The innate immune system and small RNA molecules known as microRNA are key factors in the development of scleroderma, according to a study based on previously published research.
The study’s senior author was Stephen O’Reilly, a senior lecturer in immunology at Northumbria University’s Faculty of Health and Life Sciences in the United Kingdom.
Inflammation, blood vessel problems and fibrosis — or tissue scarring — lead to poor prognosis and death in scleroderma.
Fibrosis is mainly driven by excessive activation of fibroblasts, the most common cells in connective tissue. This over-activation leads to build-ups of the protein collagen in the extracellular matrix, which provides biochemical and structural support to cells. The result is fibrosis.
An innate immune response accompanies the activation of fibroblasts. The innate immune system is one of two immune system categories, the other being the adaptive immune system. Inflammation is an innate immune response.
At the moment there are limited treatment options for scleroderma. Immunosuppression — that is, suppression of the immune system — offers only modest benefits in the lungs and skin.
Treatments could be built around inflammasomes. An inflammasome is a complex of proteins within cells that is part of the innate immune system. When an inflammasome detects bacteria and other invaders, the immune system uses molecules called cytokines to trigger an inflammatory response.
Scientists say one inflammasome in particular is involved in many inflammatory conditions — the NLR family pyrin domain containing 3 (NLRP3) inflammasome.
Recent evidence indicates that the NLRP3 inflammasome plays a role in scleroderma by regulating a micro RNA known as microRNA-155, or miR-155. MicroRNAs mediate genes’ production of proteins, and scientists have reported that specific miRNAs are involved in scleroderma fibrosis.
In that study, researchers showed that when genes failed to produce NLRP3, there was a decrease in miR-155 levels and collagen formation in fibroblasts. The same was true when genes inhibited the production of caspase-1, a protein that participates in inflammatory responses by promoting maturation of cytokines.
“Thus, it appears the inflammasome regulates miR-155 and collagen levels.” the researchers wrote. This suggests “that the interplay between the innate immune system and microRNA expression and the subsequent activation of fibroblasts have a dominant pathogenetic [harmful] role in [scleroderma],” they wrote.
Other findings were that levels of miR-155 are higher in skin and lung fibroblasts in scleroderma, and that deleting miR-155 in a cell model returns collagen formation to normal levels.
The researchers also discovered that deleting miR-155 stopped skin fibrosis in mice with scleroderma. This suggested that a treatment for skin fibrosis could revolve around blocking miR-155.
Current research, including an ongoing Phase 1/2 clinical trial (NCT01538719) being conducted by Boston University and Regeneron Pharmaceuticals, focuses on treating scleroderma by inhibiting IL-1. The Interleukin-1 family of 11 cytokines plays a crucial role in regulating inflammation. The notion of inhibiting IL-1 to treat scleroderma is supported by studies showing that IL-1 blockers are an effective way to alleviate hereditary inflammatory disorders and gout.
The Northumbria researchers said scientists have yet to identify miR-155’s mechanism of action and the molecules it suppresses. But studies suggest that “enhanced NLRP3 activity and IL-1β production in response” to an unknown influence “may be what fuels the disease progression,” they wrote.
They also reported that cytokine transforming growth factor-β1 (TGF-β1), a key regulator of fibrosis, is involved in regulating miR-155. “This further emphasizes that miR-155 is a key proponent of the fibrosis observed in [scleroderma] and may also play a key role in other pro-fibrotic diseases where TGF-β1 is involved,” the team wrote.
The researchers said further studies are necessary on scleroderma fibrosis. Mice engineered to overproduce miR-155 could help scientists assess whether higher levels of miR-155 would lead to increased collagen production and fibrosis, the team said.
Focusing on “miR-155-driven effects, specifically on NLRP3 inflammasome activity,” could open up new avenues to treatments, they noted.
They suggested that a recently developed small molecule inhibitor of the NLRP3 complex, called MCC950, could be a good therapy-development candidate.