Ketamine and rapamycin dampen the upregulation of IDO in pro-inflammatory macrophages

ARENA,ARS; OLEXE, CM; ORTIZ WILCZYÑSKI, JM; ONETO, P; CARRERA SILVA, EA; DARAY, FM; ERRASTI, AE

Mar del Plata

Congreso; LXVII REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA (SAIC); 2022

In the last decade, evidence shows that increased pro-inflammatory IL-6, IL-12, IL-1β, TNF-α and IFN-γ cytokines as well as activated circulating monocytes play a significant role in the initiation and maintenance of mood disorder (MD). The increased inflammation alters the tryptophan metabolism toward the kynurenine pathway, which is mediated by the IDO enzyme leading to the production of neurotoxic quinolinic acid (NMDA agonist). Sub-anesthetic doses of the NMDA antagonist, ketamine, has demonstrated a rapid and sustained antidepressant effect acting not only in CNS but also as anti-inflammatory signal in the periphery and increasing neuroprotective kynurenic acid serum level. We previously showed that patients with MD have increased activated monocytes in the blood, and that ketamine skew monocytes to an anti-inflammatory M2 macrophages. Here, we aim to characterize the effect of ketamine and rapamycin on the IDO pathway in polarized macrophages.Circulating monocytes were isolated and differentiated into non-polarized (M0) and polarized M1 (IFN-γ plus LPS), M2a (IL-4) and M2c (IL-10 or dexamethasone) macrophages after 5 days of culture. The expression of IDO, and kynurenic and quinolinic acid pathway enzymes, as well as TNF-α, IL-1β, CD163, and CD206, were evaluated in the presence of ketamine (10 μM) and/or rapamycin (1 nM) by qPCR.Pro-inflammatory M1 macrophages, induced by IFN-γ plus LPS, strongly up-regulates the IDO expression (105 fold, N=12) compared to acutely isolated monocytes and M0, M2a and M2c macrophages. The treatment of pro-inflammatory M1 macrophages with ketamine and rapamycin in combination significantly reduced (p