New study reveals surprising insights into macrophages’ role in fibrosis, challenging previous beliefs and opening doors for innovative treatments.

Researchers have conducted the first study to compare lung macrophages across various lung injury models. Their findings reveal that macrophages previously labeled as “pro-fibrotic” cannot independently cause fibrosis. This breakthrough paves the way for further research into how macrophage programming influences lung repair. The study was recently published in JCI Insight. ()

What are Macrophages

Macrophages are immune cells that reside in and protect the lungs and are also recruited to the lungs in high numbers during injury or disease. They are key to the initiation and resolution of various types of lung injuries, but also are involved in pathways that lead to lung scarring (fibrosis). It is currently unclear what mechanisms differentiate macrophages that lead to healthy repair from those that lead to fibrosis. This research sought to explore if different genetic groups of macrophages were involved in these different outcomes.

“We now know the role of macrophages have been misunderstood,” said William Janssen, MD, section head of Critical Care Medicine at National Jewish Health and senior co-author of the research. “This research helps advance the goal of the pulmonary community to harness macrophages in the pursuit of achieving lung repair.”

Researchers initially compared macrophage activity in two models of disease, one that was known to follow a healthy repair path and one that resulted in fibrosis, over time to determine if there were differences in the macrophage populations. The initial findings helped identify populations of responder macrophages that were recruited to the lungs in all types of lung injury. The researchers then analyzed the transcribed genes in these macrophage populations at multiple time points to better understand what differences existed.

Further analysis found these macrophages in lung tissue samples from multiple diseases, including asthma and COVID, with a wide range of recovery outcomes. This finding prompted follow-up investigations into what led to dysfunctional healing and fibrosis in some lung diseases and not in others.

“When you take a step back and look at clinical data differently, you start to see something new,” said Alexandra McCubbrey, PhD, a researcher at National Jewish Health and senior co-author of the study. Further research into the different injury models at different time points showed that the microenvironment of the lung caused subtle changes in protein expression and macrophage survival. These changes, in the fibrotic injury model, caused distinct pathways to be activated that led the cells toward a less effective repair, as a response to the environment and external signals.

“Our goal is to figure out how to rebuild the injured lung,” said Dr. Janssen. His continuing research is aimed to better understand what programs macrophages and determine if they can be harnessed to encourage healthy repair even in formerly fibrotic disease.

Reference:

1. Gpnmb and Spp1 mark a conserved macrophage injury response masking fibrosis-specific programming in the lung – (https://insight.jci.org/articles/view/182700)

Source-Eurekalert