Interleukin-17A (IL-17A) — a molecule that is involved in immune and inflammatory responses — accelerates brain inflammation and degeneration in animal models of Parkinson’s disease, a study has found.
Parkinson’s disease is characterized by the gradual loss of dopaminergic neurons in the substantia nigra — a region of the brain responsible for movement control — together with brain inflammation caused by the over-activation of microglia, which are cells that support and protect neuronal cells, and are more reactive and proliferative than neurons.
“Our recent results show that Th17 cells contribute to PD [Parkinson’s disease] neuroinflammation and neurodegeneration. In revealing the mechanism by which Th17 cells injure dopaminergic neurons, we found that Th17 cells directly contact and kill neuronal cells by an interaction between two adhesion molecules expressed on membrane of these cells,” the investigators explained.
“Nevertheless, it needs clarification whether IL-17A … can directly damage dopaminergic neurons,” they added.
Of note, Th17 are the subtype of T-cells that produces IL-17 and have been associated with several inflammatory processes; a cytokine is a molecule that mediates and regulates immune and inflammatory responses.
In this study, a group of researchers from Nantong University in China set out to investigate how IL-17A might contribute to the development and progression of Parkinson’s in two different animal models of disease.
To trigger the onset of Parkinson’s, researchers treated mice with MPTP, a neurotoxin that induces brain inflammation, loss of dopaminergic neurons, and motor impairments, as seen in patients with the disease.
In parallel, rats were treated with MPP+, another neurotoxin closely related to MPTP, that also induces the onset of symptoms similar to those experienced by patients with Parkinson’s disease.
Results showed that treatment with both neurotoxins led to a disruption of the blood-brain barrier (BBB, a semipermeable membrane that isolates the brain from the blood that circulates in the body) and to a significant increase in the levels of IL-17A in the substantia nigra of both animal models.
To examine if BBB disruption in response to neurotoxins was sufficient to allow immune cells to enter into the animals’ brains, researchers injected them with T-effector cells that had been activated in a lab dish and measured their level of penetrance into the brain.
Of note, T-effector cells are T-cells that are immediately prepared to fight a pathogen because they have a “memory” of previously encountering it; these cells also include the Th17 subgroup.
Findings revealed that when injected into animals that had been treated with neurotoxins, T-effector cells were able to travel and enter into the animals’ brains. However, when injected into healthy animals that had never been treated with neurotoxins, T-effector cells failed to infiltrate the brain.
In addition, researchers found that when T-effector cells infiltrated the brain, they worsened animals’ symptoms; dopaminergic neurons were destroyed faster, microglia became over-activated faster and motor impairments were more severe.
Conversely, when researchers blocked the activity of IL-17A in rats’ brains (by injecting an anti-IL-17A antibody) they found that all Parkinson-like symptoms the animals experienced were significantly reduced. Likewise, when they performed a similar analysis in mice that had been genetically modified to lack IL-17A, they found that neuron degeneration, microglia activation and motor deficits were decreased greatly.
Additional in vitro experiments revealed that IL-17A had a direct impact on microglia activation, but not on neuron survival. According to the team, IL-17A requires the presence of microglia to accelerate neuronal loss.
Moreover, they discovered this effect was stronger in the presence of tumor necrosis factor alpha (TNF-a), a signaling molecule involved in immune and inflammatory responses, produced and released by activated microglia.
“[These] findings suggest that IL-17A accelerates neurodegeneration in PD [by inducing the] activation [of microglia] and at least partly [by promoting the release of other pro-inflammatory molecules, such as TNF-a],” the researchers wrote.
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