Targeting Pro-scarring Immune Cells Thwarts, Reduces PF in Mice

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Using nanoparticles to deliver an anti-scarring RNA molecule to pro-scarring lung macrophages — a type of immune cell — prevented and reduced lung tissue fibrosis in a mouse model of pulmonary fibrosis (PF), a study shows.

To specifically target pro-fibrotic macrophages, researchers at University of Illinois College of Medicine (UICM) coated these tiny particles with mannose, a simple sugar molecule that binds to a specific receptor protein found at high levels at the surface of macrophages involved in PF.

“The body’s inflammatory processes are very complex,” Abhalaxmi Singh, PhD, the study’s first author and a visiting research assistant professor in UICM’s department of pharmacology and regenerative medicine, said in a university press release.

“Finding treatments for diseases that result from lingering or excessive inflammation are very difficult because the treatments that prevent harmful inflammation also, unfortunately, prevent helpful inflammation which fights infections and heals injuries,” Singh added. “To have a targeted treatment that addressed a root cause of harmful inflammation work in an animal model is exciting.”

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“Macrophages are exciting, complex cells and … coating the nanoparticle with sugar to bind to the mannose receptor is an intriguing and precise way to ensure targeted delivery of a silencing RNA treatment to this subset of cells that contribute to fibrosis,” said Asrar Malik, PhD, the study’s senior author, the Schweppe Family distinguished professor, and head of the pharmacology and regenerative medicine department at UICM.

Further studies are needed to confirm the approach’s therapeutic potential before it can be tested in people with PF, the researchers noted.

The study, “Nanoparticle targeting of de novo profibrotic macrophages mitigates lung fibrosis,” was published in Proceedings of the National Academy of Sciences.

PF is characterized by excessive inflammation and abnormal remodeling of lung tissue that leads to lung scarring, or fibrosis, and increased stiffness, making it difficult for patients to breathe.

Previous research suggests the disease is driven by abnormalities in several cells in the alveoli, the tiny air sacs in the lungs where gases are exchanged and that are progressively damaged in PF.

Macrophages, a type of immune cell, traveling to the alveoli following excessive inflammation were shown to acquire a pro-fibrotic profile and produce a major pro-fibrotic molecule called TGF-beta 1.

This promotes myofibroblasts — the main cellular drivers of lung fibrosis — to mature and produce extracellular matrix (ECM) proteins. ECM molecules surround and support cells, but can cause tissue scarring when produced excessively.

“Beyond the limited efficacy of dampening the activation of fibroblasts with [therapies] such as [Esbriet (pirfenidone)] or [Ofev (nintedanib)], there is no approach targeting the specific disease-inducing macrophage population,” the researchers wrote.

Malik and his team’s innovative approach specifically targets pro-fibrotic alveolar macrophages.

They took advantage of the fact that CD206, a cell surface receptor protein that binds to a simple sugar called mannose, was previously shown to be overly produced by alveolar macrophages during PF in both mouse models and patients.

This suggested that CD206-positive alveolar macrophages may be the ones acquiring the pro-fibrotic profile and that targeting them may help prevent further macrophage-induced scarring.

The new approach consists of using mannose-coated nanoparticles to deliver a TGF-beta 1-suppressing RNA molecule specifically to CD206-positive alveolar macrophages.

The binding between mannose at the surface of the nanoparticles and the CD206 receptor at the surface of pro-fibrotic macrophages provides an entry point for the nanoparticles, which release the anti-TGF-beta 1 molecule into cells.

This is expected to lower TGF-beta 1 production and the pro-fibrotic effects of this macrophage population, ultimately preventing or reducing further lung fibrosis.

Using a PF-inducible mouse model, researchers found that TGF-beta 1 production was reduced only in the nanoparticle-internalizing macrophages, confirming the specificity of their approach.

Delivering these nanoparticles directly into the bloodstream of the mice before the disease was established resulted in lung fibrosis being partially prevented relative to untreated animals. This was accompanied by significantly lower levels of pro-fibrotic and ECM molecules, and significant lung function improvements — nearly reaching levels observed in healthy mice.

Also, treatment given after fibrosis was established significantly reduced it, suggesting it could reverse already established disease.

“We demonstrate the therapeutic efficacy of using [mannose-coated] nanoparticles to target a specific subset of profibrotic lung macrophages and thus mitigate lung fibrosis,” the researchers wrote.

According to the release, the team, in collaboration with researchers at the University of California at San Francisco, has already started testing the treatment in human lung tissue samples.

Malik, Singh, and other study authors are members of Nano Biotherapeutics, a startup company launched to advance the targeted nanoparticle-based delivery platform for treating acute and chronic inflammation and tissue injury in the heart and lungs.