Dexamethasone reduces inflammation, scarring in SSc mouse model: Study
Corticosteroid had similar effect on T-cells derived from SSC patients
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Dexamethasone, a type of corticosteroid, reduced skin thickening, inflammation, and the activity of genes that induce fibrosis (scarring) in a mouse model of systemic sclerosis (SSc), according to a study.
The study also demonstrated that dexamethasone reduced the levels of pro-inflammatory molecules produced by certain T-cells derived from SSc patients. In SSc, these immune cells can become excessively active, releasing pro-inflammatory molecules that contribute to the development of fibrosis.
“In summary, [dexamethasone] showed immunomodulatory and antifibrotic effects in SSc, evidencing its actions in treating the disease,” researchers wrote.
The study, “Dexamethasone modulates cytokine and chemokine secretion by CD4 + T cells from SSc patients and exerts antifibrotic effects in HOCl-induced SSc mice,” was published in Inflammopharmacology.
Scleroderma characterized by inflammation, fibrosis of skin
SSc, or scleroderma, is characterized by inflammation and fibrosis in the skin and several internal organs. The disease is driven by the dysregulation of the immune response, resulting in the production of self-reactive antibodies and immune molecules, including cytokines and chemokines, as well as blood vessel damage and excessive production of scar tissue components by fibroblasts.
Corticosteroids such as dexamethasone are anti-inflammatory medications commonly used to manage autoimmune diseases. However, “available clinical and preclinical studies are controversial and insufficient to demonstrate the effects of and the mechanisms of action involved in SSc,” the researchers wrote.
To learn more, researchers in Brazil analyzed the effects of dexamethasone on immune cells derived from 20 patients and 10 healthy controls, particularly T-cells containing the CD4 protein marker and macrophages, as well as in a mouse model of SSc.
The patients had a mean age of 53.2 years, and all exhibited skin involvement and Raynaud’s phenomenon, a condition characterized by the fingers and toes feeling numb, prickly, and frigid in response to cold temperatures or stress. Regarding scleroderma type, half had limited SSc, characterized by skin symptoms limited to certain parts of the body, while the other half had diffuse SSc, with more widespread skin involvement and a greater risk of internal organ involvement.
Dexamethasone reduced skin thickening in mice after 6 weeks
In patients’ T-cells, dexamethasone significantly reversed the high release of cytokines, including interleukin (IL)-4, IL-6, IL-13, and TNF, and chemokines (CXCL10, CXCL9, CCL5, and IL-8) induced by anti-CD3 and anti-CD28 antibodies, which trigger T-cell activation.
Similar effects were seen for IL-4, IL-13, and TNF in cells derived from healthy volunteers. In macrophages from patients, dexamethasone did not significantly alter the levels of cytokines IL-6 and TNF, nor did it alter the levels of the chemokine IL-8.
Mice modeling SSc were given hypochlorous acid (HOCl) into the skin to cause skin thickening. Dexamethasone significantly reduced skin thickening after six weeks.
Dexamethasone also reversed signs of skin swelling, but not the deposition of collagen, the main component of scar tissue.
Further analysis demonstrated that SSc mice had elevated activity of the pro-fibrotic genes Col1a1 and Tgf-beta1 in the skin, as well as Tgf-beta1 in the lungs, compared to control animals. Treatment with dexamethasone significantly reduced the activity of these genes, as well as the skin activity of the Acta2 gene, a marker of fibroblast activation.
Dexamethasone also significantly reduced the levels of IL-4 produced by spleen immune cells derived from SSc mice.
“In summary, we have shown for the first time that dexamethasone can modulate the production of important cytokines and chemokines involved in … systemic sclerosis in culture of CD4+ T lymphocytes, as well as to present immunomodulatory and antifibrotic activity in vivo in an experimental model of SSc,” the scientists wrote. “Furthermore, the findings contribute to a better understanding of the action of glucocorticoids in SSc.”
