Sepsis occurs when the body rolls over in an attempt to fight infection. Immune cells rush in, overreact and destroy tissues and organs, often resulting in organ failure and death.
Researchers from the University of California, San Diego School of Medicine recently found that removal of the PHLPP1 enzyme improved the results in a mouse model of sepsis. PHLPP1 controls many cell behavior by removing phosphates (small chemical markers) from other proteins. And now, it turns out, PHLPP1 also affects inflammation.
The study, published on August 13, 2019 in Elip, introduces the possibility that inhibition of PHLPP1 may be the basis for new treatments for sepsis in humans.
"Most inflammation research is usually focused on kinases, enzymes that add phosphate tags to other proteins," said senior author Alexandra Newton, PhD, professor of the Department of Pharmacology at UC San Diego. "It's exciting to have a whole new purpose for sepsis – the enzymes that remove them."
The tonne team discovered PHLPP1 several years ago and have since detailed the role of tumor suppression. Following these findings, Tonton came to Dr. Chris Glas College, UC San Diego College of Medicine, an inflammation expert.
Together, their teams discovered many genes in the immune cells affected by PHLPP1. But in particular the effect of PHLPP1 on inflammation may be related to the fact that it removes phosphates from the transcription factor known as STAT1, which is known to control inflammatory genes.
The tonton team took mice modified to lack the PHLPP1 gene to another colleague from the UC School of Medicine in San Diego, Dr Victor Nietzsche, a bacterial infection expert. In separate experiments, Nizett's team administered live bacteria E. coli and lipopolysaccharide (LPS), a component of the cellular identity of the bacterium that drives wild-type immune systems to both PHLPP1 and normal mice.
The difference surprised Newton: Mice without PHLPP1 fared much better. While all normal mice died of sepsis after five days of infection, half of the PHLPP1-deficient mice survived.
The Tutun team has been working with additional collaborators to screen thousands of chemicals to identify the few that block PHLPP1. Now that they know that PHLPP1 inhibitors can form the basis for new anti-sepsis drugs, researchers hope to test these compounds on the immune cells in the laboratory and in the mouse model of sepsis.
Currently, sepsis is treated by preventing and treating a genuine infection, often with antibiotics, while maintaining the health of the organs with oxygen and intravenous fluids. However, according to the Centers for Disease Control and Prevention, at least 1.7 million adults in the United States develop sepsis every year and nearly 270,000 die as a result. One in three patients who die in hospital have sepsis.
"Sepsis is the leading cause of death in intensive care units worldwide, but unfortunately there is no approved sepsis treatment," Nizett said. "The findings, as our primary signaling pathways that control the behavior of immune cells during sepsis, offer clues to controlling the dangerous inflammation of sepsis while preserving the critical properties of killing white blood cell bacteria."
Reference: Xenia Cohen Katzenelson, et al. (2019) PHLPP1 counter-regulates STAT1-mediated inflammatory signaling. Elip DOI: https://doi.org/10.7554/eLife.48609.001
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