Scientists discover treatment target for sepsis

March 14, 2018 by Anna Williams, Northwestern University

In a study published in Nature Communications, Northwestern Medicine scientists demonstrated the key role a molecule called oxPAPC plays in regulating the inflammatory response—findings which could inform the development of new therapies for the body's life-threatening response to serious infections.

Lan Chu, a sixth-year doctoral student in Feinberg's Driskill Graduate Program in Life Sciences (DGP), was the first author of the study.

Sepsis is a serious medical condition caused by the body's harmful, systemic to an infection. Inflammatory chemicals released into the bloodstream to fight the infection can lead to blood clotting, tissue damage, organ failure and death.

"Sepsis is a major health issue, with very high mortality. But we don't really have a therapy to treat it right now," explained principal investigator Christian Stehlik, Ph.D., the John P. Gallagher Research Professor of Rheumatology.

A common cause of is a type of bacteria called gram-negative bacteria. Immune cells in the body recognize lipopolysaccharide (LPS)—a major component of the membrane of these bacteria—which in turn triggers the potent inflammatory response.

Previously, it was understood that TLR4, a protein on the surface of , was responsible for recognizing LPS. But clinical trials of therapies targeting the TLR4 protein as a treatment for sepsis had been largely unsuccessful.

More recently, scientists discovered that immune cells actually have a second additional receptor for LPS: an intracellular protein called caspase-11 (in mice, or caspase-4 and caspase-5 in humans).

Caspase-11 binds to LPS and activates what's known as a non-canonical inflammasome response, which plays a role in sepsis. Controlling caspase-11 could thus be a novel strategy to preventing the inflammatory overreaction seen in sepsis.

But until now, it was not understood how the caspase-11 molecule is regulated.

In the current study, the scientists discovered that a phospholipid called oxPAPC regulates caspase-11 in human and animal macrophages. The molecule does so by competing with LPS to bind to caspase-11. "If there's enough oxPAPC, LPS cannot bind, and the excessive inflammatory response is prevented," explained Stehlik, also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

In the study, the scientists also demonstrated that when oxPAPC is injected into mice who are then challenged with LPS, septic shock was prevented.

"Our work provides the first evidence for a negative regulator of non-canonical inflammasomes, and thus provides a basis for novel therapies targeting inflammasomes and inflammation-induced diseases," Chu said.

In the future, for example, synthetic versions of oxPAPC—or molecules that mimic its role—could potentially be administrated to septic patients as therapy, which might temper the .

"At least in mice so far, oxPAPC seems to be really effective at preventing death. What we hope is that, by extension, this could also be used as a for patients in the future," Stehlik said.

In ongoing studies, Stehlik laboratory is now investigating how oxPAC is taken up by macrophages and what receptors might be involved in that process.

Explore further: New insights into protein's role in inflammatory response

More information: Lan H. Chu et al. The oxidized phospholipid oxPAPC protects from septic shock by targeting the non-canonical inflammasome in macrophages, Nature Communications (2018). DOI: 10.1038/s41467-018-03409-3

Related Stories

New insights into protein's role in inflammatory response

July 28, 2017
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.

A new look at caspase 12 research

June 1, 2016
Inflammasomes are assemblies that are central to inflammatory responses. Dr. Lieselotte Vande Walle, Daniel Jiménez Fernández and colleagues from Prof. Mo Lamkanfi's group (VIB/UGent) shed new light on the function of caspase ...

Novel research lays the groundwork for new therapies against sepsis

April 8, 2016
Sepsis represents a serious complication of infection and is one of the leading causes of death and critical illness worldwide due in part to the lack of effective therapies. A report in the American Journal of Pathology ...

Can we hypercharge vaccines? Tapping a chemical we already make could enhance T-cell production

April 21, 2016
Researchers at Boston Children's Hospital report that a fatty chemical naturally found in damaged tissues can induce an unexpected kind of immune response, causing immune cells to go into a "hyperactive" state that is highly ...

How white blood cells jump into action in response to foreign microbes

September 21, 2016
Pro-inflammatory molecules in the blood are essential for fighting off microbial invaders. But too much of these immune-signaling factors, and the body can go into septic shock. A team from the A*STAR Singapore Immunology ...

Recommended for you

HIV vaccine protects non-human primates from infection

December 14, 2018
For more than 20 years, scientists at Scripps Research have chipped away at the challenges of designing an HIV vaccine. Now new research, published in Immunity, shows that their experimental vaccine strategy works in non-human ...

RNA processing and antiviral immunity

December 14, 2018
The RIG-I like receptors (RLRs) are intracellular enzyme sentries that detect viral infection and initiate a first line of antiviral defense. The cellular molecules that activate RLRs in vivo are not clear.

The 'greying' of T cells: Scientists pinpoint metabolic pathway behind age-related immunity loss

December 13, 2018
The elderly suffer more serious complications from infections and benefit less from vaccination than the general population. Scientists have long known that a weakened immune system is to blame but the exact mechanisms behind ...

Scientists create most accurate tool yet developed to predict asthma in young children

December 13, 2018
Scientists at Cincinnati Children's Hospital Medical Center have created and tested a decision tool that appears to be the most accurate, non-invasive method yet developed to predict asthma in young children.

New genetic study could lead to better treatment of severe asthma

December 12, 2018
The largest-ever genetic study of people with moderate-to-severe asthma has revealed new insights into the underlying causes of the disease which could help improve its diagnosis and treatment.

Researchers discover unique immune cell likely drives chronic inflammation

December 11, 2018
For the first time, researchers have identified that an immune cell subset called gamma delta T cells that may be causing and/or perpetuating the systemic inflammation found in normal aging in the general geriatric population ...

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.