Loss of STIM1 and STIM2 in Salivary Glands Disrupts ANO1 Function but Does Not Induce Sjogren's Disease

Area of Science:

• Cellular biology
• Immunology
• Physiology

Background:

• Store-operated Ca2+ entry (SOCE) mediated by STIM1/2 proteins and ORAI1 channels is vital for salivary fluid secretion.
• SOCE is implicated in Sjogren's disease (SjD), but STIM1/2 dysfunction in salivary glands remains unstudied in animal models.

Purpose of the Study:

• To investigate the role of STIM1 and STIM2 proteins in salivary gland function and their potential involvement in Sjogren's disease pathogenesis.
• To explore the relationship between SOCE, ANO1 channel activity, and salivary fluid secretion.

Main Methods:

• Generation of mice lacking Stim1 and Stim2 in salivary glands (Stim1/2K14Cre(+)).
• Assessment of Ca2+ levels, saliva secretion, and SOCE function in knockout mice.
• Analysis of ANO1 channel activation, toll-like receptor (TLR) expression, and autoantibody levels.
• Examination of salivary gland biopsies from SjD patients.

Main Results:

• Stim1/2K14Cre(+) mice exhibited reduced Ca2+ levels and hyposalivation.
• SOCE was essential for activating the Ca2+-activated Cl- channel ANO1 and subsequent fluid secretion.
• Aging knockout mice did not develop SjD-like features, showing downregulated Tlr8 expression.
• SjD patient salivary glands displayed increased STIM1 and TLR7/8 expression.

Conclusions:

• SOCE, through STIM1/2 and ORAI1, is critical for ANO1 function and salivary gland fluid secretion.
• A potential link exists between SOCE, TLR signaling, and Sjogren's disease pathogenesis.
• STIM1/2 dysfunction in salivary glands may not directly cause SjD but highlights a role in the disease's molecular pathways.