Calpain Proteins in Myeloid Cells May Be SSc Therapeutic Target
Blocking the activity of calpain proteins reduced scarring in the skin and inflammation in the lungs in a mouse model of scleroderma, a new study shows, suggesting these proteins may be therapeutic targets for this disease.
The study, “Myeloid cell-specific deletion of Capns1 prevents macrophage polarization toward the M1 phenotype and reduces interstitial lung disease in the bleomycin model of systemic sclerosis,” was published in Arthritis Research & Therapy.
Scleroderma, or SSc, is marked by scarring in the skin and the possible involvement of internal organs. Interstitial lung disease (ILD), when scarring affects the lungs and impairs breathing, is a leading cause of severe health problems for people with SSc.
A team led by scientists in China investigated whether the calpain proteins are involved in developing ILD in SSc. Calpain proteins are implicated in a number of cellular signaling cascades and research has suggested they play roles in signaling pathways that help drive fibrosis (scarring) in the lungs. The scientists had previously reported that calpain activity was increased in the blood of people with SSc.
“However, it has never been reported whether calpain plays a role in development of SSc-related ILD,” the scientists wrote.
The team first examined calpain levels in a mouse model of SSc induced by an injection with the chemical bleomycin. Results showed calpain activity was significantly increased in the lungs of mice with SSc-like disease compared to controls.
“This result demonstrates that calpain activity is induced in the lungs of mice by [bleomycin] treatment under conditions that model SSc/ILD,” the researchers wrote.
The scientists next used genetic engineering techniques to create mice with abnormally low levels of two calpain proteins (calpain-1 and calpain-2) in their myeloid cells — a class of immune cell that’s been implicated in SSc-related ILD. Macrophages, the “cellular eaters” capable of gobbling up infectious bacteria, have been implicated in developing scleroderma and its progression.
Further testing showed that mice lacking calpains in their myeloid cells developed substantially less skin scarring after being injected with bleomycin. Scarring and infiltration of inflammatory cells in the lungs, indicative of ILD, also was significantly reduced in these mice.
Similar results were obtained in experiments wherein mice were treated with a calpain-blocking compound called PD150606.
“Taken together, these results indicated that disruption of calpain in myeloid cells reduces ILD in this mouse of the bleomycin model of SSc,” the researchers wrote.
Additional analyses of immune cells indicated calpain deficiency significantly reduced macrophage M1 polarization, a process where macrophages become activated in a more pro-inflammatory state that’s known to be involved in the runaway inflammatory reaction that drives SSc. This was accompanied by the reduced production of pro-inflammatory signaling molecules.
“The protective effects of [calpain deficiency] were recapitulated by systemic pharmacological inhibition of calpain in bleomycin model of SSc-related ILD and were associated with prevention of lung macrophage polarization toward the M1 phenotype,” the research team wrote. “To the best of our knowledge, our study demonstrates for the first time that myeloid cell calpain plays an important role in bleomycin model of SSc-related ILD.”
The researchers said calpain may be a potential therapeutic target for a bleomycin model of SSc-ILD.
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