Circadian control of innate immunity in macrophages by miR-155 targeting Bmal1

Abstract

The response to an innate immune challenge is conditioned by the time of day, but the molecular basis for this remains unclear. In myeloid cells, there is a temporal regulation to induction by lipopolysaccharide (LPS) of the proinflammatory microRNA miR-155 that correlates inversely with levels of BMAL1. BMAL1 in the myeloid lineage inhibits activation of NF-κB and miR-155 induction and protects mice from LPS-induced sepsis. Bmal1 has two miR-155-binding sites in its 3′-UTR, and, in response to LPS, miR-155 binds to these two target sites, leading to suppression of Bmal1 mRNA and protein in mice and humans. miR-155 deletion perturbs circadian function, gives rise to a shorter circadian day, and ablates the circadian effect on cytokine responses to LPS. Thus, the molecular clock controls miR-155 induction that can repress BMAL1 directly. This leads to an innate immune response that is variably responsive to challenges across the circadian day.inflammation | sepsis | circadian clock | miR-155 | Bmal1

Immunometabolism: Is it under the eye of the clock?

“…REV-ERBs are capable of repressing Bmal1 transcription [20], whereas RORs cause transcriptional activation of Bmal1 [21]. It is believed that post transcriptional modifications, including control by miRNAs [22], provide another layer of organisation to this tightly regulated system. The BMAL1:CLOCK heterodimer can bind thousands of sites in the genome and it is the oscillation of this binding that leads to circadian expression of clock-controlled genes.…”

“…• 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.…”

“…• Impaired Th17 cell development [132] ROR˛/ Global • No Th17 cell populations [133] • Resistant to EAE [134] the myeloid lineage [22]. With myeloid lineage specific deletion of Bmal1, the time of day variation in response to bacteria and LPS induced lethality is lost [22,80].…”

Resveratrol Ameliorates Cardiac Hypertrophy by Down‐regulation of miR‐155 Through Activation of Breast Cancer Type 1 Susceptibility Protein

“…In a previous study, we elucidated the feasibility of using our constructed miRNA reporter imaging system to monitor the location and magnitude of expression levels of miR‐22 in cardiac hypertrophy in vitro and in vivo 19. Most recently, miR‐155 was reported to be expressed in atherosclerotic plaques and proinflammatory macrophages and the in vivo function of miR‐155 in cardiomyocyte hypertrophy was also manifested 20, 21, 22. Another excellent study in this research area by Shyam's group demonstrated a previously unknown role for BRCA1 in epigenetic control of miR‐155 23…”

A New Perspective for Parkinson’s Disease: Circadian Rhythm

“…Above all, the epigenetic alterations in NPSA2 expression may be the primary cause of changes in Bmal1 and Bmal2 in the leukocytes of PD patients [96]. Curtis AM et al identified the importance of Bmal1 in modulating the inflammatory response, by regulating miR-155 and some proinflammatory cytokines including TNF-a [97].…”