When a tissue experiences inflammation, its cells will remember it. By binding proteins to their genetic material during the peak of inflammation, cells mark where they stopped in the last battle. The inflammatory memory is activated at the next exposure. Cells use past experience to respond more efficiently, even to threats they have not previously encountered. The skin heals a wound faster if it has been exposed to an irritant such as a toxin or pathogen; Immune cells can attack new viruses after a vaccine teaches them to recognize a single virus.
Now, a new study in Cell Stem Cell describes the mechanism of inflammatory memory, commonly known as trained immunity, and suggests that the phenomenon could be universal in diverse cell-types.
“This happens in natural killer cells, T cells, dendritic cells in human skin and epidermal stem cells in mice,” says Samantha B. Larsen, a former graduate student in Elaine Fuchs’ laboratory at Rockefeller University. “The similarities in mechanism are striking and may explain the relapsing and remitting nature of chronic inflammatory dis-order in humans.”
By default, when we think of our immune system, we think of a specific immunity, that group of T and B cells that have been trained through experience or vaccination to remember the specific contours of the last pathogen that entered in our bodies. However, for many cells there is a less specific strategy known as trained immunity. The effects are short-lived but more extensive. Trained immunity enables cells to respond to entirely new threats based on general memories of inflammation.
Scientists have long suspected that cells that are traditionally not involved in the immune response also have the rudimentary ability to remember past insults and to learn from experience. Fuchs ’lab emphasized this point in a study published in Nature in 2017, showing that mouse skin that recovered from irritation healed 2.5 times faster than normal skin when exposed to irritation on later-date.
One explanation, according to Fuchs’ team, could be epigenetic changes in the genome of skin cells: During inflammation, regions of DNA that are often tightly wound around histone proteins un-ravel in order to transcribe a genetic response to an attack. Even after the dust settles, a handful of these memory domains remain open & changed. Some of the histones associated with it have been modified since the attack, and proteins known as transcription factors have attached to exposed DNA. A once native cell is now eager for its next fight.
But the molecular mechanism that explains this process, and how the cell could use it to respond to inflammation and injury it has never seen before, remains a mystery.
In the memory Domain
So Fuchs’ laboratory again exposed the skin of the mice to irritants and observed how the skin’s stem cells changed. “We focus on the regions of the genome that become accessible during inflammation and remain accessible afterwards,” says Christopher Cowley, graduate student. in Fuchs’ laboratory. “We call these regions memory domains, and our aim was to explore the factors that open them, keep them open, and reactivate them a second time.”
They examined about 50,000 regions within the stem cell DNA that had unraveled in response to the threat, but a few months later only about 1,000 remained open and accessible, distinguish themselves as domains of memory. Interestingly, many of these memory domains were the same regions that had been most amazingly un-raveled in the early days of skin inflammation.
Scientists went deeper and discovered a two-step mechanism in the heart of trained immunity. The process revolves around transcription factors, Proteins that control gene expression & hinges on the twin transcription factors known as JUN & FOS.
The stimulus-specific transcription factor STAT3 reacts first and is used to coordinate a genetic response to a particular type of inflammation. This protein gives JUNFOS the baton, which perches on un-spooled genetic material to join melee. The specific transcription factor that set off the original alarm will eventually come home; FOS will float away when tumult quiets down. But JUN is the sentinel guarding the domain of open memory with ragtag band of other transcription factors waiting for its next battle.
If the irritation strikes again, JUN is ready. It quickly recruits FOS back into the memory domain and the duo charges into the fray. This time around, no specific transcription factor is required to respond to a particular type of inflammation and keep the ball rolling. The system unilaterally activates in response to nearly any stress—alacrity that may not continuously profit the rest of the body.
Better forget it
A trained immunity can seem like a boon to human health. Veteran immune cells appear to produce broader immune responses; Experienced skin cells should heal faster when injured.
But the same mechanism that keeps cells on high alert can trigger a kind of molecular paranoia in chronic inflammatory diseases. When Fuchs’ lab examined data collected, for example, from patients with systemic sclerosis, They found evidence that JUN may be sitting in the memory domains of the affected cells, eager to initiate a discussion in response to the slightest disagreement.
“These arguments do not always have to be unpleasant, because animals benefit from rapid wound healing and plants that are exposed to one pathogen are often protected from others,” says Fuchs. “However, chronic inflammatory dis-order can owe their painful existence to the memory of your cells and FOS and JUN, which are universally responsive to stress.”
Scientists hope that clarifying a possible cause of chronic inflammatory diseases could help researchers develop treatments for these diseases. “The factors and pathways that we identify here could be targeted both in the early stages of the disease and later during the relapse stages. the disease, ”says Cowley. Larsen adds, “Perhaps these transcription factors could be used as a general target to inhibit re-call of memories that cause chronic inflammation.
The findings were published on Science Direct.