Protein That Helps to Regulate Innate Immune System Seen to Slow ALS Progression in Early Study in Mice
The protein TRIF can prevent resident immune cells of the brain from activating abnormally and slow the progression of amyotrophic lateral sclerosis (ALS), researchers in Japan working in a mouse model of the disease report.
Their work, “Innate immune adaptor TRIF deficiency accelerates disease progression of ALS mice with accumulation of aberrantly activated astrocytes,” was published at Cell Death & Differentiation.
Several studies have demonstrates that deregulated immune cells and increased inflammation can contribute to the development and progression of neurodegenerative disorders like amyotrophic lateral sclerosis (ALS). But, until now, it was not clear if innate immune responses were also implicated in ALS.
The innate immune system is the defense mechanism that exists at birth. It is not specific to a particular target, but rather is the body’s first response to “foreign” threats like invading bacteria or a virus. Within a few hours of such an invasion, these immune cells activate and work to rapidly eliminate the threat.
Led by Koji Yamanaka, a professor at Nagoya University, the research team found that loss of the innate immune adaptor TRIF significantly promoted disease progression and shortened the lifespans of mice with ALS.
TRIF and myD88 are two key proteins that regulate signals that activate innate immune cells. The team genetically engineered ALS mice that lack either the TRIF or MyD88 protein.
Loss of MyD88 did not change disease onset, progression, or survival time in the mice, the researchers found. But a lack of TRIF did shorten overall survival time by 24 days in the mouse model compared to control animals. This finding suggests that a “TRIF-dependent innate immune pathway determines disease progression,” the researchers wrote.
Further experiments also showed that TRIF deficiency led to lower numbers of some infiltrating immune cells in the spinal cord of these mice. However, this did not significantly alter survival time, suggesting this was not the process mediating TRIF effects on ALS.
The team then analyzed various resident immune cells of the brain and spinal cord, and found that many of these cells — called astrocytes — were abnormally activated and producing toxic, inflammatory molecules.
Activation of TRIF prevented this damaging astrocyte activity and promoted astrocytes’ death through a process known as apoptosis. Activation of MyD88 again had no effect on these immune cells.
In the absence of TRIF, these abnormal astrocytes also accumulated in lesions. The team found that as the number of these immune cells expanded, survival time of the ALS mice decreased, suggesting that these activated astrocytes were toxic to motor nerve cells.
“These results revealed for the first time that the TRIF pathway is involved in eliminating aberrantly activated astrocytes to maintain the microenvironment surrounding motor neurons in ALS mice,” Yamanaka said in a news release.
They also revealed a new role for the innate immune system in ALS, one that may provide “a clue to develop a new therapeutic approach for protecting ALS motor neurons,” Yamanaka added.
