Toll-like receptor expression and function in type I bipolar disorder

Abstract

Bipolar disorder (BD) has been associated with immune imbalance and low-grade inflammation. The underlying mechanisms remain largely obscure but may involve changes in cell signaling. Toll-like receptors (TLRs) are widely expressed by immune cells. Specific binding of TLRs to pathogen- or danger-associated signals leads to inflammatory responses. Here, we analyzed the frequencies of TLR-1, TLR-2, TLR-4, TLR-5 and TLR-6 in monocytes, regulatory T cells (Tregs) and activated T cells from type I BD euthymic patients and healthy controls (HCs). Monocytes were stimulated in vitro with specific TLR agonists (flagellin, LPS, LTA, BLP and PGN) and immunophenotyped. Cytokines (IL-8, IL-1beta, IL-6, IL-10, TNF-alpha and IL-12p70) were assessed with cytometric bead arrays. At baseline, increased percentages of TLR-1+ and TLR-2+ monocytes and reduced expression of TLR-5 were observed in BD. Following stimulation, the percentage of TLR-1+, TLR-2+, and TLR-6+ monocytes was higher in BD subjects than in HCs. Increased levels of IL-8, IL-12p70 and TNF were observed following stimulation with TLR-1, TLR-2 and TLR-6 agonists, suggesting increased signaling via these receptors in BD. In contrast to HCs, BD patients exhibited no changes in TLR-5 expression following stimulation. The percentage of TLR-2+ Treg cells as well as activated T cells expressing both TLR-2 and TLR-5 increased in BD patients. Given the importance of TLRs in triggering immune responses, our data indicate a role for these receptors in the low-grade inflammatory profile documented in BD.