C/EBPβ-Dependent Epigenetic Memory Induces Trained Immunity in Hematopoietic Stem Cells

Area of Science:

• Immunology
• Stem Cell Biology
• Epigenetics

Background:

• Hematopoietic stem cells (HSCs) are crucial for lifelong immune cell production and can respond to infection.
• The long-term impact of immune stimulation on HSC function and immune memory is not fully understood.

Purpose of the Study:

• To investigate the sustained effects of acute immune stimulation on HSCs and their role in innate immunity.
• To elucidate the epigenetic mechanisms underlying HSC memory formation.

Main Methods:

• Mice were treated with lipopolysaccharide (LPS) to induce acute immune stimulation.
• HSC abundance, composition, progeny, and gene expression were analyzed.
• Chromatin accessibility of myeloid lineage enhancers was assessed.
• C/EBPβ deletion was used to investigate its role in epigenetic modifications.
• Innate immunity against Pseudomonas aeruginosa was evaluated.

Main Results:

• Acute LPS stimulation caused transient changes in HSCs but persistent alterations in myeloid enhancer accessibility.
• Increased enhancer accessibility enhanced immune gene responsiveness to secondary stimulation.
• Pre-exposed HSCs showed increased myelopoiesis and improved innate immunity.
• C/EBPβ was identified as a key transcription factor for LPS-induced epigenetic changes and HSC training.

Conclusions:

• Short-term immune signaling can induce C/EBPβ-dependent epigenetic changes in HSCs, leading to trained immunity.
• This establishes a mechanism for epigenetic inscription of infection history in HSCs, functioning as innate immune memory.
• HSC-trained immunity enhances myelopoiesis and improves defense against secondary bacterial infections.