A DNA sensor protein called STING was found to play an unexpected protective role in fibrosis development by regulating inflammatory immune responses in an induced idiopathic pulmonary fibrosis (IPF) mouse model, a study has discovered.
The study, “Protective Role of the Nucleic Acid Sensor STING in Pulmonary Fibrosis,” was published in the journal Frontiers in Immunology.
While the exact cause of IPF is unclear, it is thought to arise due to abnormal wound healing, leading to aberrant tissue remodeling and, ultimately, to fibrosis and scarring. Immune cells are also recruited to the lungs and participate in proinflammatory and profibrotic processes.
When cells are damaged, DNA can leak from the nucleus to the cytosol, the cellular compartment outside the nucleus. The presence of DNA components in the cytosol is sensed by an enzyme called cGAS, which triggers the protein STING to activate the production of immune signaling proteins known as interferons (IFN), leading to an immune response against damaged cells.
However, the role of the cGAS–STING pathway in the development of fibrosis has not been fully explored.
Now, a team of researchers at the University of Orleans in France investigated this pathway in IPF using a standard mouse model in which mice were exposed to bleomycin (BLM) to induce lung fibrosis. Mice lacking the genes that encode for cGAS and STING were also included in the experiments.
The first set of experiments showed that, in the lungs of IPF mice, the DNA levels were significantly increased in the bronchoalveolar lavage fluid (BALF), the liquid obtained from rinsing lungs with saline.
These mice also showed a substantial increase in the activity of both cGAS and STING genes, as well as increased levels of both proteins. Moreover, STING levels were not affected in IPF mice that were cGAS-deficient, nor were cGAS levels impacted in mice that lack STING.
An analysis of the acute inflammatory phase that occurs one day after BLM exposure found that, despite an increase of DNA content in BALF, cGAS or STING deficiency had no major effect on total BALF cell numbers or in the number of immune cells known as neutrophils — a type of white blood cell that leads immune responses. These results support a “minor cGAS/STING contribution in early inflammation,” the researchers wrote.
Next, they found that, compared to BLM-treated IPF mice or those lacking cGAS, mice with STING deficiency showed more weight loss 14 days post-BLM exposure, with some animals not surviving. Markers for lung remodeling were also increased in the lungs of STING-deficient animals compared with controls.
STING-deficient mice had higher lung cell accumulation, more immune cells, and extended areas of fibrosis. Collagen levels in BALF were also elevated in these mice. In contrast, IPF cGAS-deficient mice showed intermediate bodyweight loss, lung remodeling markers, and fibrosis, “suggesting that other DNA sensors might be involved,” the scientists wrote.
As the STING signaling pathway is a well-characterized inducer of the interferon type I immune signaling protein, mice lacking the gene that encodes for this protein were examined to test its role in fibrosis.
In contrast to IPF STING-deficient mice, those lacking interferon type I showed comparable weight loss to normal mice. Furthermore, markers for lung remodeling were increased in IPF mice compared to interferon-type-I-deficient mice, while STING-deficient mice had high levels of these markers. Also, interferon-deficient mice did not have enhanced lung fibrosis.
“Together, these results suggest that STING is protective against BLM-induced fibrosis in a type I IFN-independent manner,” the team wrote.
Finally, the fibrotic stage of the disease is known to be accompanied by the recruitment of immune cells. As expected, in BLM-treated mice, the primary cells found in BALF were immune T-cells and B-cells, whereas the numbers of neutrophils were low.
In contrast, neutrophils remained high in the lungs and BALF of STING-deficient mice, and persisted by days 8 to 14 post-BLM treatment, “suggesting prolonged inflammation.” Moreover, STING-deficient neutrophils showed a strong increase in a marker for neutrophil activation, which suggested that “STING controls neutrophil persistence and function,” the team wrote.
“As a whole, our data show an unexpected regulatory function of STING to limit BLM-induced pulmonary fibrosis associated with neutrophilic inflammation regulation,” the researchers concluded, noting that “STING deficiency leads to exacerbated pulmonary fibrosis.”
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