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Newly Described Cells May Regulate Inflammation in Viral Lung Infections

lung macrophages
Lung tissue filled with pigmented macrophages. A unique set of macrophages may control the inflammatory response to viral infection. | Yale Rosen/Flickr

A unique subset of white blood cells that reside within the lungs, called nerve- and airway-associated macrophages (NAMs), are key controllers of inflammation during viral infection like influenza, according to a new study of the cells in mice.

These results, published March 27 in Science Immunology, show NAMs are distinct from their more well-known cousins, alveolar macrophages (AMs). AMs are the primary macrophage population in the lungs and directly clear viruses, while NAMs help regulate the immune response to the virus.

Learning more about inflammatory processes in the respiratory tract can help inform the development of targeted therapies to relieve harmful responses during flu, bronchitis and other diseases characterized by excessive inflammation and tissue damage in the lungs — including the rapidly developing COVID-19 pandemic.

"It is becoming increasingly clear that severe complications from COVID-19 are related to immunopathology of the lungs," said senior author Kamal Khanna, associate professor of microbiology at New York University's Grossman School of Medicine. "Our study shows that there appears to be a division of labor among pulmonary [lung] macrophage subsets."

Given that NAMs also exist in human lungs, it will be critical to determine whether they play a role in mediating tissue repair and regulating inflammation during COVID-19 infection, added Khanna.

While viruses are the agents of infection and cause a great deal of harm on their own, when it comes to the aches, fever, chills and other painful symptoms that we feel during an infection, our own immune response is to blame. While these symptoms indicate that the immune system is doing its job, the resulting inflammation can also weaken the body and cause substantial damage if left unregulated.

When the inflammatory immune response becomes uncontrolled and excessive, it can essentially "melt" tissues away and leave the body vulnerable to new infections like pneumonia.

"During respiratory viral infection the ideal immune response has to strike a delicate balance between robust inflammation to eradicate the virus and at the same time regulatory mechanisms have to function appropriately to prevent damaging inflammation," said Khanna.

Timing is critical. According to Khanna, robust inflammation is good for the body early on in infection because it will help clear the virus, but once most viruses have been eliminated, the body must begin suppressing the immune response, to ensure the recovery of tissues where viruses were fought.

Particle-engulfing white blood cells called macrophages are critical first responders to viral attacks, positioned strategically throughout the body's tissues to produce inflammatory molecules and devour foreign invaders. But emerging evidence indicates the cells can step back and play more of a regulatory role as well. By helping repair tissues and cleaning up dead cells, the cells ensure the organ returns to its baseline condition after an infection has been cleared.

Compared to macrophages generated in the lab for research, there is not as much information on tissue-resident macrophages. NAMs have been particularly challenging to characterize because they compose a smaller population than AMs and are clustered around specialized structures, like the airway nerves. As such, NAMs are very difficult to obtain in great numbers.

For this reason, Khanna and his colleagues combined extensive approaches to visualize cells within living bodies with improvements in isolating cells to develop the most efficient way to observe and obtain NAMs in larger numbers. They applied these techniques in three different mouse models where either AMs or NAMs were depleted to differentiate the roles and characteristics of each subset. They discovered NAMs were embryonically derived, self-renewing, and altogether genetically and developmentally distinct from AMs.

Infecting these mouse models with a mouse-specific strain of influenza A, the researchers found NAMs proliferated robustly following infection, and in the absence of these cells, the inflammatory response went largely unchecked.

However, depleting only NAMs did not seem to impact the animals' survival, while depleting AMs did, most likely because AMs could engulf the flu virus and reduce viral numbers, the researchers found. They concluded that while AMs take charge of clearing viruses, NAMs may play a supportive, yet crucial role in regulating post-infection inflammation.

"As we come to understand more about how NAMs regulate infection-induced inflammation, we can target these macrophages to help resolve damaging inflammation caused by respiratory viral infections, such as COVID-19," said Khanna. He suggests several strategies for exploration, including augmenting NAM function or increasing their numbers at the right time during viral infections — at later time points after viruses have been cleared from the body.

Khanna and his colleagues have also recently formed a group for COVID-19 research. Having obtained strains of COVID-19, the group has devised a proposal to investigate how different subsets of lung macrophages may respond to a COVID-19 infection.

"We are hoping to soon start evaluating how these macrophage subsets function during COVID-19 infection in humans and in mice models," Khanna said. These efforts will include "performing cutting edge imaging approaches to visualize these macrophages in human and mouse lungs, as well as genomic studies to determine if the function of NAMs is compromised in severely ill patients."