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Induced cell death destabilizes plaques

Many chronic disorders arise from misdirected immune responses. IPEK researchers from the Söhnlein Lab now show that neutrophils exacerbate atherosclerosis by inducing smooth muscle-cell death and that a tailored peptide inhibits the process.

In a collaborative study carried out by an international team of researchers, which appears in the journal NatureOliver Söhnlein and his colleagues focus on the role of neutrophils, which form a large part of the innate immune system.

“Every inflammatory reaction results in some collateral damage, because neutrophils also attack healthy cells,” he explains.

The new report describes how neutrophils damage tissues by initiating a previously unrecognized type of induced cell death.  Neutrophils can play an especially pernicious role in the destabilization of plaques. “They bind to the smooth muscle cells that underlie the vessel wall, and are activated. Activation results in the release of chromosomal DNA and its associated histones, which are highly charged and cytotoxic. Free histones kill nearby cells – in the case of atherosclerosis, smooth muscle cells,” Söhnlein says. Histones cause the death of these cells by inducing the formation of pores in their membranes. This allows extracellular fluids to pour into the cells and causes them to burst. Loss of these cells in turn destabilizes plaques, as the latter are no longer supported by underlying smooth muscle cells.

Based on molecular modeling, Söhnlein and his group have designed and synthesized a peptide that binds to free histones and neutralizes their toxic effect. Thanks to its mode of action, the peptide should have the same effect on other disorders that are associated with chronic inflammation, such as arthritis and chronic bowel inflammation, says Söhnlein. A patent application has already been submitted. 

Nature 2019

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