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Macrophages Can “Smell” Octanal and Trigger Inflammation and Atherosclerosis

Blinding macrophages to octanal subsided inflammation and reversed disease progression in mice, opening up the possibility of blocking olfactory receptors of macrophages to treat atherosclerosis in humans.

Known to be the leading cause of death globally, cardiovascular disease accounts for about 17.9 million deaths or 32 per cent of global deaths each year. In Singapore, an estimated 19 people die from cardiovascular disease (e.g., heart disease and stroke) every day. A major risk factor of stroke is atherosclerosis, where arteries thicken or harden due to a build-up of plaque in the inner lining of an artery. While atherosclerosis is often linked to the accumulation of fats, cholesterol, and other substances, this condition does not simply arise due to those factors. It is an inflammatory disease in the arteries that involves immune cells like macrophages.

Recently, researchers at La Jolla Institute for Immunology have made a surprising discovery about the way in which immune cells in the arteries cause inflammation – they can “sniff” out their surroundings. In their study, the scientists not only showed how inflammation can lead to cardiovascular disease and atherosclerosis in mice, but also successfully reversed this inflammation by blocking macrophages from sensing a “fragrant” compound known as octanal.

“Macrophages are some of the most important cells in our immune system,” said study first author Marco Orecchioni, Ph.D., an instructor at LJI. “They are constantly checking for signals. We could say they ‘sniff’ their environment and respond.”

Previously, in a 2019 study led by LJI Scientific Associate Sara McArdle, Ph.D, research, macrophages in blood vessels were found to possess some of the olfactory receptors needed to “smell” molecules. In 2020, LJI scientists then reported that these macrophages sense octanal with the help of an olfactory receptor called OR6A2.

“Smelly molecules can be pro-inflammatory,” said study leader LJI Professor Klaus Ley, M.D., a member of the LJI Center for Autoimmunity and Inflammation. In the specific case of octanal, Ley likened the odour to “chicken that is not so nice anymore.”

Now in the current study, Professor Ley and colleagues showed for the first time how sniffing out octanal can boost inflammation in the arteries. According to the researchers, people who exhibit cardiovascular markers, such as high LDL cholesterol levels, also have elevated levels of octanal. While it is known that the human body holds a small amount of octanal, the surplus detected may be caused by diet or oxidative stress.

To precisely determine the effects of sensing octanal, Orecchioni injected octanal into normal “wild type” mice and into mice where the gene for the mouse macrophage receptor Olfr2, which corresponds to OR6A2 in humans, had been deleted. They then compared the condition of the mice groups and discovered that inflammation aggravates as the Olfr2 receptor senses octanal. Over time, the arteries started to develop the lesions observed in atherosclerosis. To confirm their findings, the team subjected the mice to citral, a molecule with a lemon-like odour that blocks Olfr2, and found that the inflammation subsided. By blinding the macrophages to octanal, disease progression was successfully reversed.

Given these results, Ley and Orecchioni believe that it may be possible to block OR6A2 in humans. “These receptors are very well known as drug targets,” said Ley. “In fact, most drugs on the market today act on this type of receptor, called a GPCR.”

Currently, the team is examining the roles of other olfactory receptors found on macrophages and how OR6A2 operates in humans. While keen to pursue research into atherosclerosis, Orecchioni is also curious as to whether olfactory receptors may play a role in metabolic diseases, such as type 2 diabetes. “This study is just the first hint of something new,” he said. “It’s opened up years of research ahead of us.” [APBN]

Source: Orecchioni et al. (2022). Olfactory receptor 2 in vascular macrophages drives atherosclerosis by NLRP3-dependent IL-1 production. Science, 375(6577), 214-221.