Trained innate immunity modulates osteoblast and osteoclast differentiation.

Area of Science:

• Immunology
• Bone Biology
• Regenerative Medicine

Background:

• Macrophages are crucial for bone repair and regeneration.
• Innate immune memory, through trained immunity or tolerance, alters macrophage function.
• Understanding macrophage memory's impact on bone cells is vital for regenerative therapies.

Purpose of the Study:

• To investigate how trained and tolerized macrophages affect human mesenchymal stromal cell (hMSC) osteoblast differentiation.
• To assess the influence of trained and tolerized macrophages on osteoclast differentiation.
• To explore the role of macrophage innate immune memory in bone regenerative processes.

Main Methods:

• In vitro induction of macrophage trained immunity (BCG) and tolerance (LPS).
• Coculture of differentiated macrophages with hMSCs under resting and inflammatory conditions.
• Measurement of osteogenic markers (ALP, mineralization) and cytokine profiles.
• Assessment of macrophage osteoclast differentiation capacity.

Main Results:

• BCG-trained macrophages enhanced alkaline phosphatase (ALP) under resting conditions.
• LPS-tolerized macrophages increased ALP under inflammatory conditions.
• Trained macrophages promoted hMSC mineralization, while tolerized macrophages inhibited it.
• Osteoclast differentiation was unaffected by trained macrophages but significantly reduced by tolerized ones.

Conclusions:

• Macrophage innate immune memory differentially impacts osteoblast and osteoclast differentiation.
• Trained macrophages show potential for enhancing bone regeneration.
• Tolerized macrophages may impede bone healing and affect bone remodeling.
• These findings underscore the importance of immune cell states in bone regenerative medicine.