferase, KMO: kynurenine 3-monooxygenase or kynurenine 3-hydroxylase, KYNU: kynureninase.

Fig. 2

Monoaminergic antidepressants and ω-3 fatty acids reverse the IL-β-induced reduction of human hippocampal cells neurogenesis. Treatment with IL-1β decrease DCX-positive cells (immature neuronal phenotype), and MAP2 positive cells (mature neuronal phenotype) (a). Treatment with EPA, DHA, sertraline or venlafaxine reverse the IL-1β-induced decrease in DCX positive cells (b), and MAP2-positive cells (c); ^****p < 0.0001.

Fig. 3

IL-1β modulates the production of metabolites and enzymes of the kynurenine pathway. Treatment with IL-1β affected the kynurenine pathway by (a) increasing levels of kynurenine and quinolinic acid and decreasing levels of anthranilic acid released into the supernatant, and (b) up-regulating the expression of IDO, KMO, KYNU and ACMSD; ^*p < 0.05, ^**p < 0.01, ^****p < 0.0001.

Fig. 4

Antidepressants and ω-3 fatty acids modulate changes of kynurenine pathway metabolites caused by IL-1β treatment. Co-treatment of cells with IL-1β and ω-3 fatty acids partially abrogated the increase in kynurenine caused by the cytokine (a). Co-treatment with sertraline fully reverted the decrease in levels of ANA caused by IL-1β (b). Co-incubation with DHA and sertraline partially reverted the increase in QUIN levels caused by IL-1β (c). No significant changes in PIC were observed by any co-incubation (d); ^*p < 0.05, ^**p < 0.001.

Fig. 5

Antidepressants and ω-3 fatty acids modulate IL-1β-induced changes to the expression of enzymes of the kynurenine pathway. Co-treatment of cells with IL-1β and ω-3 fatty acids or antidepressants decreased the expression of IDO (a). Co-treatment with DHA, sertraline or venlafaxine decreased expression of KMO (b). Co-treatment with DHA upregulated KMO production (c). Co-incubation with sertraline or venlafaxine decreased the upregulation of ACMSD (d); ^*p < 0.05, ^**p < 0.01, ^***p < 0.001, ^****p < 0.0001.