Immune and nerve cells work together to fight gut infections

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By IMPC

Published 6th July 2018

Nerve cells in the gut play a crucial role in the body’s ability to marshal an immune response to infection, according to a new study from Weill Cornell Medicine scientists.

The study, published in Nature, shows that the immune system and nervous system have co-evolved to respond to infectious threats. This means that scientists looking for ways to treat diseases like inflammatory bowel disease or asthma that involve an excessive immune system response may also have to address the nervous system’s role.

“The immune system and neuronal system don’t act independently,” said senior author Dr. David Artis, director of the Jill Roberts Institute for Research in Inflammatory Bowel Disease and the Michael Kors Professor of Immunology at Weill Cornell Medicine. “They are working together.”

“These guys are dancing like a tango,” Dr. Klose said. The lining of the gut is home to many immune system cells, which serve as a defense against parasites and other infections. It is also loaded with nerve cells. Lead author Dr. Christoph Klose, a postdoctoral associate at the Roberts Institute, found that immune system cells in the gut, called group 2 innate lymphoid cells (ILC2s), are intertwined with nerve cells called cholinergic neurons.

The intestinal barrier. Color-enhanced image of the intestinal lining, which serves as a barrier and limits dissemination of the microbiota. Credit: Greg Sonnenberg and David Artis, Weill Cornell Medicine.

The cells’ close proximity led the researchers to wonder if they may be communicating. That’s when they discovered that the ILC2 cells had a receptor for a protein called neuromedin U (NMU), which acts as a messenger for the nerve cells. In laboratory experiments, the investigators found that exposing ILC2 cells to NMU causes the ILC2 cells to rapidly multiply and secrete chemicals called cytokines that may help trigger an immune response or cause inflammation.

Administering NMU to mice infected with a gut parasite triggered inflammation and a powerful immune response that helped the mice more quickly expel the parasites. Conversely, mice genetically engineered to lack receptors for NMU were more susceptible to the parasites, allowing them to multiply rapidly in the rodents’ gut. The study shows that the NMU-producing nerve cells help prime the ILC2 cells, enabling them to rapidly and effectively respond to infection.

“Where we are most excited is thinking about multiple chronic inflammatory diseases that might be related to this neuronal-immune axis and where we might be able to intervene,” Dr. Artis said. The findings may have important implications for scientists studying inflammatory diseases, including asthma, food allergies and inflammatory bowel disease (IBD). Dr. Artis said it was too soon to say whether NMU itself or its receptors could be treatment targets, but he said studying these pathways might lead to potential new therapies for these diseases.

 

Research article: The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation

A study led by Kevin King, a bioengineer and physician at the University of California San Diego, has found that the immune system plays a surprising role in the aftermath of heart attacks. The research could lead to new therapeutic strategies for heart disease. Mice for this study originated from the Jackson Laboratory and the European Conditional Mouse Mutagenesis Program (EUCOMM).

The team, which also includes researchers from the Center for Systems Biology at Massachusetts General Hospital (MGH), Brigham and Women’s Hospital, Harvard Medical School, and the University of Massachusetts, presents the findings in the journal Nature Medicine. Ischemic heart disease is the most common cause of death in the world and it begins with a heart attack. During this process, heart cells die, prompting immune cells to enter the dead tissue, clear debris and orchestrate stabilization of the heart wall.

But what is it about dying cells in the heart that stimulates the immune system? To answer this, researchers looked deep inside thousands of individual cardiac immune cells and mapped their individual transcriptomes using a method called single cell RNA-Seq. This led to the discovery that after a heart attack, DNA from dying cells masquerades as a virus and activates an ancient antiviral program called the type I interferon response in specialized immune cells. The researchers named these “interferon inducible cells (IFNICs).”

When investigators blocked the interferon response, either genetically or with a neutralizing antibody given after the heart attack, there was less inflammation, less heart dysfunction, and improved survival. Specifically, blocking antiviral responses in mice improved survival from 60 percent to over 95 percent. These findings reveal a new potential therapeutic opportunity to prevent heart attacks from progressing to heart failure in patients.

“We are interested to learn whether interferons contribute to adverse cardiovascular outcomes after heart attacks in humans,” said King, who did most of the work on the study while he was a cardiology fellow at Brigham and Women’s Hospital and at the Center for Systems Biology at MGH in Boston.

The immune system has evolved innate antiviral programs to defend against a diverse range of invading pathogens. Immune cells do this by detecting molecular fingerprints of pathogens, activating a protein called IRF3, and secreting interferons, which orchestrate a defense program mediated by hundreds of interferon-stimulated genes. Investigators found that surprisingly, the antiviral interferon response is also turned on after a heart attack despite the absence of any infection. Their results point to dying cell DNA as the cause of this confusion because the immune system interprets it as the molecular signature of a virus.

Surprisingly, the immune cells participating in the interferon response were a previously unrecognized subset of cardiac macrophages. These cells could not be identified by conventional flow sorting because unique markers on the cell surface were not known. By using single cell RNA Seq, an emerging technique that combines microfluidic nanoliter droplet reactors with single cell barcoding and next generation sequencing, the researchers were able to examine expression of every gene in over 4,000 cardiac immune cells and found the specialized IFNIC population of responsible cells.

Future studies will aim to better understand the interferon response and the IFNIC cell type and explore their roles in the infarcted and remodeling heart. The team is also working to understand the interferon response in other tissues and diseases where cell death occurs.

 

Research article: IRF3 and type I interferons fuel a fatal response to myocardial infarction

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By IMPC

Published 3rd July 2018

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