Selective serotonin reuptake inhibitor attenuates the hyperresponsiveness of TLR2+ and TLR4+ Th17/Tc17-like cells in multiple sclerosis patients with major depression

Abstract

Elevated frequency of Th17-like cells expressing Toll-like receptors (TLRs) has been recently associated with relapsing-remitting multiple sclerosis (MS) pathogenesis, a chronic inflammatory demyelinating autoimmune disease of the central nervous system. We aimed to investigate the impact of current major depressive disorder (MDD) on the behaviour of these cells following in vitro stimulation with TLR2, TLR4, TLR5 and TLR9 agonists. Here, the level of both cell proliferation and cytokine production related to Th17/Tc17 phenotypes in response to TLR2 (Pam3C) and TLR4 (LPS) ligands was significantly higher in CD4⁺ and CD8⁺ T-cell cultures from MS/MDD patients when compared to non-depressed patients. These cytokine levels were positively associated with neurological disabilities in patients. No difference for responsiveness to TLR5 (flagellin) and TLR9 (ODN) agonists was observed. LPS, but not Pam3C, induced significant IL-10 release, mainly in patients without MDD. Interestingly, more intense expression of TLR2 and TLR4 on these cells was observed in MDD patients. Finally, in vitro addition of serotonin and treatment of MDD patients with selective serotonin reuptake inhibitors (SSRIs) reduced the production of Th17/Tc17-related cytokines by CD4⁺ and CD8⁺ T cells in response to Pam3C and LPS. However, only SSRI therapy diminished the frequency and intensity of TLR2 and TLR4 expression on circulating CD4⁺ and CD8⁺ T cells. In summary, although preliminary, our findings suggest that adverse events that elevate circulating levels of TLR2 and TLR4 ligands can affect MS pathogenesis, particularly among depressed patients.

Keywords: Multiple sclerosis; PAMP; TLR; Tc17; Th17; cytokines; major depressive disorder; selective serotonin reuptake inhibitors; serotonin.