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Blocking Olfactory Receptors in Macrophages Reduces Inflammation in Blood Vessel Walls

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#1 reason

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Posted 21 January 2022 - 08:02 PM

Chronic inflammatory signaling is an important issue in aging, both generally throughout the body, and in localized hot spots such as atherosclerotic lesions in blood vessel walls. Macrophage cells responsible for clearing out molecular waste and repairing damage in blood vessels are made less effective by inflammatory signaling. The feedback loop of ineffective macrophages becoming incapacitated by the toxic lesion environment, while inflammation draws in more macrophages, is at the center of the progression of atherosclerosis. Ultimately these fatty lesions grow to the point of rupture, and the result is a heart attack or stroke.

In today's research materials, scientists report on a less well studied component of inflammation, in that macrophages express olfactory receptors also found in cells in the nose, and can identify aldehydes in the bloodstream. The cells react with raised inflammatory signaling. The presence of such compounds increases with age, and this contributes to the growing dysfunction of macrophage cells that should be working to keep blood vessel walls free from metabolic waste and damage.

A cautionary note on this front is that past efforts to treat atherosclerosis by suppression of inflammatory signaling did not produce exceptional results. The outcomes looked little better than therapies that lower LDL cholesterol in the bloodstream, producing only a minor reduction in the size of existing lesions. Since mortality risk scales with the size and number of lesions, the great unmet need here is a way to rapidly and safely remove lesions. Present strategies can only slow the condition, and do little for the high risk groups in which patients already exhibit sizeable lesions.

Immune cells can sniff out octanal in blood, triggering dangerous inflammation and atherosclerosis

Everyone has a small amount of octanal in their blood, but scientists have shown that people with markers of cardiovascular disease, such as high LDL cholesterol, also have higher levels of octanal. This extra octanal can end up in blood due to diet or a phenomenon in cells called oxidative stress. The human nose is already good at smelling octanal. A 2019 study was the first to show that macrophages in blood vessel walls also have some of the olfactory receptors needed to "smell" molecules. These macrophages can sense octanal, thanks to an olfactory receptor called OR6A2. The new study is the first to show precisely how sniffing out octanal can boost inflammation in the arteries.

Researchers tested the effects of injecting octanal into wild type mice and into mice where the gene for the mouse macrophage receptor Olfr2 (which corresponds to OR6A2 in humans) was deleted. By comparing these mouse groups, researchers found that inflammation gets much worse as the Olfr2 receptor senses octanal. Over time, the arteries even begin to develop the lesions seen in atherosclerosis. The researchers then used a molecule called citral (which has a lemon-like odor), known to block this mouse olfactory receptor, and saw that inflammation went down. By making macrophages blind to octanal, they reversed the disease progression.

Olfactory receptor 2 in vascular macrophages drives atherosclerosis by NLRP3-dependent IL-1 production

Atherosclerosis is an inflammatory disease of the artery walls and involves immune cells such as macrophages. Olfactory receptors (OLFRs) are G protein-coupled chemoreceptors that have a central role in detecting odorants and the sense of smell. We found that mouse vascular macrophages express the olfactory receptor Olfr2 and all associated trafficking and signaling molecules. Olfr2 detects the compound octanal, which activates the NLRP3 inflammasome and induces interleukin-1β secretion in human and mouse macrophages.

We found that human and mouse blood plasma contains octanal, a product of lipid peroxidation, at concentrations sufficient to activate Olfr2 and the human ortholog olfactory receptor 6A2 (OR6A2). Boosting octanal levels exacerbated atherosclerosis, whereas genetic targeting of Olfr2 in mice significantly reduced atherosclerotic plaques. Our findings suggest that inhibiting OR6A2 may provide a promising strategy to prevent and treat atherosclerosis.

View the full article at FightAging

#2 adamh

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Posted 29 January 2022 - 10:44 PM

Citral is considered safe and even used in food. If it dramatically reduces inflammation in mice, it may do the same for us. I'm thinking of getting some lemon myrtle or other citral containing herb and taking it each day

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