LL37/self-DNA complexes mediate monocyte reprogramming

Area of Science:

• Immunology
• Epigenetics
• Metabolic changes

Background:

• LL37 and self-DNA complexes are implicated in autoimmune diseases such as psoriasis and lupus.
• These complexes can induce lasting changes in myeloid cells, affecting immune responses.

Purpose of the Study:

• To investigate the long-term metabolic and epigenetic effects of LL37/self-DNA complexes on monocytes.
• To explore the role of KDM6A/B in the trained immune phenotype induced by LL37/self-DNA.

Main Methods:

• Treatment of monocytes with LL37/self-DNA complexes.
• Analysis of metabolic activity (glycolysis, oxidative phosphorylation) and cytokine release.
• Assessment of KDM6A/B expression and functional inhibition.
• Evaluation of effects on naïve CD4+ T cells.

Main Results:

• LL37/self-DNA complexes induced heightened metabolic rates and pro-inflammatory cytokine release in monocytes, mimicking psoriatic monocytes.
• KDM6A/B demethylase was upregulated in treated monocytes and those from psoriatic patients.
• Inhibition of KDM6A/B reversed the trained immune phenotype, reducing inflammation and T cell induction.

Conclusions:

• LL37/self-DNA-induced innate immune memory contributes to psoriasis pathogenesis.
• KDM6A/B plays a critical role in mediating the trained immune response in monocytes.
• Targeting KDM6A/B may offer a therapeutic strategy for psoriasis and related autoimmune conditions.