New insights into protein's role in inflammatory response

July 28, 2017 by Anna Williams, Northwestern University

A protein called POP2 inhibits a key inflammatory pathway, calming the body's inflammatory response before it can become destructive, Northwestern Medicine scientists have demonstrated in mouse models.

The study, published in the journal Nature Communications, adds to the understanding of how the body maintains a balanced inflammatory and could have important implications in the development of future therapies for .

"We found these proteins nine years ago, but all the research was done in cell studies, so we weren't sure if it had a function with inflammation in vivo. This study now shows that POP2 really has a profound impact on dampening these responses," said senior author Christian Stehlik, PhD, the John P. Gallagher Research Professor of Rheumatology.

Andrea Dorfleutner, PhD, research associate professor of Medicine in the Division of Rheumatology, was also a senior author of the study. Rojo Ratsimandresy, PhD, a postdoctoral fellow in Stehlik's lab, was the first author. He will join Feinberg's faculty as a research assistant professor of Medicine in the Division of Rheumatology in September.

POP2 is one of three members of the PYRIN domain-only family of proteins, which was discovered by Stehlik's laboratory. Over the last decade, his research has largely focused on these proteins—POP1, POP2 and POP3—and their role in resolving .

Specifically, the three proteins each act on unique types of inflammasomes—protein complexes that release pro-inflammatory cytokines—in order to tightly control the and prevent systemic inflammation after an initial response.

In the current study, the scientists demonstrated that POP2 is distinctive among the family of PYRIN domain-only proteins in performing two essential functions in vivo: "POP2 both blocks inflammasomes and inhibits NF-κB, a pro-inflammatory transcription factor that leads to the initial priming of inflammasome responses," Dorfleutner said.

"Together, these two activities inhibit the inflammatory response—and that's why POP2 is probably so potent," explained Stehlik, also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

Because mice lack the genes for the PYRIN domain-only proteins, the scientists engineered mice to express human POP2, using a promoter that drives expression of the protein in immune cells called macrophages. These cells are important for sensing tissue damage and infections.

"We found that only expressing this protein in this one particular cell type can, in vivo, completely ameliorate these inflammatory responses," Stehlik said.

The scientists further showed, in cell culture studies, that a synthetic version of POP2 added to healthy macrophages blocked the same inflammatory pathway, similar to when the is expressed in . Ongoing research is now working to optimize cellular delivery, with the goal of bringing synthetic POP2 to preclinical mouse models.

The Northwestern team has previously demonstrated that synthetic versions of POP1 injected into mice significantly dampen inflammation.

"The hope is that eventually it can be used to target the increasing number of in humans," Stehlik said.

Explore further: Protein scouts for dangerous bacteria: How the immune system detects listeria and other bad bacteria

More information: Rojo A. Ratsimandresy et al. The PYRIN domain-only protein POP2 inhibits inflammasome priming and activation, Nature Communications (2017). DOI: 10.1038/ncomms15556

Related Stories

Protein scouts for dangerous bacteria: How the immune system detects listeria and other bad bacteria

February 23, 2012
Millions of "good" bacteria exist harmoniously on the skin and in the intestines of healthy people. When harmful bacteria attack, the immune system fights back by sending out white blood cells to destroy the disease-causing ...

Study offers new insight into powerful inflammatory regulator

May 1, 2017
A new study in mice reveals how a protein called Brd4 boosts the inflammatory response—for better and for worse, depending on the ailment. The study is the first to show that this protein, while problematic in some circumstances, ...

Stem cells may significantly improve tendon healing by regulating inflammation

May 23, 2017
New research published online in The FASEB Journal suggests that tendon stem (TSCs) may be able to significantly improve tendon healing by regulating inflammation, which contributes to scar-like tendon healing and chronic ...

Cytokine controls immune cells that trigger inflammatory bowel disease, study finds

April 18, 2017
A certain cytokine, or small protein that helps cells communicate during immune responses, can control whether immune cells promote or suppress inflammatory bowel disease, a finding that could lead to new treatments, according ...

Researchers find piece in inflammatory disease puzzle

May 23, 2017
Inflammation is the process by which the body responds to injury or infection but when this process becomes out of control it can cause disease. Monash Biomedicine Discovery Institute (BDI) researchers, in collaboration with ...

Study pinpoints key pathway in inflammation and aging

May 9, 2017
In patients with colitis, a serious condition affecting the gut, the immune system turns against the body's own microbes, causing inflammation. To combat this inflammation, scientists have focused in on a chemical signal ...

Recommended for you

Researchers make significant discovery around how inflammation works

April 23, 2018
A research team from Queen's University Belfast, in collaboration with an international team of experts, have made ground-breaking insights into how inflammatory diseases work.

Analysis of 32 studies shows preschool, daycare do not raise asthma risk

April 10, 2018
A study that involved combing through more than 50 years of data to assess the link between asthma and daycare and preschool attendance may provide welcome reassurance to working parents. Early child care does not boost children's ...

New drug therapy could lead to more effective treatment for millions with asthma

February 7, 2018
Rutgers New Jersey Medical School researchers identified a new treatment that could lead to more effective drug therapy for millions of individuals with asthma and other respiratory disorders such as chronic obstruction pulmonary ...

Chronic inflammation causes loss of muscle mass during aging

January 12, 2018
People start losing muscle mass at the age of 40—about some 10 percent of the total muscle mass for each 10-year period, which may lead to fall-related injuries, slowing metabolism and reduced quality of life. Today, very ...

Breathing exercises help asthma patients with quality of life

December 13, 2017
A study led by the University of Southampton has found that people who continue to get problems from their asthma, despite receiving standard treatment, experience an improved quality of life when they are taught breathing ...

Study highlights the need for research into prevention of inflammatory bowel disease

December 7, 2017
Countries in Africa, Asia, the Middle East and South America have seen a rise in incidence of inflammatory bowel disease as they have become increasingly industrialised and westernised, a new study has found.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.