Immune Cells Work as ‘Friend and Foe’ in ANCA-associated Vasculitis

Study points to role of infiltrating macrophages, DNA sensing system

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Similar to neutrophils, circulating immune macrophage cells contribute to lung bleeding and damage caused by ANCA-associated vasculitis (AAV), a study showed.

These circulating macrophages were found to have an abnormally activated DNA sensing system — typically used to detect foreign DNA and fight infections — that promotes inflammation.

Deleting these macrophages or suppressing components of the DNA sensing pathway significantly reduced lung bleeding in a new AAV mouse model. In turn, depleting the animals of lung-resident macrophages, which clear pro-inflammatory triggers derived from blood vessel damage, promoted disease progression.

“The challenge in finding new therapies is that very little is known about the mechanisms that trigger the disease,” Natalio Garbi, PhD, the study’s senior author and a professor at the Institute of Molecular Medicine and Experimental Immunology (IMMEI) at Bonn University Hospital, in Germany, said in a university press release.

“By better understanding the molecular processes of severe ANCA vasculitis, we have been able to identify potential drug targets in the preclinical model that are already approved for other diseases,” said Garbi, a member of the ImmunoSensation2 cluster of excellence at Bonn.

Further studies are needed to assess the potential of these approved medications in also treating AAV.

The study, “Monocyte-derived macrophages aggravate pulmonary vasculitis via cGAS/STING/IFN-mediated nucleic acid sensing,” was published in the Journal of Experimental Medicine.

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In AAV, the immune system produces antibodies called anti-neutrophil cytoplasmic antibodies, or ANCAs, that mistakenly target one of two proteins — proteinase 3 (PR3) or myeloperoxidase (MPO) — found in immune cells called neutrophils.

This results in an overactivation of neutrophils, causing inflammation and damage to small and medium-sized blood vessels, including those in the lungs, kidneys, and skin.

Targeted therapies are needed, as available AAV treatments mainly involve immunosuppression, which is associated with side effects that include an increased risk of infection. But limited knowledge of the disease’s underlying mechanisms has hampered their development.

Now, Garbi’s team, working with colleagues in Germany, the Netherlands, Switzerland, and the U.K., showed a DNA sensing system which typically works as a defense mechanism against infection is implicated in AAV.

In cells, DNA is typically located in the nucleus, the compartment where all genetic information is stored, or in mitochondria, the cells’ powerhouses. But when bacteria or viruses enter cells, they can leave a trail of DNA outside the nucleus that is detected by a DNA sensing defense system.

This system relies on cGAS, a sensing enzyme that produces a molecule called cGAMP to activate the STING protein. STING then promotes the production of pro-inflammatory type 1 interferon (IFN-I) through the activation of the JAK/STAT signaling.

This system and its induced inflammatory response should prevent pathogens, or disease-causing agents, from multiplying. It also can promote the death of heavily infected cells.

“It becomes problematic when these mechanisms are not triggered by pathogens but by our own cellular DNA,” Garbi said.

“In our study, we show that for reasons still unknown, DNA is released from the cell nucleus and activates the signaling pathway,” which “leads to blood vessel destruction and frank hemorrhage,” Garbi added.

Working with immune cells from 31 AAV patients, researchers showed these cells had significantly higher levels of cGAMP and an overly activated interferon pathway relative to cells from 57 healthy people.

Mouse model developed

To better understand the role of the DNA sensing system in AAV, the team developed a new mouse model of AAV-related lung damage.

Healthy mice were injected with anti-MPO antibodies and bacterial products were then introduced into their lungs to mimic an infection, such as those occurring during an AAV flare. Animals developed lung disease and severe bleeding, mimicking AAV.

DNA accumulated outside the nucleus during disease onset, triggering cGAS/STING-dependent IFN-I release that promoted blood vessel damage, lung bleeds, and lung dysfunction, the researchers found.

Further analyses showed that circulating macrophages, a type of immune cell, recruited to the lungs by neutrophil overactivation were the main producers of damaging IFN-beta, a type of IFN-I. Mice lacking circulating macrophages experienced significantly fewer pulmonary hemorrhages.

In contrast, eliminating specific macrophages that reside on alveoli, the tiny sacs of the lungs where gas exchanges occur, worsened disease progression. These cells were found to reduce pro-inflammatory stimuli by helping to clear red blood cells leaking from damaged blood vessels and by limiting infiltration of IFN-beta–producing macrophages.

DNA sensing via the STING/IFN axis by infiltrating macrophages “aggravate disease progression, while alveolar macrophages contribute to tissue [balance] by clearing the red blood cells,” Nina Kessler, the study’s first author and a PhD student in Garbi’s lab, said in a video detailing the study’s main findings.

“Immune cells are both friends and foes of the disease,” said Susanne Viehmann, PhD, a scientist at IMMEI and study co-author.

Pharmacological suppression of DNA sensing pathway players — STING, JAK/STAT, or IFN-I — significantly eased disease severity and accelerated recovery in these mice.

“Our study unveils the importance of STING/IFN-I axis in promoting pulmonary AAV progression and identifies cellular and molecular targets to ameliorate disease outcomes,” the researchers wrote.

“We were able to show in experiments with mice that the symptoms of this autoimmune disease — such as pulmonary hemorrhage — improve when this signaling pathway is blocked with drugs,” Kessler said.

One such medication, baricitinib, a JAK suppressor sold as Olumiant, is approved in the U.S. to treat rheumatoid arthritis and alopecia areata, two autoimmune diseases.