Lung-patrolling immune cells tied to persistent inflammation in CF
Study findings may help identify novel potential therapeutic targets
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Immune cells that patrol the lungs, called alveolar macrophages, may help sustain persistent inflammation in cystic fibrosis (CF), according to a new study.
Researchers found that alveolar macrophages in people with CF differed from healthy cells, showing inflammatory activity, abnormal cholesterol handling, and altered communication with other immune cells that may help sustain lung inflammation. Cholesterol is a fatty substance needed for normal cell function, but abnormal buildup inside immune cells has been linked to inflammation.
“Our results may identify novel potential therapeutic targets to treat CF lung inflammation,” researchers wrote.
The study, “Alveolar macrophage subtypes express cholesterol and inflammation genes in cystic fibrosis,” was published in Life Science Alliance.
In CF, alveolar macrophages may adopt overly inflammatory state
CF is caused by mutations in a gene that encodes CFTR, a protein that regulates the movement of salt and water in and out of cells. Without enough working CFTR, thick, sticky mucus builds up in the lungs and other organs, driving disease symptoms.
In the lungs, mucus traps bacteria, contributing to chronic infections and ongoing inflammation that gradually damages lung tissue. While infections clearly fuel inflammation in CF, evidence suggests that chronic lung inflammation may also develop independently of infection.
CFTR modulators, a class of medicines that boost the function of defective CFTR protein, have substantially improved survival and quality of life. Yet inflammation often lingers, and lung function can continue to decline over time, even if at a slower pace.
This persistent inflammation has been linked to the activity of neutrophils, infection-fighting immune cells that accumulate in the lungs of people with CF. But researchers increasingly suspect that alveolar macrophages may also be involved. These immune cells patrol the lungs, clearing inhaled particles and debris, helping launch immune responses against pathogens, and maintaining the balance of fatty substances.
Previous studies have suggested that alveolar macrophages may adopt an overly inflammatory state in CF. However, how different macrophage populations contribute to lung inflammation in CF — and how they communicate with other immune cells in the lungs — remains poorly understood.
Some macrophage subtypes appeared particularly altered in CF
To learn more, researchers at Dartmouth compared bronchoalveolar lavage fluid, a sample of lung fluid collected during bronchoscopy, from seven adults with CF and seven sex- and age- matched healthy controls.
All participants with CF had mild-to-moderate lung disease, carried at least one F508del mutation — the most common CF-causing mutation — and had been receiving CFTR modulators for at least a year. Five had lung infections with Pseudomonas aeruginosa, but all had remained free of pulmonary exacerbations (flare-ups) during the previous year.
As expected, alveolar macrophages were the most abundant immune cells identified in the lung fluid samples, followed by monocytes. In people with CF, these cells showed increased activity of genes involved in inflammation and pathways that promote the buildup of cholesterol inside cells.
This caught the researchers’ attention because cholesterol accumulation within macrophages has been linked to proinflammatory responses in chronic inflammatory diseases, such as atherosclerosis. Based on their findings, the researchers suggested that “a potentially similar proinflammatory pathway” may be involved in alveolar macrophages in CF.
When looking more closely at alveolar macrophages, they found that these cells were far from forming a single, uniform population. Instead, they identified 12 distinct macrophage subtypes, each with its own genetic profile and likely function in the lungs.
Some of these subtypes appeared particularly altered in CF. Alveolar macrophages expressing LDLR, a gene encoding a receptor protein involved in cholesterol uptake, and CDKN1A, which has been linked to proinflammatory activity, were more abundant in people with CF. The researchers said the increase in LDLR-expressing macrophages may reflect a more proinflammatory profile, similar to what is seen in atherosclerosis.
The researchers then examined how immune cells communicate with one another. Their analysis showed increased communication between immune cells in samples from people with CF compared with healthy controls, with strong interactions involving alveolar macrophages and monocytes.
Many of these signals were linked to inflammation and to the recruitment of immune cells within lung tissue. The scientists also identified strong interactions between macrophages and recruited monocytes that may help newly arrived immune cells adapt within the lungs. Macrophages also communicated more strongly with other immune cells through signaling pathways linked to tissue retention and cell survival.
While additional studies are needed, the researchers said the findings identify “key pathways involved in cell-cell interactions” that may contribute to persistent lung inflammation and that “could be targeted to treat persistent inflammation” in people with CF.
