Potential Chronotherapeutic Optimization of Antimalarials in Systemic Lupus Erythematosus: Is Toll-Like Receptor 9 Expression Dependent on the Circadian Cycle in Humans?

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.

The mechanisms of hydroxychloroquine in rheumatoid arthritis treatment: Inhibition of dendritic cell functions via Toll like receptor 9 signaling

“…Early findings demonstrated that TLR9 was required for DCs to detect microbial nucleic acids during infection [ 32 ]. Later, TLR9 was found as a vital molecule for DCs to recognize and process nucleic acids molecules, which plays a pivotal function in the development of autoimmune diseases such as SLE [ 33 ] and psoriasis [ 34 ]. In this study, we found the expression of CXCR4, CCR7, CD83, 86 and IFN-α were up-regulated in RA serum-stimulated DCs and this effect was inhibited by HCQ, indicating that some substances in RA serum induced DC activation were blocked by HCQ.…”

Autophagy as an emerging target for COVID-19: lessons from an old friend, chloroquine

“…HCQ, although less toxic than CQ, still displays some well-known undesirable properties. The main concern is with regard to cardiomyopathy and heart failure, and the development of retinopathy due to HCQ affinity to melanin-containing cells, a secondary effect noticed in patients with lupus disease [78][79][80][81]. Therefore, it is recommended that the daily dose of CQ/HCQ in autoimmune patients should not exceed 5 mg/kg/d.…”

Sleep Problems in Chronic Inflammatory Diseases: Prevalence, Treatment, and New Perspectives: A Narrative Review

“…Moreover, drug chronotherapy (a form of therapy in which the administration of drugs is based on the 24 h circadian rhythm) with glucocorticosteroids and disease-modifying anti-rheumatic drugs was shown to be beneficial in RA [ 120 , 121 , 122 ]. This approach also appears promising in other diseases, such as SLE, but more studies would be desirable [ 123 ].…”