Targeting Ion Channel Piezo1 in T-cells Eased MS in Mice

Removing an ion channel called Piezo1 from immune T-cells lessened disease severity in a mouse model of multiple sclerosis (MS), a study showed.

Notably, these beneficial effects were associated with an expansion of regulatory T-cells (Tregs) — a type of immune cell that typically dampens immune and inflammatory responses — without affecting other key T-cell functions.

“We found that Piezo1 selectively restrains Treg cells, limiting their potential to mitigate autoimmune neuroinflammation,” Michael D. Cahalan, PhD, the study’s senior author at the University of California Irvine (UCI) School of Medicine, said in a press release. Cahalan is a distinguished professor and chair in the department of physiology and biophysics at the school.

Given that Piezo1’s role “appears to be quite specific to Tregs,” targeting this ion channel “might be a new and ideal strategy to cure MS while preserving the immune system’s ability to fight new infections,” said Shivashankar Othy, PhD, one of the study’s co-first authors at Cahalan’s lab. Othy has worked for the past 12 years to find ways to harness Tregs’ therapeutic potential.

The study, “Piezo1 channels restrain regulatory T cells but are dispensable for effector CD4+ T cell responses,” was published in the journal Science Advances.

T-cells are a type of immune cell involved in the fight against infections and

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cancer, but also participate in autoimmune diseases such as MS.

In MS, effector helper T-cells (Th cells) help to drive the abnormal immune attacks on the nervous system, while Tregs suppress the activity of other immune cells, reducing immune and inflammatory responses and helping prevent autoimmunity.

While the main goal in MS treatment development is to specifically suppress the immune cells that drive these abnormal attacks, without promoting overall immune suppression, this is challenging.

Current MS disease-modifying therapies promote, in one way or another, a general suppression of the immune system or of its key players, potentially impairing immune responses against threats and increasing the risk of infections.

Now, Cahalan’s team, along with colleagues at UCI and Vertex Pharmaceuticals, provided evidence that suppressing an ion channel called Piezo1 may be an effective way of targeting MS-driving immune attacks, without affecting the body’s ability to fight real threats.

Piezo1 is a mechanosensitive ion channel, meaning that it lets ions move in and out of the cells when subjected to mechanical stimuli. Previous studies highlighted its involvement in several processes, such as blood vessel development, bone formation, wound healing, cancer, and inflammatory responses to bacterial infections.

However, its role in T-cell function remained unclear until now.

By genetically deleting Piezo1 specifically in T-cells of healthy mice, the researchers found that the ion channel was not essential for T-cell migration into lymph nodes, movement around cells, growth, and maturation into pro-inflammatory Th cells.

This was unexpected, as these T-cell functions rely on calcium, which is transported through cells by several ion channels, including Piezo1.

However, Piezo deletion in T-cells boosted their maturation into Tregs, leading to increased Treg numbers, compared with mice with unmodified T-cells. This was associated with higher activation of the transforming growth factor-beta signaling, which is key for the maturation, function, and survival of Tregs.

Given Piezo’s ability to restrain Treg cells, and their protective role against autoimmunity, the team then evaluated the effects of genetically deleting Piezo1 in T-cells of a mouse model of MS called experimental autoimmune encephalomyelitis (EAE).

Results showed that this deletion led to a shift in T-cell balance toward Tregs, which was associated with significantly less-severe disease, faster disease remission, and greater survival rates relative to unmodified EAE mice.

“Genetically deleting Piezo1 in transgenic mice, resulted in an expanded pool of Treg cells, which were more capable of effectively reducing neuroinflammation and with it the severity of the disease,” Cahalan said.

Notably, deleting the ion channel specifically in Tregs of EAE mice resulted in similar benefits, such as reduced clinical signs and disease severity, and improved survival, confirming Piezo1’s Treg-specific role in MS.

These findings highlight that Piezo1 “selectively restrains Treg cells, without influencing activation events or effector T cell functions,” the researchers wrote.

“Given the vital importance of Treg cells in the amelioration of EAE, we suggest that inhibition of Piezo1 could be beneficial in treatment of neuroinflammatory disorders,” the team added.

Further research on Piezo1’s function is needed “to understand therapeutic potential, and to more fully understand the processes through which cells sense and respond to mechanical stimuli during immune responses,” the researchers concluded.