Danger Signals, Cell Damage, and Sterile Inflammation
Often when we think about inflammation, it’s in the context of our body fighting a disease, our bodies’ immune cells waging war on a pathogen, such as a virus. While fighting disease-causing pathogens is a major aspect of our immune system, the inflammatory response doesn’t need a pathogen in order to be activated. When you stub your toe or twist your ankle and get swelling, you’re witnessing inflammation in the absence of a pathogen, a process known as sterile inflammation. So, why is the body triggering inflammation if there’s no pathogen to fight? What is the body reacting to?
To answer these questions, it’s important to understand how the body senses and reacts to pathogens. Disease-causing microbes exhibit common and conserved features that can be detected and recognized by our cells. These features are called pathogen-associated molecular patterns, or PAMPs. These include structures on the surface of bacteria, compounds produced by microbes, and DNA and RNA variants associated with pathogens like viruses. These PAMPs bind to receptors on our cells called pattern recognition receptors (PRRs). When these receptors are activated by the binding of PAMPs, they induce cell signaling cascades that result in an inflammatory response.
PRRs play a key role in sterile inflammation. Instead of recognizing patterns from pathogens, the PRRs recognize structures of damage signals coming from injured cells. These signals are called damage-associated molecular patterns, or DAMPs. When a cell is damaged, it releases a variety of DAMPs that lead to an inflammatory response. These DAMPs include double stranded DNA, mitochondrial components, various ions, ATP, and other intracellular proteins. Notably, these components are important in the everyday functioning of the cells, and inside the cell, none of these components would trigger an issue. But their presence outside of the cell, where they are detected by PRRs, indicates that something is wrong. Imagine if you were walking around a neighborhood and came across a couch and TV in the middle of the road. If you saw this setup in a “normal” context, like in a living room of a house, you wouldn’t give it a second thought. But seeing these commonplace items outside of their usual environment, might make you raise your eyebrow and investigate further. This is true for our immune cells, as well, when they detect ordinary things in an extraordinary context. They notice something is amiss and respond accordingly.
DAMPs are found in this extraordinary context because they are released when a cell gets damaged and dies in an explosive, messy way. While some forms of cell death are quiet, orderly, and don’t attract undue attention, inflammatory cell death is nastier and involves the rupture of the cell and the spilling of its contents – which includes DAMPs – into its surroundings. This type of cell death can occur from multiple sources, including non-pathogen-driven disease and physical injury.
Once outside the cell, the DAMPs bind to the PRRs on sentinel cells – the neighborhood watch – which can include immune cells, as well as non-immune cells. After the sentinel cell detects trouble, it responds by producing a number of factors, including inflammatory cytokines, modulators of blood vessels to allow migrating immune cells to more easily enter the area of tissue injury, reactive oxygen species, and more. These factors, in turn, signal to the tissue neighborhood that there’s a problem, and the surrounding cells also begin secreting inflammatory factors. Leukocytes – consisting of a wide range of immune cells – detect the inflammatory factors and migrate to the site of injury. While these events occur on the microscopic level, they eventually add up to the classic clinical signs of inflammation that we’re more readily familiar with: redness, swelling, warmth, and pain.
The immune cells play important roles once at the site of injury. They clear away dying cells and cellular debris, removing extraneous DAMPs from the environment and helping reset the tissue back to normal. Through a complex interplay of signaling factors, the immune cells also play a vital role in the healing process, converting from an inflammatory role to an anti-inflammatory function. Immune cells, such as neutrophils, macrophages, monocytes, and iNKT cells, produce different sets of cytokines to stop recruiting additional immune cells to the site, preventing an unchecked immune response.
At least, this is what’s supposed to happen. More recently, researchers have proposed another class of danger signals associated with chronic sterile inflammation (see the citation at the end of this post). These factors are called lifestyle-associated molecular patterns, or LAMPs. While our immune system co-evolved with pathogens to fight infection, these researchers have suggested that our lifestyles have developed faster than our immune system can keep pace with, leading to inappropriate inflammation. As an example, they discussed how high-fat diets can lead to the accumulation of low-density lipoprotein (i.e., the “bad” cholesterol) associated with cardiovascular disease. The LDLs bind to PRRs on immune cells like macrophages. These cells then engulf the LDLs, which form cholesterol crystals inside the cell. These LDL crystal structures are known to activate an intracellular complex called the inflammasome, resulting in inflammatory signaling. While the immune system can detect LDL, it can’t effectively eliminate it. Without the removal of the toxic signal, the immune response doesn’t reach the point where it flips from its inflammatory role to its healing, anti-inflammatory role, contributing to the chronic inflammation associated with cardiovascular disease. Another example is the formation of uric acid crystals in gout. These crystals are linked, at least in part, with diet. Similarly, with LDL crystals, the uric acid crystals trigger the inflammasome leading to the inflammatory arthritis associated with gout.
Our environment can also contribute to sterile inflammation through the activation of the inflammasome. If you live in an old building or work in a mine, you may encounter asbestos or silica dust. If these are inhaled and enter the lungs, your body does not have the means to eliminate them. While asbestos particles and silica dust are taken up by macrophages, they cannot be broken down. Instead, their continued presence in the cell causes stress, and the particles activate the inflammasome triggering inflammation and contributing to chronic health issues, such as certain lung diseases.
The body’s immune response can be triggered by manmade materials, such as plastics. In some cases, this can be good, such as in response to an implantable device like an artificial heart valve or replacement joint. The immune response in these cases eventually leads to fibrosis around the implant, helping to protect it from long-term rejection by the body. However, there are some cases where the immune response is more extensive than desired, leading to over scarring and other medical concerns. Like the crystals described above, the body isn’t able to break down the synthetic materials that comprise these implants, which can trigger a chronic inflammatory response. While this response may be beneficial for implants and medical devices, it may have a less favorable significance in the context of plastic microparticles that we inadvertently consume and are exposed to everyday.
While additional work needs to be done to more fully understand the relationship of LAMPs and our overall health, sterile inflammation in response to DAMPs and other danger signals is well-established. The cells in our bodies are constantly on the lookout for the out-of-the-ordinary sighting, be it a hint of a pathogen invasion or sign of a damaging injury. Our body’s neighborhood watch is on guard, constantly surveilling the neighborhood and ready to spring into action at the first sign of danger to reset things back to normal.
This post was inspired and informed by: Zindel J and Kubes P, DAMPs, PAMPs, and LAMPs in Immunity and Sterile Inflammation. Annu. Rev. Pathol. Mech. Dis. 2020. 15:493-518.
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