STAT5 Protein Complex Implicated in MS Autoimmunity in Mice

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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A four-protein complex, or tetramer, of the protein STAT5 is involved in the development of multiple sclerosis (MS)-like autoimmune disease in mice, a new study shows.

The findings point to this protein complex and its signaling pathway as a potential treatment in MS and other autoimmune conditions, scientists noted.

The study, “Tetramerization of STAT5 promotes autoimmune-mediated neuroinflammation,” was published in PNAS.

MS is an autoimmune disorder in which the body’s immune system erroneously attacks healthy parts of the nervous system, specifically the fatty myelin sheath that surrounds nerve fibers

The immune system’s activity — whether fighting an infection, or in an autoimmune disease like MS — is governed by interconnecting networks of signaling molecules that modulate immune cell activity. How these processes go awry to give rise to autoimmune diseases remains poorly understood.

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The STAT5 protein is a transcription factor, a protein that controls how different genes are “read” within a cell. This protein “has a lot of different roles in cell proliferation and inflammation,” Kelly Monaghan, a doctoral candidate at West Virginia University and first author of the study, said in a press release.

In its active state, STAT5 usually forms a dimer, which is a two-protein complex. But sometimes, two dimers can come together to form a four-protein complex, called a tetramer, which has distinct biological activity.

“STAT5 proteins must form dimers to regulate gene expression. The interaction of two dimers results in the formation of tetramers, which regulate an independent set of target genes,” Monaghan said.

To gain insight into the role of the STAT5 tetramer in MS, the researchers induced experimental autoimmune encephalitis (EAE) — an inflammatory neurological disorder that is commonly used to model MS — in mice that had been genetically engineered such that STAT5 could not form tetramers in their cells. The disease also was induced in control mice that could form tetramers.

While EAE developed as expected in the control mice, the animals that couldn’t form STAT5 tetramers had markedly less severe EAE symptoms. Further investigation revealed, broadly, that these mice had less inflammation and nervous system damage, despite having undergone an identical protocol to induce EAE.

The EAE “wasn’t completely ablated [removed], but it was significantly reduced in severity,” Monaghan said.

Further experiments revealed that STAT5 tetramer formation is induced by a signaling molecule called GM-CSF, a growth factor known to induce the maturation of pro-inflammatory immune cells. When this STAT5 tetramer was formed, it then prompted certain immune cells to make more of another signaling molecule called CCL17.

Additional tests showed that CCL17 prompted the activation of a type of immune cell called Th17 cells, which are highly pro-inflammatory cells that have been implicated in the development of MS.

This signaling molecule also promoted the infiltration of these immune cells into the meninges, “a series of three membranes that surround the central nervous system [and] act as a sort of checkpoint … to regulate the migration of cells into the actual brain or spinal cord,” Monaghan said.

The data collectively suggest “that CCL17 is the downstream mediator of STAT5 tetramer signaling that promotes the pathogenesis [disease development] of EAE,” the researchers wrote.

“I think these findings may also have broader implications to other autoimmune diseases, too, because there may be several other autoimmune diseases that are regulated by STAT5 tetramers and the downstream signaling pathway, which is quite exciting,” Monaghan said.


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