‘Rotten egg gas’, H2S: promising role in silencing inner war
Immune system responds to infections, pathogens and other potentially problematic abnormalities in our body. It also maintains tolerance to self antigens and abrogates autoimmune disease in the form of regulatory T cells (Tregs).
A recent study led by Songtao Shi of the University of Pennsylvania elaborates the regulation of Tregs, by an unexpected factor: hydrogen sulphide (H2S). The finding reveals the possible management strategy and therapeutic intervention applicable in case of autoimmune diseases as well as other conditions such as cancer and hypertension.
Hydrogen sulfide (H2S) has long been known as a highly toxic gas and associated with the smell of rotten eggs. However several studies demonstrated that this malodorous gas is enzymatically produced by mesenchymal cells in all mammals including human. It also exerts several critical physiological actions by acting as a “gasotransmitter” like nitric oxide and carbon monoxide.
In an earlier study, the team showed that mice with reduced levels of H2S had problems with autoimmune disease. With further studies the team found that H2S is produce by Tregs in culture. Genetically engineered mice, which produced reduced levels of H2S showed strikingly low numbers of Tregs with development of autoimmune disease. Treatment of H2S deficient mice with H2S releasing compounds showed partial relief of symptoms and long life.
To delineate the molecular mechanism, the team performed a series of experiments. They found that Tregs in H2S-deficient mice had lower levels of Foxp3 (Treg marker), however the Foxp3 production pathway was not affected. These specific type of mice were observed to have hypermethylated Foxp3 gene and repression of Foxp3 gene expression. Moreover the team found that the expression of de-methylating enzymes, Tet1 and Tet2 is regulated by H2S through the process of sulfation of a transcription factor, NFYB. Lower H2S levels led to reduced expression of Tet1 and Tet2 and thus spoiled the function of Tregs. The researchers also reversed the Tregs function by the addition H2S releasing compounds.
The team is now planning to examine the role of H2S in other cell types including stem cells and also to identify potential ways to intervene the lower levels of H2S in order to prevent autoimmune problems.
Reference: Immunity, 2015; DOI: 10.1016/j.immuni.2015.07.017
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