OBJECTIVE: Changes in the brain's inflammatory status can lead to psychopathological responses, especially depression. Using animal models, recent studies have revealed that this pathology is due, in part, to innate immune responses of monocytes. METHODS: We focus on the involvement of Toll-like receptors (TLRs) and expression of genes encoding their negative regulators, SOCS1, TOLLIP, SIGIRR, MyD88s, NOD2, and TNFAIP3, in CD14+ monocytes from 34 patients with major depressive disorder (MDD) and 33 healthy controls before and after treatment with antidepressants. We also seek to investigate their association with depression severity, measured by the 17-item Hamilton Depression Rating Scale (HAMD-17). RESULTS: mRNA expression of all TLRs, except TLR3 and -5, was significantly higher in monocytes from patients with MDD than in those from controls. Conversely, the "brakes" in TLR signaling, including TOLLIP, MyD88s, NOD2, and TNFAIP3, were downregulated. In clinical findings, the remission group showed higher baseline TLR4 and lower baseline IRAK3 mRNA levels but only baseline elevated SOCS1 mRNA levels, which were inversely correlated with HAMD-17 scores, predicting worsened outcome in MDD patients. In addition, TNFAIP3 mRNA levels were increased by antidepressant treatment. CONCLUSION: Collectively, our findings suggest a role for dysregulation of TLR signaling in monocytes in MDD and identify a balancing effect of antidepressants on this dysregulation.
OBJECTIVE: Changes in the brain's inflammatory status can lead to psychopathological responses, especially depression. Using animal models, recent studies have revealed that this pathology is due, in part, to innate immune responses of monocytes. METHODS: We focus on the involvement of Toll-like receptors (TLRs) and expression of genes encoding their negative regulators, SOCS1, TOLLIP, SIGIRR, MyD88s, NOD2, and TNFAIP3, in CD14+ monocytes from 34 patients with major depressive disorder (MDD) and 33 healthy controls before and after treatment with antidepressants. We also seek to investigate their association with depression severity, measured by the 17-item Hamilton Depression Rating Scale (HAMD-17). RESULTS: mRNA expression of all TLRs, except TLR3 and -5, was significantly higher in monocytes from patients with MDD than in those from controls. Conversely, the "brakes" in TLR signaling, including TOLLIP, MyD88s, NOD2, and TNFAIP3, were downregulated. In clinical findings, the remission group showed higher baseline TLR4 and lower baseline IRAK3 mRNA levels but only baseline elevated SOCS1 mRNA levels, which were inversely correlated with HAMD-17 scores, predicting worsened outcome in MDDpatients. In addition, TNFAIP3 mRNA levels were increased by antidepressant treatment. CONCLUSION: Collectively, our findings suggest a role for dysregulation of TLR signaling in monocytes in MDD and identify a balancing effect of antidepressants on this dysregulation.
Authors: Frank Fang-Yao Lee; Kevin Davidson; Chelsea Harris; Jazalle McClendon; William J Janssen; Scott Alper Journal: J Biol Chem Date: 2020-03-16 Impact factor: 5.157