Activation of SHP-1 protein shows benefit in IPF mouse model
Scientists: Study IDs SHP-1 as target for idiopathic pulmonary fibrosis treatment
Treatment with a molecule designed to activate the SHP-1 protein led to prolonged survival and alleviation of disease-associated lung changes in a mouse model of idiopathic pulmonary fibrosis (IPF), a study found.
SHP-1 activation appeared to exert its protective effects by inhibiting the survival and pro-fibrotic activity of a family of immune cells called macrophages that are prevalent in the lungs.
The study overall “identifies SHP-1 as a druggable target for the treatment of IPF,” the scientists wrote.
The study, “Targeting pathogenic macrophages by the application of SHP-1 agonists reduces inflammation and alleviates pulmonary fibrosis,” was published in the journal Cell Death and Disease.
A chronic inflammatory lung disease, IPF is characterized by progressive scarring (fibrosis) of lung tissue and a loss of pulmonary function. While currently available treatments can delay lung function decline, they are not able to reverse fibrosis, and new treatments are needed that specifically target the processes underlying scar tissue buildup in IPF.
According to the authors, the immune system is likely a large contributor in this process. More specifically, a family of immune cells called alveolar macrophages, which make up 70% of all immune cells found in the lungs. While they normally help keep the lungs safe from threats, in some cases they can be overactive and take on a profile known as an M2 state that contributes to fibrosis.
“Thus, targeting pathogenic [disease-causing] macrophages has emerged as a strategy to limit inflammation during pulmonary fibrosis,” the authors wrote.
Regulating immune cell signaling cascades
SHP-1 is a protein involved in regulating immune cell signaling cascades. Its loss in mice is associated with inflammation, a strong accumulation of alveolar macrophages in the lungs, and an increased susceptibility to develop pulmonary fibrosis.
According to researchers, such findings suggest the activation of SHP-1 could help restrain macrophage activity, thereby protecting the lungs against inflammation and fibrosis in IPF.
To learn more, the team investigated the effects of administering an SHP-1 activator, or agonist, called SC-43 to a mouse model of the disease. After IPF was induced, mice were treated orally with SC-43, Ofev (nintedanib), which is an approved IPF therapy, or a vehicle daily for two weeks.
As expected, vehicle-treated mice, which served as controls, exhibited impaired survival accompanied by a number of cellular changes in the lungs, including fibrosis, immune cell infiltration, accumulation of fibroblasts — connective tissue cells that contribute to fibrosis — and deposition of collagen, a connective tissue protein.
‘Remarkable improvements’ with SC-43 including fibrosis reductions
SC-43 was associated with “remarkable improvements” according to authors. These included reductions in fibrosis, collagen deposition, and inflammation, as well as other cellular changes.
The therapy also was associated with increases in lung air volume, reflecting better lung capacity, and significantly prolonged survival relative to the vehicle control group.
Benefits associated with SC-43 were comparable to those provided by Ofev, the scientists noted.
Mice with IPF have a significant accumulation of a number of immune cell types in the lungs, including macrophages. SC-43 treatment was associated with a profound reduction in the numbers of macrophages, whereas treatment with Ofev most significantly lowered the numbers of another type of immune cell called neutrophils.
Monocytes, the immune cell precursors to macrophages, were significantly reduced in the bloodstream of SC-43-treated mice.
These findings suggest SC-43 can “alleviate pulmonary fibrosis by targeting macrophages and reshaping the immunofibrotic niche,” the researchers wrote.
In cell cultures of human macrophages, the SHP-1 agonist inhibited macrophage survival and led to a significant reduction in the activity of CSF1R, a protein involved in the activation of the pro-fibrotic M2-type macrophages.
M2 macrophages typically release pro-fibrotic molecules that promote the transition of fibroblasts to myofibroblasts, which are known to drive fibrosis in IPF.
This pro-fibrotic activity of M2-type macrophages was significantly reduced in the presence of SC-43 and fibroblast-to-myofibroblast transition was inhibited.
SC-43 also inhibited the release of pro-inflammatory molecules from M1-type macrophages.
Altogether, the findings establish a role of macrophages in IPF progression, and suggest SHP-1 may be a promising therapeutic target.
Scientists believe the benefits of such a treatment may be twofold: it could suppress early inflammation driven by M1 macrophages, in addition to preventing the M2-supported fibroblast-to-myofibroblast transition that drives fibrosis later on.
“Our study paves the way for further development of SHP-1 agonists against IPF,” the team wrote.
Such an approach might also be relevant for other indications, given that a “high degree of similarity has been observed between the macrophage populations isolated from IPF patients and macrophages from COVID-19 patients,” the scientists wrote.
About the Author
