Editors' ChoiceIMMUNITY

Sepsis: Up Against the Clock

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Science Translational Medicine  14 Mar 2012:
Vol. 4, Issue 125, pp. 125ec47
DOI: 10.1126/scitranslmed.3003980

It’s like clockwork: Sick patients only come to the hospital in the middle of the night, just as the on-call physician’s head hits the pillow. Although an anecdotal scenario, some diseases have similar cyclical variation in occurrence and severity throughout the day and the night. New data from Silver and colleagues now demonstrate that the innate immune system is regulated by a molecular clock, linking the time of day to immune function and, in turn, illness.

Silver et al. discovered that Toll-like receptor 9 (TLR9) expression and function vary over a 24-hour period and is regulated by the clock-specific transcription factors CLOCK and BMAL1. Compared with other TLRs, TLR9-dependent cytokine responses were uniquely impaired in mutant macrophages that lacked a molecular clock. In vivo in mice, the use of a TLR9 adjuvant during immunization elicited the greatest antigen-specific lymphocyte proliferation and interferon-γ responses; but only when administered at peak TLR9 expression, showing its clock-like function. Because TLR9 has been linked to septic shock, the authors induced sepsis in mice at both the nadir and the peak of TLR9 expression. Surprisingly, sepsis occurring during peak TLR9 expression resulted in worse clinical severity, elevated levels of the inflammatory cytokines, higher bacterial loads, and increased mortality. These findings add to our understanding of sepsis pathophysiology and suggest that future diagnostic and therapeutic interventions may require temporal consideration.

The human TLR9 promoter includes binding sites for the molecular clock transcription factors; however, the importance and relevance of the current findings are yet to be tested in people. TLR9 vaccine adjuvants are already in clinical trials, and it will be interesting to see how the cyclic behavior of TLR9 could impact a septic patient at 3:00 a.m., for example. If anything, clinicians can rest assured that an explanation to the late-night clinical problem is becoming clearer.

A. C. Silver et al., The circadian clock controls Toll-like receptor 9-mediated innate and adaptive immunity. Immunity 36, 251–261 (2012). [Abstract]

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