Researchers from the University of Osaka find that hepatocyte-derived extracellular vesicles treated with secreted phospholipase A₂ elicit a ‘lipid counterstorm’ that counters the effects of cytokine storm in mice with inflammatory conditions

Osaka, Japan – The COVID-19 pandemic highlighted some severe consequences of unchecked respiratory disease, including cytokine storm. This phenomenon affected many COVID-19 patients and is a potential side effect of many other diseases involving significant inflammation, but approaches to the treatment of these symptoms remain unclear.

Researchers from the University of Osaka and other institutions, report that a specially treated cell-derived product, called a SPLEV, strongly protects against the effects of cytokine storms. The findings have been published in Science Advances.

Cytokine storm is a runaway immune response that can be induced by infection, which triggers severe systemic inflammation, causing respiratory failure, liver damage, abnormal blood clotting, and in some cases death. There has been recent increasing interest in the role of extracellular vesicles – which are small membrane-wrapped packages of RNAs, proteins and fats – to treat this potentially life-threatening response. This interest was garnered through their known ability to fight excessive levels of inflammation.

“Mesenchymal stem cell–derived extracellular vesicles are currently attracting attention as a potential treatment for cytokine storm,” says lead author, Shunya Nakayama. “However, we recently discovered that extracellular vesicles derived from liver cells are even more potent, and that their activity can be further enhanced by treatment with the secreted phospholipase A2 enzyme (sPLA₂).”

The researchers treated liver cell extracellular vesicles with sPLA₂ to generate sPLA₂-reacted EVs, or SPLEVs; following this, the SPLEVs were injected into mice with acute respiratory distress syndrome and assessed the effects.

“The results were very clear,” explains Ai Kotani, senior author. “We found that the SPLEVs strongly suppressed lung inflammation, as evidenced by the presence of fewer immune cells in the lungs and considerably lower levels of cytokine production.”

Intriguingly, the SPLEVs seemed to preferentially interact with the lining of the lung, unlike untreated extracellular vesicles, which targeted macrophages. Further analysis showed that they acted directly on lung epithelial cells to trigger massive production of tissue-protective lipids.

“We coined the term ‘lipid counterstorm’ to describe this effect, as it successfully counters the effects of a cytokine storm induced by lung disease,” says Nakayama.

The SPLEVs also exhibited significant beneficial effects in mouse models of other diseases based on inflammation, suggesting that they could be useful for treating sepsis, coagulopathy, liver injury, colitis, and pneumonia. As lysophosphatidylglycerols increased following SPLEV treatment, the potential to develop inexpensive, cell-free artificial SPLEVs may be a valuable future therapeutic tool.
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The article, “sPLA2-reacted extracellular vesicles (SPLEVs) as a therapeutic modality for cytokine storm syndromes,” will be published in Science Advances at https://doi.org/10.1126/sciadv.adr9135.

About The University of Osaka
The University of Osaka was founded in 1931 as one of the seven imperial universities of Japan and is now one of Japan's leading comprehensive universities with a broad disciplinary spectrum. This strength is coupled with a singular drive for innovation that extends throughout the scientific process, from fundamental research to the creation of applied technology with positive economic impacts. Its commitment to innovation has been recognized in Japan and around the world. Now, The University of Osaka is leveraging its role as a Designated National University Corporation selected by the Ministry of Education, Culture, Sports, Science and Technology to contribute to innovation for human welfare, sustainable development of society, and social transformation.
Website: https://resou.osaka-u.ac.jp/en