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. 2023 Feb 22;14:1048592. doi: 10.3389/fimmu.2023.1048592

Figure 2.

Figure 2

The effects of IFN-α therapy. IFN-α disrupts IDO1, SERT and possibly GCH1 systems and HPA axis leading to neurological changes and depression. Lower 5-HT production which is linked to depression is caused by the disruption on the SERT and IDO1 systems. IFN- also causes apoptosis, hippocampal atrophy and neurodegeneration via the KYN pathway as a result of increased IDO1 by (i) inhibiting the conversion of L-TRP, precursor of 5-HT (ii) production of QUIN which increases the stimulation of hippocampal NMDA (iii) production of 3-OH-KYN leading to increased ROS production causing intranucleosomal DNA damages and (iv) production of peripheral KYN which affects the CNS and subsequently neurodegeneration due to the release of neurotoxic metabolites. IFN- therapy also increases the production of pro-inflammatory cytokines which activate the HPA axis and causes depression. Another possible target of IFN-α is on GCH1 which reduces BH4 production, reducing 5-HT and leads to depression. IFN-α, Interferon-alpha; IL-1β, Interleukin-1beta; IFN-γ, Interferon-gamma; TNF-α, TNF-alpha; 5-HT, Serotonin; SERT, Serotonin transporter; IDO1, Indoleamine 2,3 dioxygenase; KYN, Kynurenine; 3-OH-KYN, 3-hydroxy-kynurenine; QUIN, Quinolinic acid; NMDA, N-methyl-D-aspartate; CNS, Central nervous system; ROS, Reactive oxygen species; BH₄, Tetrahydrobiopterin; CRH, Corticotropin-releasing hormone; HPA, Hypothalamic-pituitary-adrenal; GCH1, GTP cyclohydrolase I.