Abstract
Toll-like receptor 9 (TLR9) belongs to the group of endosomal receptors of the innate immune system with the ability to recognize hypomethylated CpG sequences from DNA. There is scarce information about TLR9 expression and its association with the circadian cycle (CC). Different patterns of TLR9 expression are regulated by the CC in mice, with an elevated expression at Zeitgeber time 19 (1:00 a.m.); nevertheless, we still need to corroborate this in humans. In systemic lupus erythematosus (SLE), the inhibitory effect of chloroquine (CQ) on TLR9 is limited. TLR9 activation has been associated with the presence of some autoantibodies: anti-Sm/RNP, anti-histone, anti-Ro, anti-La, and anti-double-stranded DNA. Treatment with CQ for SLE has been proven to be useful, in part by interfering with HLA-antigen coupling and with TLR9 ligand recognition. Studies have shown that TLR9 inhibitors such as antimalarial drugs are able to mask TLR9-binding sites on nucleic acids. The data presented here provide the basic information that could be useful for other clinical researchers to design studies that will have an impact in achieving a chronotherapeutic effect by defining the ideal time for CQ administration in SLE patients, consequently reducing the pathological effects that follow the activation of TLR9.
Highlights
The main role of the immune system is to identify and eliminate health threats through mechanisms of both adaptive and innate immunity [1, 2]
This perspective deals with the evidence of Toll-like receptor 9 (TLR9) expression patterns related to CC and the interference of CQ in TLR9 activation, suggesting that in theory, it is possible to improve the benefit of CQ treatment based on its chronotherapeutic effect, and this might be exploited to reduce the activation of TLR9 that includes the production of autoantibodies and inflammatory cytokines in systemic lupus erythematosus (SLE)
Silver et al in 2012 published their results describing that peritoneal macrophages derived from Per2-mutant mice that were subject to conditions of 12-h light/12-h darkness and challenged with CpG-ODNs (TLR9 ligand) at different times, had a fluctuation in the expression of TLR9 mRNA, with peaks at Zeitgeber time (ZT) 11 (5:00 p.m.), which correlated with the production of low cytokine levels (TNF-α and IL-12); yet, this circadian behavior was not observed in TLR1, 2, 3, 4, 5, 6, and 7 [120]
Summary
There is scarce information about TLR9 expression and its association with the circadian cycle (CC). In systemic lupus erythematosus (SLE), the inhibitory effect of chloroquine (CQ) on TLR9 is limited. TLR9 activation has been associated with the presence of some autoantibodies: anti-Sm/RNP, anti-histone, anti-Ro, anti-La, and antidouble-stranded DNA. Treatment with CQ for SLE has been proven to be useful, in part by interfering with HLA-antigen coupling and with TLR9 ligand recognition. The data presented here provide the basic information that could be useful for other clinical researchers to design studies that will have an impact in achieving a chronotherapeutic effect by defining the ideal time for CQ administration in SLE patients, reducing the pathological effects that follow the activation of TLR9
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