The circulating of leukocytes in the vasculature to reach various organs is a crucial step that allows them to perform their function. With a sequence of interaction with the endothelial cells, the leukocytes emigrate from the circulation either by firm attachment to vascular beds or by trafficking into the tissues. Recent findings reveal that the leukocyte recruitment shows time as well as tissue specificity depending on the cell type and homing location. This spatiotemporal distribution of leukocyte subsets is driven by the circadian expression of pro-migratory molecules expressed on the leukocytes and the endothelium. Both the systemic circadian signals and the cell's intrinsic molecule clock contribute to the oscillatory expression of pro-migratory molecules. The rhythmic recruitment of leukocytes plays an important role in the time-dependency of immune responses. It also helps to update blood components and maintain the tissue circadian microenvironment. In this review, we discuss the current knowledge about the mechanisms of the circadian system regulating the leukocyte rhythmic migration, the recruitment pattern of leukocyte subsets into different tissue/organs, and the time-dependent effects behind this process.
The circadian clock coordinates physiology, metabolism, and behavior with the 24-h cycles of environmental light. Fundamental mechanisms of how the circadian clock regulates organ physiology and metabolism have been elucidated at a rapid speed in the past two decades. Here we review circadian networks in more than six organ systems associated with complex disease, which cluster around metabolic disorders, and seek to propose critical regulatory molecules controlled by the circadian clock (named clock-controlled checkpoints) in the pathogenesis of complex disease. These include clock-controlled checkpoints such as circadian nuclear receptors in liver and muscle tissues, chemokines and adhesion molecules in the vasculature. Although the progress is encouraging, many gaps in the mechanisms remain unaddressed. Future studies should focus on devising time-dependent strategies for drug delivery and engagement in well-characterized organs such as the liver, and elucidating fundamental circadian biology in so far less characterized organ systems, including the heart, blood, peripheral neurons, and reproductive systems.
Nonalcoholic steatohepatitis (NASH) is the common liver disease characterized by hepatic steatosis, inflammation, and fibrosis; there are no approved drugs to treat this disease because of incomplete understanding of pathophysiological mechanisms of NASH. Milk fat globule-epidermal growth factor-factor 8 (MFG-E8), a multifunctional glycoprotein, has shown anti-inflammation and antifibrosis. Here, MFG-E8 was shown to play a key role in NASH progression. Using methionine and choline deficient (MCD) diet-fed mice, we found MFG-E8 knockout exacerbated hepatic damage and steatosis as indicated by increased plasma transaminases activities and hepatic histopathologic change, higher hepatic triglycerides (TGs), and lipid accumulation. Moreover, liver fibrosis and inflammation elicited by MCD were aggravated in MFG-E8 knockout mice. Mechanistically, MFG-E8 knockout facilitated activation of hepatic toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling pathway in MCD-fed mice. In vitro experiment, the TLR4 specific antagonist TAK-242 rescued palmitic acid- (PA-) primed lipid formation and inflammation in MFG-E8 knockout primary murine hepatocytes. These findings indicated that MFG-E8 is involved in the progression of NASH and the possible mechanism by which MFG-E8 knockout exacerbated NASH in mice is associated with activation of the TLR4/NF-κB signaling pathway.
In the published article, there was an error in Figure 4B as published. In the original publication of this article, the same GraphPad file was accidentally linked in Figures 4B, D, which is a mistake. The corrected Figure 4B and its caption appear below.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.
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