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The CCR2 receptor and CCL-2 ligand work together to summon macrophages to the site of infection and maintain the appropriate level of surfactant.

Inherited CCR2 Mutation Linked to Polycystic Lung Disease

CCR2’s ligand, CCL-2, accumulates in the blood and can be used as a biomarker to detect CCR2 levels in patients with lung disease

The Rockefeller University
Published:Feb 08, 2024
|3 min read
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In a recent study, investigators from Rockefeller University and other institutions have discovered a never-before-documented genetic disorder that causes the improper functioning of these cells. 

The researchers made their discovery by drawing an unexpected connection between a select group of sick children. Throughout their lives, these nine children had battled severe diseases, such as pulmonary alveolar proteinosis (PAP), progressive polycystic lung disease, and recurrent bacterial and viral infections that left them gasping for breath from polycystic lung disease.

But as genomic data revealed, the children shared another characteristic: the absence of a chemical receptor that is supposed to call alveolar macrophages into action. It’s the first time that this missing receptor, called CCR2, has been linked to disease. The researchers recently published their results in Cell.

The study also found that the children are missing half of their alveolar macrophages, which are located in the air sacs of the lungs. “It was surprising to find that CCR2 is so essential for alveolar macrophages to properly function,” says Jean-Laurent Casanova, MD, PhD, professor, Howard Hughes Medical Institute investigator, and senior physician. “When it comes to lung defense and cleanup, people without it are operating at a double loss.”

Chemical communication

More formally known as C-C motif chemokine receptor 2, CCR2 sits on the surface of alveolar macrophages and responds to the presence of a chemical ligand, or binding molecule, known as CCL-2, also expressed by monocytes.

The receptor and ligand work together to summon macrophages to the site of an infection, and to maintain the appropriate level of surfactant; too little can lead to collapsed lung tissue, and too much can result in narrowed airways.

It was among these immune cells that first author Anna-Lena Neehus, PhD, of Casanova’s lab at the Institut Imagine in Paris, was seeking evidence of genetic deficiencies that might alter their behavior. While combing through the genomic data on 15,000 patients in a database, she found two Algerian sisters, then aged 13 and 10, who’d been diagnosed with severe PAP, a syndrome in which surfactant builds up and the gas exchange that takes place in alveoli is hindered.

About 90 percent of PAP cases are caused by antibodies that cripple a protein that stimulates the growth of infection-fighting white blood cells. The girls, however, didn’t have the PAP autoantibodies. Instead, they had no CCR2—a newly identified genetic mutation. Perhaps its lack was connected to their pulmonary conditions, Neehus thought. “It looked interesting and promising,” she recalls.

Neehus found seven other children in the cohort who had the same CCR2 mutation and serious lung conditions: two more pairs of siblings, and one trio of siblings. They were from the United States and Iran.

Diminished capacity

To explore the impact the variant might have on the children, the researchers analyzed the children’s clinical histories, lung tissue samples, and genetic data. Several key findings emerged. “First we discovered that these patients have only half the normal counts of pulmonary alveolar macrophages, which explains the different types of lesions they have across the pulmonary tissues,” says Casanova. 

With only half a crew, the reduced cleanup unit couldn’t keep up with its workload, leading to tissue injury. The macrophages were otherwise normal, as were the children’s other immune cells. 

Without CCR2 signaling, monocytes have no idea where they’re needed. This directionlessness also makes those with a CCR2 deficiency more susceptible to mycobacterial infections, because the macrophages can’t find their way to the tissue clusters where mycobacteria take up residence, and thus digest the invaders.

A troubled inheritance

This had dire effects for three of the children in the study, who developed bacterial infections after being vaccinated with a live-attenuated substrain of Mycobacterium bovis, an agent of tuberculosis. Their immune systems failed to assemble a legion of macrophages at the vaccination site in the shoulder, causing tissue destruction or hard nodes that had to be surgically removed, or lymph node infections. (All of the children were effectively treated with antibiotics.)

The children inherited the deficiency from their parents—and yet their parents were healthy as they were the “carriers” of the mutation. Several children were the result of consanguineous marriages, in which the parents are related. The offspring of such pairings have a higher risk of inheriting the mutation that causes CCR2 to disappear.

Diagnostic applications

The absence of CCR2 leads to another effect: An excess of the chemokine CCL-2. Lacking its receptor, CCL-2 builds up in the blood and plasma. This outcome may provide a diagnostic test for screening patients with unexplained lung or mycobacterial disease: The detection of high CCL-2 levels could provide some clarity about the condition’s genetic underpinnings.

In future research, Casanova and his team will mine their database of genomes for patients with gene mutations in CCL-2 rather than in its receptor, CCR2, to understand how such errors may influence the development of disease. Neehus says, “With more follow-up studies, we could potentially cure the patients by using gene therapy to correct the mutation.”

- This press release was originally published on The Rockefeller University website