BMAL1 as a Potential Lever to Influence Macrophage Behavior
Macrophages are innate immune cells found throughout the body, important not just for their ability to defend against infectious pathogens, but also deeply involved in tissue maintenance and regeneration. Macrophages can adopt different packages of behaviors - known as polarizations - in response to circumstances. The simple model, which likely glosses over many lesser differences that are important in some contexts, divides the macrophage population into M1 and M2 polarizations, distinguished by surface features as well as by behaviors. M1 macrophages generate inflammation and aggressively hunt down pathogens. M2 macrophages resolve inflammation and engage in tissue maintenance activities, such as ingesting cellular debris and waste products. Both polarizations are necessary, but aging brings imbalance, often characterized as too many M1 macrophages where M2 macrophages are what is needed.
Thus the research community is interested in developing the means to adjust macrophage polarization for therapeutic benefit. At the outset, this involves better understand the regulation of polarization, and the many distinct influences that contribute to a macrophage adopting one state or another. Today's research materials focus on an aspect of the regulation of circadian rhythm that is known to influence macrophage behavior, and the authors report on their efforts to dig more deeply into how this actually works. This sort of fundamental research is necessary to identify possible points of intervention for the later development of therapies.
Body clock found to control inflammatory responses in macrophages
When our body encounters an injury or infection, the immune system sends out cells known as macrophages to initiate an inflammatory response that begins the healing process. These macrophages can exist in two different states: a pro-inflammatory (M1) state, which promotes inflammation, and an anti-inflammatory (M2) state, which helps resolve inflammation and repairs the tissue. The balance between these two states is important, as disruptions can lead to uncontrolled inflammation, which in turn can give rise to chronic inflammation-associated diseases, including cancer, liver disease, diabetes, and autoimmune disorders.
Previous studies have revealed that macrophage activity is closely linked to the circadian clock, with BMAL1 playing a central role in regulating this process. Researchers have now found that BMAL1 drives macrophages toward a pro-inflammatory M1 state by activating inflammatory signaling pathways in the cell nucleus. Researchers observed that normal mice showed a marked increase in pro-inflammatory M1 macrophages along with elevated inflammatory signals after exposure to a chemical carcinogen. In contrast, mice lacking BMAL1 in their macrophages showed significantly reduced inflammation and suppressed liver tumor development.
Experiments revealed that BMAL1 binds to multi-functional protein 2 (MFP2), a fatty acid-oxidation enzyme normally found in cellular compartments called peroxisomes, and transports it into the cell nucleus. Notably, nuclear MFP2 levels fluctuate according to the time of day in a BMAL1-dependent manner. Once inside the nucleus, MFP2 increases acetyl-CoA levels, which drives acetylation of key proteins including p65, a component of the transcription factor NF-κB, a key regulator of inflammatory genes. This activates NF-κB, which functions as a switch for inflammatory genes, thereby driving macrophages into the pro-inflammatory M1 state. These findings suggest that targeting or blocking nuclear MFP2 and administering drugs at an optimal time of the day could become a new therapeutic strategy for chronic inflammatory diseases and enhance treatment efficacy while minimizing side effects.
The circadian clock regulates diverse immune functions, yet the role of clock components in macrophage inflammation remains controversial, with both pro- and anti-inflammatory effects reported. Here, we identify a previously unrecognized mechanism by which the core circadian clock component BMAL1 enhances the inflammatory response of macrophages through the nuclear translocation of the peroxisomal β-oxidation enzyme multi-functional protein 2 (MFP2). BMAL1 drives MFP2 accumulation in the nucleus, where MFP2 contributes to acetyl-CoA production and acetylation of the NF-κB subunit p65, thereby facilitating M1 polarization and inflammatory chemokine expression. Nuclear MFP2 levels oscillate in a diurnal manner in the liver, but this rhythmicity is abolished in Bmal1-deficient mice. Macrophage-specific deletion of BMAL1 alleviates diethylnitrosamine-induced hepatic inflammation and tumorigenesis, concomitant with reduced inflammatory gene expression. These findings uncover a BMAL1-dependent nuclear metabolic pathway that links circadian regulation of macrophage inflammation and suggest that targeting nuclear MFP2 may offer a therapeutic approach for inflammatory diseases and tumorigenesis.