Astrocytes, much like immune cells, can drive inflammation in MS
Lab work shows these CNS support cells respond to inflammatory factors
A subset of astrocytes — a type of support cell for the central nervous system — has a form of immune-related memory that might contribute to a worsening of multiple sclerosis (MS), according to recent research.
Much like immune cells, these astrocytes can remember inflammatory stimuli that they previously have been exposed to, and respond more strongly when encountering such perceived threats again. A pair of enzymes — p300 and ACLY — mediate these immune responses, and researchers found that suppressing them eased disease severity and inflammation in a mouse model of MS.
“These findings highlight important mechanisms relevant to neurologic disorders like MS and could guide the development of novel therapeutic interventions that target ACLY+ p300+ memory astrocytes to reduce inflammation,” Francisco Quintana, PhD, a neurology professor at Harvard Medical School and Brigham and Women’s Hospital in Boston, and the study’s senior author, said in a hospital press release.
The study, “Disease-associated astrocyte epigenetic memory promotes CNS pathology,” was published in Nature.
Astrocytes support nervous system but can be damaging in chronic inflammation
Astrocytes are star-shaped cells that are abundant in the central nervous system (CNS), comprised of the brain and spinal cord. They serve a wide range of roles in maintaining a healthy nervous system, but they’re also increasingly recognized as contributors to CNS diseases that include MS.
Astrocytes respond to inflammatory factors released by immune cells, entering into a reactive state to help with injury repair. But when this becomes chronic, it contributes to inflammation and tissue damage, both of which are implicated in neuroinflammatory conditions.
Certain types of immune cells have what’s known as immunological memory — they remember a foreign substance that they’ve seen before, and they launch a faster attack against it when encountered again.
But whether astrocytes, which contribute to immune activities but are not immune cells, also acquire such memory has not been clear.
“Immunological memory, the generation of faster and stronger responses upon repeated antigenic stimulation, is a classic hallmark of adaptive immunity,” the research team at Brigham and Women’s Hospital wrote. But “it is still unknown whether astrocytes display altered responses to repeated stimulation, how these responses are regulated, and whether specific astrocyte subsets are involved.”
In lab experiments, the researchers showed that astrocytes indeed do remember previous interactions with immune signaling molecules, and they develop stronger inflammatory responses the next time they’re exposed to them.
Astrocytes taken from mice exposed twice to certain inflammatory stimuli exhibited stronger pro-inflammatory responses than those taken from mice exposed only once, the team reported.
Similar findings were observed in astrocyte cell cultures, where a double exposure also associated with reduced nerve cell survival.
Across a series of experiments, the researchers identified that this astrocyte immune memory is driven by certain epigenetic processes within the cells. Epigenetic refers to chemical modifications to DNA molecules that influence gene activity.
In this case, a pair of enzymes — p300 and ATP-citrate lyase (ACLY) — were found to be the drivers of this epigenetic-controlled immune memory. Essentially, they work to boost the activity of inflammation-related genes in the astrocytes upon repeated exposure to stimuli from immune cells.
The scientists think that astrocyte immune memory might be a key mechanism underlying the increasingly well-established role for these cells in neuroinflammatory diseases like MS, where there is heavy infiltration into the brain of immune cells from the blood.
Astrocyte clusters with inflammatory profile found in active MS brain lesions
Because astrocytes live for long periods, they can stay in the brain and continuously respond to signals from these immune cells, becoming stronger each time.
“Considering the long lifespan and low turnover rate of astrocytes, astrocyte epigenetic memory may have important roles in the pathology of chronic neurologic disorders,” the researchers wrote.
Scientists then looked to a mouse model of MS, where they found that the number of astrocytes expressing the p300 and ACLY enzymes was high relative to healthy mice.
Notably, inactivating the genes for those enzymes in astrocytes suppressed CNS inflammation and stopped disease progression. It also suppressed gene activity related to the epigenetic memory signature that previously had been identified.
Genetic datasets of astrocytes from MS patients identified clusters of astrocytes inside active brain lesions that were positive for p300/ACLY, and which had an increased inflammatory profile. The number of such astrocytes also was higher in patients’ brains relative to the brains of people without MS.
Overall, the scientists believe that this information could be leveraged to develop treatments for MS and related diseases. ACLY inhibitors to treat cancer and certain metabolic conditions have been developed, according to the team.
“These ACLY inhibitors may be repurposed for the therapeutic modulation of ACLY+ p300+ memory astrocytes in multiple sclerosis and other neurologic disorders,” the team concluded.
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