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Key Pathway Involved in Atherosclerosis Development Identified

Computer-generated image of an atherosclerotic plaque blocking red blood cells.
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A new study has shed light on the biological mechanism underlying atherosclerosis – a hardening of the blood vessels – which could potentially lead to the development of new treatments. The research is published in Immunity.

Atherosclerosis and inflammation

Atherosclerosis is a hardening of the arteries caused by a buildup of fatty and cholesterol-rich deposits known as plaques. Atherosclerotic plaque formation in the blood vessels that supply the heart can cause significant health problems and increases the risk of complications such as strokes and heart attacks – some of the leading causes of death worldwide.

These plaques can also lead to inflammation in the blood vessel walls that attracts immune cells such as monocytes (the precursors of macrophages, another key immune cell) that penetrate the plaque. Here, the accumulation of dying cells can lead to necrosis if not carefully handled.

Atherosclerosis is also linked to the activation of the complement system – a blood-borne part of our innate immune system designed to defend our cells from pathogens. The complement system’s central component – a protein named C3 – keeps the system activated by breaking into its constituent parts, C3a and C3b. The complement system is regulated by another protein called complement factor H (CFH) – this limits macrophages’ ability to remove dying cells from the plaque, potentially aggravating necrosis.

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Complement activation has long been implicated in atherosclerosis – however, it remains unclear how important cellular versus systemic complement activation is in the development of atherosclerotic plaques.

“In contrast to the conventional understanding that the role of complement in atherosclerosis is primarily driven by liver-derived complement via the circulation, there has been increasing evidence that immune cells can also produce a defined set of complement components. However, if and how complement is controlled within these cells has been unknown,” said Dr. Christoph J. Binder, author of the study and professor of atherosclerosis research at the Medical University of Vienna. “We were able to demonstrate that inflammatory monocyte-derived macrophages accumulate complement C3, the central complement component during inflammation with a concomitant increase in the production of its master regulator, CFH.”

Complement regulation impacts atherosclerotic plaques

The researchers dissected the role of CFH – which prevents excessive activation of the complement system in circulation – in the development of atherosclerosis using several unique mouse models.

“First, we made the surprising observation that global lack of CFH displays an overall beneficial impact on plaque progression, which is dependent on its interaction with C3,” explained co-lead author Dr. Máté G. Kiss. “Building on these data, we were able to pinpoint that the protective effect is exerted on the cellular level, as selective deletion of CFH in monocytes and macrophages led to a robust decrease in both atherosclerotic lesion size and necrotic area due to an improved capacity to ingest and clear dying cells. This is the first description that highlights the functional importance of a complement regulator to control complement activation within cells with a robust impact on the development of atherosclerosis, and potentially other chronic inflammatory diseases, too.”

Additionally, the results from their work with mouse models went on to match with data that provided clear implications for disease in humans. “Importantly, we identified a distinct inflammatory macrophage subset in human coronary artery plaques that is specifically enriched for C3 and CFH,” Binder added. “Based on their gene expression profile, these cells are wired to respond to inflammation and appear to be critical for the engulfment of dying cells in human plaques – nevertheless, further investigation is warranted to test their functionality.”

Furthermore, variations in the gene that codes for CFH in humans are known to predispose them to chronic inflammatory diseases , and Binder and colleagues have also investigated some of the key genetic modulators of CFH in recognizing damaged cells and regulating complement activation.

“We could distinguish genetic variants that modify the ability of CFH to bind damaged macromolecules and dying cells. The same genetic variants may also alter the ability of CFH to regulate intracellular C3 levels in macrophages with an impact on their engulfing capacity,” said co-lead author Dr. Nikolina Papac- Miličević.

Overall, the study’s findings suggest that targeting the regulation of cell-associated complement could provide new avenues for the development of therapies for chronic inflammatory diseases that do not impair host defense mechanisms.

Reference: Kiss MG, Papac-Miličević N, Porsch F, et al. Cell-autonomous regulation of complement C3 by factor H limits macrophage efferocytosis and exacerbates atherosclerosis. Immunity. 2023;0(0). doi: 10.1016/j.immuni.2023.06.026

This article is a rework of a press release issued by the Medical University of Vienna. Material has been edited for length and content.