Disarming the immune system’s deadly lunges

PTP1B and lung inflammation in mice

image: CSHL researchers have found that treating mice with a drug candidate that inhibits a protein called PTP1B can prevent fatal pneumonia in mice. Shown here are 3D images of mouse lungs treated with (left) and without (right) the PTP1B inhibitor drug candidate. The drug candidate prevented a lethal amount of lung damage, shown in cyan, from overactive immune cells called neutrophils.
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Credit: Tonks lab/CSHL, 2022

Neutrophils, the most abundant type of white blood cell, are the body’s first line of defense against infection. Foreign pathogens can stress the body and activate neutrophils. When activated, neutrophils employ various weapons to protect the body. But if overactivated, these weapons can damage the body’s own tissue. Lung tissues are saturated with blood vessels, making them highly susceptible to neutrophil attack. If severe enough, acute lung injuries can lead to acute respiratory distress syndrome (ARDS), the leading cause of death from COVID-19.

Nicholas Tonks, the Caryl Boies Professor of Cancer Research at Cold Spring Harbor Laboratory (CSHL), and his team have found a drug candidate that can prevent fatal pneumonia in mice by inhibiting a protein called PTP1B. Their discovery could help develop better treatments for severe inflammatory conditions such as sepsis and COVID-19.

“When you think about COVID-19, acute lung injury and ARDS underlie the fatal aspects of the disease,” says Tonks. “And when the pandemic took hold, we wondered if there was anything we could do to help, to provide an understanding of this aspect of the disease and suggest ways to treat it.”

Tonks’ graduate student Dongyan Song investigated whether using a PTP1B inhibitor drug candidate could moderate the lethal consequences of overactive neutrophils in mice. She found that pre-treating mice with the PTP1B inhibitor reduced lung tissue damage. When left untreated, less than half of the mice survived acute lung injury and ARDS. But when they were pretreated, they all survived.

The researchers took advantage of a natural process, called neutrophil senescence, that the body uses to control immune cell lifespan. As they age, neutrophils become less dangerous. Tonks’ team discovered PTP1B inhibition accelerates neutrophil aging. “An old neutrophil is like a soldier without a weapon,” explains Song. “So no matter how many neutrophils flood an area, they won’t be able to do serious damage.”

This project was part of a program of COVID-related research at CSHL. Tonks says collaboration with CSHL Professor Mikala Egeblad, postdoc Jose M. Adrover and CSHL Research Associate Professor Scott Lyons was critical to this discovery. Going forward, he and Song are working to increase the understanding of how PTP1B inhibitors affect the immune system. Tonks hopes his lab’s continued research leads to new treatments and preventive measures for various inflammatory diseases. His laboratory is currently working with DepYmed, Inc. to enter PTP1B inhibitor drug candidates into clinical trials.

Tonks’ lab studies signal transduction, the process that controls how cells respond to signals from their environment. In particular, they focus on the PTP protein family, which Tonks discovered over 30 years ago. Since then, he has sought to develop small molecule drug candidates that target these proteins, which may provide new approaches to the treatment of major human diseases, including cancer and metabolic and neurodegenerative diseases.

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