Research ArticleImmunology

Desynchronization of the molecular clock contributes to the heterogeneity of the inflammatory response

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Science Signaling  05 Mar 2019:
Vol. 12, Issue 571, eaau1851
DOI: 10.1126/scisignal.aau1851

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Desynchronized macrophage responses

Within a population of cells that are genetically and developmentally identical, individual cells do not necessarily respond identically to the same stimulus. Such differences may be due to cell-intrinsic variables, extracellular factors, or stochastic events. Allen et al. found that the proportion of macrophages within a population that produced the cytokine IL-12p40 in response to an inflammatory stimulus depended on the phase of the circadian clock (a cell-intrinsic factor) and the relative expression of clock genes. Although the central body clock resets the clock in peripheral tissues daily, the clocks of individual cells within a population gradually become desynchronized. These findings demonstrate that such differences in clock phase between individual macrophages contribute to the heterogeneity in their response to inflammatory stimuli.


Heterogeneity in the behavior of genetically and developmentally equivalent cells is becoming increasingly appreciated. There are several sources of cellular heterogeneity, including both intrinsic and extrinsic noise. We found that some aspects of heterogeneity in the response of macrophages to bacterial lipopolysaccharide (LPS) were due to intercellular desynchronization of the molecular clock, a cell-intrinsic oscillator. We found that the ratio of the relative expression of two clock genes, Nfil3 and Dbp, expressed in opposite phases of the clock, determined the fraction of cells that produced the cytokine IL-12p40 in response to LPS. The clock can be entrained by various environmental stimuli, making it a mechanism by which population-level heterogeneity and the inflammatory response can be regulated.

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