Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells

Area of Science:

• Immunology
• Metabolic pathways
• Cellular biology

Background:

• Dendritic cells (DCs) are implicated in autoimmune disease pathogenesis.
• Understanding DC regulatory mechanisms is crucial for developing targeted therapies.
• Genetic factors influencing DC function are linked to autoimmune disorders.

Purpose of the Study:

• To identify regulatory mechanisms controlling DC function in autoimmunity.
• To elucidate the role of immunometabolism in DC-mediated immune responses.
• To develop novel therapeutic strategies for T cell autoimmunity.

Main Methods:

• Single-cell and bulk transcriptional and metabolic analyses.
• Cell-specific gene perturbation studies.
• Engineering of a lactate-producing probiotic.

Main Results:

• Identified a negative feedback loop in DCs involving lactate and NDUFA4L2.
• Lactate upregulates NDUFA4L2 via hypoxia-inducible factor 1α (HIF-1α).
• NDUFA4L2 limits mitochondrial reactive oxygen species, suppressing pathogenic T cell activation.

Conclusions:

• An immunometabolic pathway regulating DC function and limiting autoimmune pathology was identified.
• A synthetic probiotic engineered to activate this pathway suppresses T cell autoimmunity.
• This study provides a novel therapeutic approach for autoimmune diseases.