An ancient part of the immune system could advance heart disease research

A cell-based look at how the body responds to immune threats may one day help researchers find better treatments for this major U.S. killer

For more than a decade, researchers have known that a core component of human immune function – called complement – can influence how the body responds to immune threats. Now researchers from the NIH and around the world say they’ve gained new knowledge about how the body responds to these threats inside of cells, too. They specifically found that complement can activate pro-inflammatory responses, such as cholesterol crystals that can start accumulating within cells.

Since cholesterol buildup and inflammation are known risk factors for heart disease, understanding this intracellular system better may help researchers develop future treatments for cardiovascular disease, the number one killer in the U.S., explains Claudia Kemper, Ph.D., a senior investigator in the Division of Intramural Research at NHLBI. In fact, adds Kemper, who also leads the Laboratory for Complement and Inflammation Research, part of the scientific team who made this discovery, “it may be the birth of a new area for complement activities.”

Kemper shares insight about this field and these findings, which published today in Science Immunology.

First, what is complement?

Complement is an evolutionary old part of our immune system. It is mostly generated by the liver and circulates in blood as a protein system that can detect and remove pathogens, infected or dying cells, and malignantly transformed cells, which can lead to cancer.

Normally, the complement system – which serves as an internal alarm or immune guard – protects us. However, under certain circumstances, the system can malfunction and turn against the host. When that happens, the malfunction can set off or worsen a broad range of inflammatory and autoimmune conditions, including arthritis and atherosclerosis.

What did researchers find that is new in this study?

Researchers knew that in the majority of human diseases, an overactive or underactive complement system is involved on some level. Previously, researchers thought complement operated exclusively in the blood and extracellular space. But earlier work from our Kemper laboratory had shown, surprisingly, that complement can be activated and operate inside of cells. We call this system the “complosome.” What was not clear is how it exerts its function.

In this study, we found that complement proteins can directly modulate the activity of mitochondria, the cell’s energy power houses, in macrophages – a central type of immune cell.

Under normal circumstances, complement contributes to well-functioning macrophage activity. However, in individuals that choose a very high-fat diet, this internal complement “guard” – we like to call it the mitochondrial-complement axis – first senses an increased, sustained lipid environment within macrophages. Then, it triggers an unwanted chronic inflammatory state in these cells. This process ultimately drives atherosclerosis and cardiovascular disease.

How might these findings change the field of immunology and cardiovascular research?

The “complosome” as a concept is about 10 years old, but it’s gaining traction. Publications about this topic are increasing. So far, the complosome can be found in just about all cells researchers have studied – not just immune cells.

However, we have only scratched the surface of complosome biology, and currently we have more questions than answers when it comes to its functions in health and disease. What is becoming clear is that targeting the extracellular complement system may not be sufficient to help prevent atherosclerosis – and that we may need to target the intracellular system as well.

Could researchers use these findings in personalized therapeutics to help people who have coronary artery disease or related conditions?

We really need to learn more about this type of intracellular communication first before we can think about how we may be able to modulate it to help treat disease. So, I think what you are seeing here is maybe the birth of a new area. It’s a worthy target. But we are far away from being able to target it successfully in a controlled manner. Still, it is exciting that this new knowledge may enable us to potentially find new therapeutics against one of the biggest killers in our Western world: cardiovascular disease.

How might these findings advance insight about how complement responds to other immune threats, including COVID-19?

COVID-19 is a disease characterized by detrimental vascular inflammation, and we have shown just recently that SARS-CoV2 [the virus that causes the disease] triggers intracellular complement activation in certain cells in the lung, called epithelial cells. We also have shown that this virus-induced activity contributes to COVID-19 pathogenesis. In other words, complement can activate and sustain inflammation – and contribute to rare but severe cases of COVID-19.

Thus, we believe that the complosome-mitochondrial axis is of broad physiological importance across cells. We also believe that that disturbances in this activity contribute to other acute or chronic conditions, such as gout or arthritis. This, however, is currently a hypothesis that needs to be explored experimentally and clinically.

What do you want people to take away about this research?

Understanding the intracellular functions of complement, the complosome, is a team effort and came as a result of research conducted at NHLBI and other NIH research institutions, and with scientists throughout the world. We hope that our work inspires other groups, both here at the NIH and beyond, to think along the same lines and join us in these research efforts.

Where can people go to learn more about this research?

Our lab continues to study how complement proteins help regulate cell functions in health and disease. You can visit our webpage to learn more about complement and inflammation research.

For a copy of the recent Science Immunology study, visit www.science.org/doi/10.1126/sciimmunol.abf2489.