Dermatomyositis autoantigen CHD4 forms immune stimulatory complexes with endogenous DNA

Area of Science:

• Immunology
• Dermatology
• Molecular Biology

Background:

• Dermatomyositis (DM) is an autoimmune connective tissue disease characterized by inflammation.
• Patients with DM often exhibit antinuclear antibodies targeting Mi-2, identified as Chromodomain-helicase-DNA-binding protein 4 (CHD4).
• CHD4 is found at higher levels in DM skin biopsies.

Purpose of the Study:

• To investigate the role of Chromodomain-helicase-DNA-binding protein 4 (CHD4) in the pathophysiology of dermatomyositis.
• To explore the mechanism by which CHD4-DNA complexes influence inflammatory gene expression in skin cells.

Main Methods:

• Analysis of CHD4 expression in DM skin biopsies.
• In vitro studies using UV-radiated and transfected HaCaT cells to form and localize CHD4-DNA complexes.
• Measurement of interferon (IFN)-regulated gene expression and functional CXCL10 protein levels.

Main Results:

• CHD4 binds endogenous DNA with high affinity, forming stable complexes.
• CHD4-DNA complexes, localized in the cytoplasm of HaCaT cells, significantly amplify the expression of interferon-regulated genes compared to DNA alone.
• Functional CXCL10 protein levels were also elevated in the presence of CHD4-DNA complexes.

Conclusions:

• CHD4-DNA complex formation enhances type I interferon pathway activation in keratinocytes.
• This mechanism involving CHD4-DNA signaling may contribute to the persistent inflammation observed in dermatomyositis skin lesions.
• Targeting CHD4 or its interaction with DNA could offer new therapeutic strategies for dermatomyositis.