Targeting a key protein of the innate immune system called TLR4 could be a new way of treating people with pulmonary fibrosis (PF) and other fibrotic disorders, according to a Northwestern University study.
The study, “TLR4-dependent fibroblast activation drives persistent organ fibrosis in skin and lung,” was published in the journal JCI Insight.
Fibrosis (scarring), seen in several chronic inflammatory diseases, results from the buildup of components of the extracellular matrix (ECM), a collection of molecules that provide structural and biochemical support to cells. Fibrosis is part of the normal healing process — as scar tissue — but when this process turns uncontrolled and pathological it damages such organs as the lungs, liver, kidney, skin or the heart.
What drives the variability of fibrosis across different patients is still scarcely understood, but abnormal functioning of the innate immune system is viewed as a potential key contributor. [Innate immunity refers to nonspecific defense mechanisms that come into play immediately or soon after an antigen — a foreign substance, like bacteria or a protein — appears in the body.]
Scientists believe that most fibrotic cases probably start as normal injury repair. However, “if the immune system produces too much of an initial scar, it can’t go back to normal,” John Varga, the study’s senior author, said in a press release. “You have an unhealed scar that keeps growing and can wipe out the entire organ.”
TLR proteins play a crucial role in the defense against microbial infection. They also recognize damage-associated molecule patterns (DAMPs), which are molecules released by stressed cells that act as danger signals to induce and augment an inflammatory response to noninfectious injuries. The group of DAMP proteins contains specific components of the extracellular matrix that bind to the TLR family member known as TLR4.
TLR4 is associated with chronic inflammatory conditions, and researchers are exploring approaches that might block its effects. However, whether blocking TLR4 could be effective against fibrosis remains unknown.
The research team has previously shown that the fibrotic skin and lungs of patients with scleroderma (a chronic disease that affects connective tissue, and is also characterized by fibrosis development) had higher levels of specific DAMPs. The investigators also revealed their common localization to myofibroblasts containing TLR4. These cells release collagen during the fibrosis development.
Work in mice also showed that an absence or lack of working TLR4 protected from fibrosis induced in these animals.
Now, the researchers studied whether TLR4 cellular function is altered in scleroderma, and if targeting this protein may treat fibrosis. They also analyzed if, similar to infectious pathogens, DAMPs mediate their effects through a complex between TLR4 and the receptor MD2.
Findings revealed that the amount of MD2 and TLR4 messenger RNA — which contains the instructions to make proteins — was higher than usual in skin biopsies from scleroderma patients. The data also showed increased expression of TLR4-responsive genes, called a TLR4 gene signature, in a subset of patients. These genes were associated with inflammation and wound healing.
Finally, the team found that selectively blocking MD2 with a small molecule named T5342126 abolished fibrotic responses in vitro and in patient-derived skin cells. Importantly, this molecule also prevented and reversed fibrosis in three mouse models.
Results also showed that TLR4-deprived fibroblasts — cells will function in ways similar to myofibroblasts and are involved in fibrosis — were protected from skin and lung fibrosis.
“Together, results from these human [cell] and mouse studies implicate MD2/TLR4-dependent fibroblast activation as a key driver of persistent organ fibrosis,” the investigators wrote.
“Our study opens a new door into fibrosis by looking at it as an aberrant innate immune response and suggesting a novel approach to treat it,” Varga said.
However, he cautioned that even if the MD2 blocker is able to be refined to the point of a potential treatment, it would only be relevant to those patients (the subset) with altered expression of TLR4-related genes. “It’s an initial compound that would need to be developed and tweaked. It would need significant funding to go to the next step,” Varga added.
Swati Bhattacharyya, PhD, the study’s lead author, added: “There is an emerging direction for treating fibrosis with precision medicine.” And, noting the variable progression of fibrosis among patients, said: “Some people live with fibrotic disease for 30 years while others die in two years. We need to identify the rapid progressors from the slow progressors. That’s where precision medicine becomes really critical.”
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