Toll-like receptor 9 is required for chronic stress-induced immune suppression.

OBJECTIVES Mental and physical stress can suppress the immune system in both humans and animals. The mechanism by which stress affects immune responses, however, remains poorly defined. Toll-like receptors (TLRs) play a key role in modulating immune responses and cell survival. The mechanisms by which TLRs modulate chronic stress are largely unexplored. METHODS Six- to 8-week-old male mice were subjected to chronic 12-hour daily physical restraint stress. Apoptotic cells were determined by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) assay. We examined cytokine levels by enzyme-linked immunosorbent Assay (ELISA). The expression of CYP11A1 was determined by quantitative real-time RT-PCR. RESULTS TLR9-deficient mice were resistant to chronic stress-induced lymphocyte apoptosis. In addition, in TLR9 knockout (KO) mice, chronic stress-induced upregulation of corticosterone levels was significantly decreased. Notably, lymphocytes from both TLR9 KO and wild-type mice were similarly sensitive to corticosteroid-induced cell apoptosis. Moreover, TLR9 deficiency blocked the chronic stress-induced imbalance in T helper (Th) 1 and Th2 cytokine levels. CONCLUSION Taken together, our findings reveal that TLR9 plays an essential role in chronic stress-induced immune suppression.