Anticeramide Improves Sjögren's Syndrome by Blocking BMP6-Induced Th1

Area of Science:

• Immunology
• Rheumatology
• Molecular Biology

Background:

• T-cell dysfunction is a key factor in Sjögren's syndrome (SS) pathogenesis.
• Increased bone morphogenetic protein 6 (BMP6) expression is linked to SS, but its role and downstream signaling remain unclear.

Purpose of the Study:

• To investigate the effects of BMP6 on naive CD4+ T cells and elucidate its molecular mechanisms in SS.
• To evaluate the therapeutic potential of targeting the BMP6-induced pathway in an SS animal model.

Main Methods:

• Investigated BMP6 effects on naive CD4+ T cells in vitro.
• Analyzed the ceramide/nuclear factor-kappaB pathway.
• Utilized an SS animal model (NOD/LtJ mice) treated with an anti-ceramide agent (myriocin) for in vivo studies.

Main Results:

• BMP6 upregulates interferon-gamma (IFN-γ) secretion from CD4+ T cells via the ceramide/nuclear factor-kappaB pathway, without affecting T-cell activation or proliferation.
• Anti-ceramide treatment in an SS mouse model significantly reduced IFN-γ expression and Th1 frequency in salivary glands.
• Treatment suppressed salivary gland inflammation and maintained salivary flow rates, ameliorating SS-like symptoms.

Conclusions:

• BMP6 promotes T-cell dysfunction in SS through a specific molecular pathway.
• Targeting the ceramide pathway offers a potential therapeutic strategy to reverse SS progression and alleviate symptoms.