Protein That Helps Cells Break Down Sugar Also Promotes Inflammation, Study Suggests

A protein involved in cell metabolism, called PKM2, was found to be central to switching ‘on’ immune cells that play critical roles in inflammatory and autoimmune diseases such as multiple sclerosis (MS), an early study reports.

Blocking the activity of PKM2 (pyruvate kinase M2) eased MS-like symptoms in mice, suggesting that PKM2 may be a  target for treating several diseases rooted in abnormal immune activation, including MS and psoriasis.

The findings are described in the study “Pharmacological Activation of Pyruvate Kinase M2 Inhibits CD4⁺ T Cell Pathogenicity and Suppresses Autoimmunity,” published in the journal Cell Metabolism.

One of PKM2’s main roles is the breakdown of sugar (glucose) inside cells, during an essential metabolic process called glycolysis. But PKM2 is versatile, and believed to be involved in many other cell functions.

Some studies suggest that PKM2 is important for the working of certain types of immune cells. But its role with T-cells, a crucial group of immune cells, is poorly understood.

A research team led by investigators in Trinity College Dublin looked specifically at the potential role of PKM2 in CD4⁺ T-cells, also known as T-helper (Th) cells, a type of immune cell at the heart of several autoimmune and allergic diseases.

Using both human and mouse cells in vitro (cultured in the lab), researchers found that the activation of CD4⁺ T-cells was accompanied by higher-than-normal production of PKM2, and certain modifications that made it accumulate in the cell’s nucleus (where most of the genetic material is contained).

This led the scientists to hypothesize that one of the additional roles of PKM2 is mediating, or regulating, T-cell activation. (Activated cells are cells, like T-cells, that change in response to a stimulus.)

To confirm their hypothesis, researchers used a compound that blocked PKM2 activity — called TEPP-46 — and demonstrated that targeting PKM2 indeed limited the excessive switching ‘on,’ or activation, of CD4⁺ T-cells, as well their proliferation and production of inflammatory signals called cytokines.

The compound also prevented their conversion into Th17 and Th1 cells, which are considered major agents of inflammation and autoimmunity.

“Th17 and Th1 cells are very important for the damage that happens in autoimmune diseases such as psoriasis and multiple sclerosis. We have found that interfering with PKM2 blocks these cells and limits inflammation,” Stefano Angiari, PhD, with the Trinity Biomedical Sciences Institute and the study’s lead author, said in a press release.

Treating mouse models of MS with the same PKM2-blocking compound was seen to both ease disease symptoms and slow their development.

Researchers also discovered that PKM2’s harmful effects were linked to a boost in glycolysis, and that targeting PKM2 limited T-cell activation by inhibiting glycolysis.

“PKM2 is a fascinating protein that has a role in how cells use glucose for energy, but it also moonlights [has additional functions] in the immune system, where we have found it can be especially troublesome,” said Luke O’Neill, PhD, professor at Trinity Biomedical Sciences Institute and the study’s senior author.

“We are currently exploring it as a new target for therapies that might work in patients with diseases like psoriasis and multiple sclerosis, where treatment options are limited,” O’Neill added.

Based on these findings, the team concluded: “our results suggest that pharmacological targeting of PKM2 may represent a valuable therapeutic approach in T-cell-mediated inflammation and autoimmunity.”