Learning how to control inflammation could have huge implications for the treatment of many diseases. Breaking research discovers how macrophages turn mitochondria into toxic chemical-producing inflammation-promoters.
Inflammation plays a significant role in a number of serious medical conditions. Efforts to understand and control it are ongoing.
Inflammation is the body's attempt to protect itself from harmful stimuli. For instance, after a knock to the knee, inflammation helps prevent further damage; it has evolved to become an essential part of our immune system.
However, during disease, the inflammatory response can go awry and cause damage to healthy tissue; it is a powerful mechanism that must be tightly controlled.
For instance, inflammatory bowel disease, arthritis, and septic shock all involve high levels of poorly controlled inflammation.
Macrophages and inflammation
Macrophages (meaning "big eaters") are a type of white blood cell that engulf and digest cellular debris and foreign substances. These biological dustbins maraud within and between cells throughout the body, destroying pathogens as they roam.
Alongside their taste for microbes and other invaders, they play a substantial role in orchestrating the immune response. Macrophages stimulate the immune system and help to call it to action when necessary.
As part of this role, macrophages are known to promote inflammation. However, once the time has come for the inflammation response to stop, they switch roles, suppressing inflammation and busying themselves with repairing damaged tissue.
A team of scientists from the Inflammation Research Group at Trinity College Dublin in the Republic of Ireland joined forces with researchers based at the Medical Research Council Mitochondrial Biology Unit in the United Kingdom.
These two institutions linked up with another seven across Europe to take a fresh look at the role of macrophages in inflammation.
Mitochondria's roles switched
The investigators found that during the initial phase of the macrophage response, the cells alter the activity of mitochondria.
Mitochondria are often referred to as the "powerhouse" of the cell. They are present in nearly all cell types and generate the vast majority of the cell's supply of adenosine triphosphate (ATP) - the primary source of chemical energy in cells.
During inflammation, macrophages were found to halt mitochondria's production of energy and switch them to producing toxic compounds that further amplify inflammation.
"Mitochondria are well known as the key energy generators in our cells, but we found that during inflammation they switch from that role to instead making toxic products from oxygen using an enzyme called succinate dehydrogenase, which promotes inflammation."
Co-lead author Dr. Evanna Mills
This change in enzyme activity specifically increases production of mitochondrial reactive oxygen species, high levels of which can damage cell structures.
Succinate dehydrogenase is involved in the process of energy generation in mitochondria, but it also plays a role in tumor suppression, making it an enzyme of interest to medical researchers.
The scientists hope that this new knowledge might help them to generate interventions that mute this toxic response. If it can be controlled in some way, tissue damage might be minimized.
Co-lead author Dr. Beth Kelly says: "Preventing this process turns the macrophage into a more benign anti-inflammatory cell, so if we can find a way of mediating the macrophage response, we might be able to preferentially calm down the inflammation."
This research contributes to a new and swiftly growing area of study known as immunometabolism. This specialty looks at the interface between the immune system and metabolic responses in disease; among other things, it hopes to create a deeper understanding of the vast complexities of inflammation.
The end goal of immunometabolism is to design novel therapeutic approaches that could assist in the treatment of difficult to manage disease.