Complement-Producing Macrophages in Atherosclerosis

Atherosclerosis is, fundamentally, a condition centered around the function, capabilities, and age-related dysfunction of macrophage cells. These innate immune cells are responsible for clearing excess cholesterol, transported via LDL particles, from blood vessel walls. As macrophages become more dysfunctional with age, or otherwise shift in their activities due to rising inflammatory signaling, deposits of cholesterol can reach a tipping point at which they can no longer be cleared and turn into atherosclerotic lesions. Macrophages in the lesions are overwhelmed by the excess of cholesterol, become inflammatory, and die, adding their mass to the growing lesion while also calling in more macrophages to suffer the same fate.

Researchers have identified a specific subtype of complement-producing macrophages that are present in both mouse as well as human atherosclerotic plaques. The complement system is a family of blood-borne proteins with crucial importance in host defense from pathogens. In addition, complement exerts critical housekeeping functions by aiding the removal of damaged and dying cells by macrophages. Part of the complement is continuously active by the generation of cleavage products of the central component C3 - a process that is highly regulated by CFH. Complement activation has long been implicated in human atherosclerosis - however, the pathologic importance of cellular versus systemic complement activation in lesion progression has not been appreciated.

"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. 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."

"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. Building on these data, we were able 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. Importantly, we identified a distinct inflammatory macrophage subset in human coronary artery plaques that is specifically enriched for C3 and CFH. 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."


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