Circadian Gene Bmal1 Regulates Diurnal Oscillations of Ly6C ^hi Inflammatory Monocytes

Abstract

Circadian clocks have evolved to regulate physiologic and behavioral rhythms in anticipation of changes in the environment. Although the molecular clock is present in innate immune cells, its role in monocyte homeostasis remains unknown. Here, we report that Ly6Chi inflammatory monocytes exhibit diurnal variation, which controls their trafficking to sites of inflammation. This cyclic pattern of trafficking confers protection against Listeria monocytogenes and is regulated by the repressive activity of the circadian gene BMAL1. Accordingly, myeloid cell-specific deletion of BMAL1 induces expression of monocyte-attracting chemokines and disrupts rhythmic cycling of Ly6Chi monocytes, predisposing mice to development of pathologies associated with acute and chronic inflammation. These findings have unveiled a critical role for BMAL1 in controlling the diurnal rhythms in Ly6Chi monocyte numbers.

Immunometabolism: Is it under the eye of the clock?

“…With myeloid lineage specific deletion of Bmal1, the time of day variation in response to bacteria and LPS induced lethality is lost [22,80]. Monocytes and macrophages lacking Bmal1 produce greater levels of pro-inflammatory cytokines and chemokines while producing reduced levels of the antiinflammatory cytokine IL-10 ( Fig.…”

“…• 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.…”

Circadian rhythm‐related genes: implication in autoimmunity and type 1 diabetes

“…Many other examples have been published since, some of which concern highly specific immune functions. Recent studies showed for example that Th17 differentiation is controlled by the circadian clock [18], that the circadian gene Bmal1 regulates diurnal oscillations of Ly6C(hi) inflammatory monocytes [19], or that the circadian clock protein CRY regulates the expression of proinflammatory cytokines [8].…”

“…Many other examples have been published since, some of which concern highly specific immune functions. Recent studies showed for example that Th17 differentiation is controlled by the circadian clock [18], that the circadian gene Bmal1 regulates diurnal oscillations of Ly6C(hi) inflammatory monocytes [19], or that the circadian clock protein CRY regulates the expression of proinflammatory cytokines [8].In this context, it does not seem surprising that autoimmune disease is influenced by the circadian rhythm. This observation has particularly been made in rheumatoid arthritis, where patients suffer more from stiffness and pain in the morning than during other times of the day.…”

Human and mouse leukocytes: different clockwork

“…[4][5][6] For instance, oscillations of Bmal1 expression in inflammatory monocytes regulate chemokine genes and immune response. 7 Inverted oscillations in circulating leukocytes have been previously reported in (nocturnal) mice and (diurnal) humans. [4][5][6] In both species, leukocytes are preferentially released from the bone marrow into circulation during the resting period.…”