Abstract
Circadian rhythms refer to biologic processes that oscillate with an approximate 24-h period. These rhythms direct nearly all aspects of animal behavior and physiology. The aim of our study was to determine if Toll-like receptor (TLR) expression and responsiveness exhibit time-of-day dependent differences. Therefore, we isolated an adherent splenocyte population, which consisted primarily of B cells, dendritic cells, and macrophages, over the course of a 24-h light-dark period and measured daily changes in Tlr1-8 mRNA levels and cytokine expression after cells were challenged at Zeitgeber time (ZT) 1 or ZT13 with a TLR ligand. In addition, we assessed TLR3 protein levels in adherent splenocytes over the 24-h light-dark period and challenged mice at ZT1 or ZT13 with poly(I:C), the TLR3 ligand. Our study revealed that in this adherent cell population, all Tlrs exhibited rhythmic expression except Tlr2 and Tlr5, and all TLRs, except TLR8, demonstrated daily variations in responsiveness after challenge with their respective ligand. We also revealed that TLR3 protein levels fluctuate over the daily light-dark cycle in adherent splenocytes and mice exhibit a time-of-day dependent immune response when challenged with poly(I:C). Finally, we demonstrated that mRNA levels of Tlr2 and Tlr6 display rhythmic expression in splenic macrophages. Taken together, these findings could have important implications for TLR-directed therapeutics.
Highlights
Circadian rhythms refer to biological processes, from gene expression to behavior, that oscillate with an approximate 24-h period [1]
We revealed that TLR3 protein levels fluctuate over the daily light-dark cycle in adherent splenocytes and mice exhibit a time-of-day dependent immune response when challenged with poly(I:C)
Toll-like receptor (TLR) are a class of pattern recognition receptor (PRR) located in endosomal compartments or on the surface of certain immune cells that identify pathogen-associated molecular patterns (PAMPs), conserved microbial components that are exclusive to microorganisms
Summary
Circadian (daily) rhythms refer to biological processes, from gene expression to behavior, that oscillate with an approximate 24-h period [1]. While external cues such as activity, food consumption, and temperature can direct daily rhythms, daily changes in light intensity entrain the suprachiasmatic nucleus (SCN, i.e., the master clock), more than any other environmental factor [2]. We have previously demonstrated that the circadian clock directly modulates Toll-like receptor (TLR) 9 expression and responsiveness, which has time-of-day dependent implications regarding TLR9mediated innate and adaptive immunity [9]. In addition to initiating the innate immune response, TLR-PAMP recognition directs the adaptive immune response [11]
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