Fig 1.
Regulatory network of the coupled immune system and circadian clock.
Schematic diagram of the acute immune response model (orange shapes) and the circadian clock (blue shapes) in the lung of a rat. In the circadian clock model, slanted boxes denote mRNAs; blue rectangles denote proteins; ovals denote protein complexes. Dotted arrows represent transactivation; blunt dashed arrows represent inhibition. In the acute inflammation model, P denotes endotoxin; D, damage marker; N, activated phagocytic cells; CA, slow-acting anti-inflammatory cytokines.
Fig 2.
Male-to-female relative abundance of mRNAs for controls and shifters, normalized by control male-to-female ratios.
Fig 3.
Predicted clock gene time profiles.
Comparison of predicted time profiles (solid lines) for Per, Cry, Rev-Erb, Ror and Bmal1, with experimental data (circles) for Per2, Cry1, Rev-Erbα, Rorc, and Bmal1 mRNA expression levels obtained in mouse lungs in constant darkness. Gray shading and white regions correspond to activity and restcycles, respectively.
Fig 4.
Predicted cytokine time profiles.
Comparison of predicted time-courses of IL-6, TNF-α and IL-10 (solid line), against experimental data (circle) (mean ± SD), in response to endotoxin challenge at dosages of 3 mg/kg, 12mg/kg and 6mg/kg.
Fig 5.
Inflammatory response after infection at CT0 and CT12.
Model simulations of the time course of IL-6, TNF-α, IL-10 and the damage marker for the control model in response to endotoxin dose 3mg/kg administered at CT0 and CT12.
Fig 6.
Phase relations between CRY, REV-ERB and ROR.
Baseline model simulation of the main clock genes involved in the inflammatory response. Normalized temporal expression profiles of CRY, REV-ERB and ROR proteins, relative to their respective mean value.
Fig 7.
Model simulations of the time course of IL-10 (A) and the damage marker (B) in response to endotoxin dose 3mg/kg administered CT12. Three scenarios are simulated: Rev-Erb KO, Cry KO and Ror KO.
Fig 8.
Sex-specific response to infection during CJL at CT0 and CT12.
Model simulations of the time course of IL-6, TNF-α, IL-10 and the damage marker for controls (black) against CJL males (blue) and CJL females (pink) in response to endotoxin challenge of 3mg/kg administered at CT0 and CT12.
Fig 9.
Simulated acute inflammation across different circadian times.
IL-6 (A), TNF-α (B), IL-10 (C), Damage marker (D). The endotoxin dose is 3mg/kg. Left column, no CJL; middle column, CJL females; right column, CJL males.