ADAR1 May Be Therapeutic Target for SSc: Mouse Study

Researchers study high levels of the ADAR1 protein in macrophages

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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A trio of mice climb in and around a beaker and several vials of blood in a laboratory.

The protein ADAR1 occurs in great amounts in macrophages, a type of immune cell that appears in the early stages of systemic sclerosis (SSc), making the cells more active and stirring up a “turmoil” of inflammation, a mouse study found.

Researchers also observed that mice in which the disease was induced by injection of a chemical — bleomycin — developed fewer symptoms in their skin and lungs when engineered to have ADAR1 deficiency in macrophages. Their macrophages also made fewer certain inflammatory molecules.

The findings suggest that “targeting ADAR1 could be a potential novel therapeutic strategy for treating sclerosis,” the researchers wrote.

The study, “ADAR1 promotes systemic sclerosis via modulating classic macrophage activation,” was published in the journal Frontiers in Immunology.

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Scleroderma is an autoimmune disease that causes inflammation and makes cells produce more collagen than usual, and too much collagen causes tissues to thicken and scar. This is called fibrosis.

Macrophages can detect and remove bacteria and other harmful organisms, and prompt other immune cells to take action in inflammation. Activated macrophages usually are divided into M1-like macrophages and M2-like macrophages; whereas, M1 macrophages are involved mainly in pro-inflammatory responses, M2 macrophages are implicated in anti-inflammatory responses.

ADAR1 (short for adenosine deaminase acting on RNA) is an RNA editor that works by making discrete changes to RNA, the form in which a gene’s information is read by cells. While ADAR1 holds a yet-unclear role in inflammation, it is known that samples of the skin and blood taken from people with SSc are rich in the protein.

To know more, the researchers turned to mice where fibrosis is induced by bleomycin.

In the skin, RNA levels of ADAR1 increased by almost 10 times in the first day after injection of bleomycin, and those of the protein also were increased significantly after one week. At the same time, there was an increase in the levels of collagen and in skin thickness, which indicates fibrosis. There also was an increase in the number of macrophages.

Two types of lab mice

To better understand the link between ADAR1 and fibrosis, the researchers turned to mice engineered to have ADAR1 deficiency. These mice showed markedly attenuated collagen deposition and skin thickness after bleomycin injection.

Similar observations were made when the researchers used mice lacking any ADAR1 in immune cells that include macrophages. Likewise, lung structure damage induced by bleomycin was alleviated in these mice.

These findings suggested “a crucial role for ADAR1 in the development of SSc,” the researchers wrote.

To find out exactly what ADAR1 does in macrophages, the team compared the levels of inflammatory molecules in the skin with those of wild-type (control) mice.

After injection of bleomycin, the skin of control mice had about three times as much inducible nitric oxide synthase — an enzyme that generates nitric oxide, which has a key role in the development of inflammation — as that of mice lacking ADAR1 in macrophages. It also had about double the amount of interleukin-1beta, a cytokine made by macrophages and other cells that is associated with acute and chronic inflammation.

Afterbleomycin injection, lack of ADAR1 in macrophages significantly blocked activation of nuclear factor-kappa B, a type of molecule that regulates gene activity and turns on M1 macrophages, as opposed to what was found in control mouse skin.

These findings suggest that “ADAR1 appears to promote sclerosis by stimulating macrophage inflammatory response,” the researchers concluded.