Italians Find Molecule That Inhibits Anti-inflammatory and Anti-bacterial Defenses in CF

Italian researchers have discovered a molecule that prevents cystic fibrosis patients’ anti-inflammatory and anti-bacterial defenses from working as well as they should.

Scientists may be able to target the molecule, microRNA-181, to develop CF therapies.

The team published their study in the journal Nature. The title is  “MicroRNA-181b is increased in cystic fibrosis cells and impairs lipoxin A4 receptor-dependent mechanisms of inflammation resolution and antimicrobial defense.”

CF is a life-threatening genetic disease. It is caused by mutations of the CFTR gene that produce faulty versions of an essential protein, or too little of the protein. The protein is cystic fibrosis transmembrane conductance regulator, or CFTR.

The protein plays a key role in the production of sweat, digestive fluids, and mucus in the lungs and other parts of the body. Abnormal versions of CFTR, or too little of it, lead to a salt imbalance that causes a buildup of thick and sticky mucus that can obstruct the airways. This promotes abnormally high levels of inflammation and bacterial infections, leading to lung damage and scarring, or fibrosis.

The mechanisms that limit the severity and duration of inflammation, and promote its resolution, are thought to be defective in CF patients. LXA4 is a protein involved in these mechanisms. It fights inflammation by binding to a protein receptor called ALX/FPR2. Children with CF have low levels of LXA4.

MicroRNAs, or miRNAs, are small molecules of RNA that regulate genes’ production of protein. Researchers had previously discovered that miR-181b inhibits the ALX/FPR2 receptor, preventing the receptor’s anti-inflammatory activity.

The Italian team decided to see if miR-181b would inhibit the receptor in two cell models of CF. They looked at bronchial lung tissue and macrophages — immune cells that promote inflammation to defend the body against invaders — from both CF patients and healthy people.

They discovered that CF patients’ cells had higher levels of miR-181b than healthy people, leading to lower levels of ALX/FPR2. This meant that miR-181b impaired ALX/FPR2’s anti-inflammatory capability in the CF cells.

When the team added an miR-181b inhibitor to the cells, ALX/FPR2 levels increased, enhancing LXA4’s anti-inflammatory activity.

The team also discovered that CFTR, the protein that is defective in CF patients. controlled miR-181b levels. This suggested a link between CFTR and the mechanisms that control inflammation.

“We uncovered the upregulation of miR-181b in CF cells, which contributes to impair the endogenous anti-inflammatory, anti-microbial defense pathway centered on the ALX/FPR2 receptor,” the researchers wrote.

“Thus, targeting miR-181b may represent a novel strategy to enhance anti-inflammatory and anti-microbial defense mechanisms in CF,” they added.