Circadian clock regulates the host response to Salmonella

Abstract

Organisms adapt to day-night cycles through highly specialized circadian machinery, whose molecular components anticipate and drive changes in organism behavior and metabolism. Although many effectors of the immune system are known to follow daily oscillations, the role of the circadian clock in the immune response to acute infections is not understood. Here we show that the circadian clock modulates the inflammatory response during acute infection with the pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium). Mice infected with S. Typhimurium were colonized to higher levels and developed a higher proinflammatory response during the early rest period for mice, compared with other times of the day. We also demonstrate that a functional clock is required for optimal S. Typhimurium colonization and maximal induction of several proinflammatory genes. These findings point to a clock-regulated mechanism of activation of the immune response against an enteric pathogen and may suggest potential therapeutic strategies for chronopharmacologic interventions.clock genes | inflammation | gastroenteritis | intestine | microbes

Immunometabolism: Is it under the eye of the clock?

“…Mice infected with Salmonella typhimurium (S. typhimurium) at ZT16 display a greater ability to clear the bacteria from the colon 72 hr post infections versus mice treated at ZT4 [65]. This demonstrates that during the active phase, the innate immune system is primed to mount an anti-bacterial response.…”

“…CLOCK complexes with p65 causing increased acetylation and phosphorylation of p65 and enhancing the activity of the NF-B complex [115]. Both CLOCK mutant MEFs [116] and bone marrow derived macrophages (BMDMs) lacking CLOCK, are less responsive to LPS, and TNF␣ induced NF-B activation [65]. Therefore CLOCK may drive, whereas BMAL1 may limit, pro-inflammatory responses in macrophages.…”

“…• 30% increased weight gain on high fat diet [80] • Increased susceptibility to sepsis with LPS or Listeria [22,65] • Greater IL-6, TNF␣ [22] • Lower IL-10 [22] Clock Global • Partial diabetes [160] • Reduced NF-B activation in MEFs and BMDMs. [66,116] Clock 19 Global • Obese and display impaired glucose sensitivity with insulin resistance and reduced islet size [112,113] • Increased plasma triglyceride and glucose levels [85,114] • Increased fibrotic damage in model of pulmonary fibrosis [87] • Impaired anti-oxidant defense [87] Cry1/Cry2 Global • Increased NAD+ and ATP.…”

Depression in Autoimmune Diseases

“…For example the macrophage response to Salmonella is decreased in mice with an inactive clock gene (Bellet et al, 2013), and the extent of secretion of TNF and IL-6 by LPS stimulated macrophages follows a circadian rhythm (Keller et al, 2009). Besides effects of the circadian system on the immune response, the immune system also influences the circadian clock.…”

Tumor Necrosis Factor and Transforming Growth Factor β Regulate Clock Genes by Controlling the Expression of the Cold Inducible RNA-binding Protein (CIRBP)

“…The extent of secretion of TNF and IL-6 by LPS-stimulated macrophages follows a circadian rhythm (5). The macrophage response to LPS is decreased in mice with an inactivation of the Clock gene (6). Compared with bone marrow-derived macrophages obtained from wild type (WT) mice, the expression of cytokines including IL-1␤, IL-6, TNF, IFN␣, and IFN␥ was significantly lower in clock mutant mice.…”