Suction —————
Ah, the fragrant snail powder!!!
For animals and people, the nose is a very important sensory. After the gas is inhaled into the nose, these small volatile molecules act on olfactory receptors (also called olfactory receptors) in the nose, and then transmit information to the brain through the olfactory nerve.
But did you know that the immune cells in the arteries can also "smell", which can also cause cardiovascular disease!
Klaus Ley and his colleagues from the La Jolla Institute of Immunology in the United States found that the presence of the olfactory receptor OR6A2 on the surface of macrophages in human arteries can interact with an odorous molecule called octanal, triggering an NLRP3-mediated inflammatory response that drives the progression of atherosclerosis [1].
In addition, the researchers also successfully alleviated the atherosclerosis disease of mice by inhibiting the activity of OLFR2 (equivalent to human OR6A2) on mouse vascular macrophages.
The article was recently published in the journal Science.
Screenshot of the first page of the paper
Although we often say that macrophages in the immune system often show a keen sense of smell for pathogens that invade the body, quickly take them down in one fell swoop, or further pass on messages to call on the brethren to arrest them.
But this is also a metaphor ah hey!
Researchers at the La Jolla Institute of Immunology in the United States have found in 2019 and 2020 that macrophages in human arteries really "have a sense of smell", can express olfactory receptors such as OR6A2, and even prove that OR6A2 can recognize and bind to octylaldehyde [2,3].
So what does octaldehyde really taste like? Seriously, when smelled with the nose outside the body, the researchers described it as a "not fresh taste of cooked chicken." (Chicken is crunchy!) Wrong walked wrong)
When placed in our bodies, lipid peroxidation produces caprylylaldehyde when the blood or tissues and organs are under oxidative stress [4]. Studies have shown that everyone has a small amount of octylaldehyde in their blood, and for people with high levels of ox-reduced low-density lipoprotein (ox LDL) in the blood, this "bad" cholesterol not only accumulates in the walls of blood vessels and causes atherosclerosis, but also produces more peroxide products, resulting in higher levels of octylaldehyde in the blood [5].
Since damage to vascular macrophage function is also associated with the development of atherosclerosis[5], Ley and his colleagues wondered whether the progression of atherosclerosis would be affected when macrophages "smelled" in the blood environment, that is, octanaldehyde.
So they first constructed a mouse model of OLFR2 deletion and injected octylaldehyde into these mice and wild-type mice respectively to observe the interaction of octylaldehyde with macrophages in arteries.
A series of studies have shown that when vascular macrophages interact with octylaldehyde through OLFR2, they will not only induce the level of cAMP, Ca2+, and ROS molecules in macrophages, but also activate the NLRP3 inflammasomes, resulting in macrophage synthesis and secretion of pro-inflammatory factors IL-1α and IL-1β, triggering an inflammatory response.
Moreover, the inflammatory response also worsens with the increase in the amount of octylaldehyde injected. The arteries of wild-type mice injected with octylaldehyde even began to develop atherosclerotic lesions.
Change in octanal (Oct) injection volumes of 3, 10, and 30 μM
For atherosclerotic mice (Apoe−/−), octylaldehyde levels in the blood more than doubled after 8 weeks of injection of octanaldehyde (10 μg/g). According to the results of pathological section staining, the lesion area of mice also more than doubled; tumor necrosis factor (TNF) in the blood and IL-1β levels were further increased.
Atherosclerotic mice injected with octylaldehyde worsened
Simply put, OLFR2 on mouse vascular macrophages can drive the occurrence of atherosclerosis when it interacts with a certain dose of octylaldehyde.
It is worth mentioning that Ley and his colleagues found that in addition to the high levels of ox LDL in the blood that caused an increase in octylaldehyde levels, the high-fat diet also caused the level of octylaldehyde in the blood of mice.
When wild-type mice (C57BL/6) were fed a normal diet (rat food) and a high-fat diet (42% calories from fat), the levels of octylaldehyde in the blood of the former were slightly reduced, while the levels of octylaldehyde in the latter were nearly doubled. Similar results can be observed in atherosclerotic mice (Apoe−/−, Ldlr−/−).
Macrophages smell the mouth in the breath of crime
(CD: normal diet; WD, HCD: high-fat diet)
In response to the fact that vascular macrophages can induce atherosclerosis after "knowing the incense", the researchers have also come up with countermeasures, intending to plug the "nostrils" of macrophages.
They found citral, an inhibitor of OLFR2 on mouse macrophages, a compound that smells like lemon[6]. After injecting atherosclerotic mice (Apoe−/−) with citral (10 μg/g) to inhibit the activity of OLFR2, the researchers found that after 16 weeks, the mice's inflammation was reduced, the atherosclerosis was reduced by about 40%, and the mice's body weight and white blood cell levels were not affected.
Plugging nostrils is effective
What's more, the researchers have shown in in vitro experiments that the above conclusions also apply to macrophages in human arteries.
OR6A2 on human vascular macrophages is a homologous gene expression product with OLFR2 in mice, and when human macrophages interact with octylaldehyde through OR6A2, a similar inflammatory response occurs and can be inhibited by citral. In addition, they demonstrated in samples from 196 participants that caprylylline levels in the blood were associated with atherosclerosis.
In summary, Ley and his colleagues found that the presence of OR6A2 or OLFR2 olfactory receptors on macrophages in human or mouse arteries triggers an NLRP3-mediated inflammatory response when interacting with octanal in the blood, promoting the development of atherosclerosis.
When inhibiting OLFR2 activity on mouse macrophages, symptoms of atherosclerosis in mice can be improved.
In fact, there are many drugs that inhibit the receptor activity of OR6A2, a GPCR type. Researchers suggest that perhaps in humans, inhibiting OR6A2 activity on macrophages in the arteries may also alleviate the condition of patients with atherosclerosis [7].
All in all, the results of this study provide a new and interesting effective strategy for the treatment of atherosclerosis:
Plug the "nostrils" of macrophages in the arteries!
bibliography:
[1]https://www.science.org/doi/10.1126/science.abg3067
[2] S. McArdle, K. Ley, et al, Migratory and dancing macrophage subsets in atherosclerotic lesions. Circ. Res. 125, 1038–1051 (2019).
[3] A. Zernecke, K. Ley, et al, Meta-analysis of leukocyte diversity in atherosclerotic mouse aortas. Circ. Res. 127, 402–426 (2020).
[4] W. B. Rizzo, Fatty aldehyde and fatty alcohol metabolism: Review and importance for epidermal structure and function. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 1841, 377–389 (2014).
[5] Libby P. The changing landscape of atherosclerosis. Nature. 2021 Apr;592(7855):524-533. doi: 10.1038/s41586-021-03392-8. Epub 2021 Apr 21. PMID: 33883728.
[6] R. C. Araneda, Z. Peterlin, X. Zhang, A. Chesler, S. Firestein, A pharmacological profile of the aldehyde receptor repertoire in rat olfactory epithelium. J. Physiol. 555, 743–756 (2004).
[7]https://www.lji.org/news-events/news/post/macrophages-in-the-artery-wall-smell-their-surroundings/
This article is written by | Eddie Zhang