Trained innate immunity modulates osteoblast and osteoclast differentiation

Trained innate immunity modulates osteoblast and osteoclast differentiation

Rahmani, N. R. (University Medical Center Utrecht; Universiteit Utrecht)
Belluomo, R. (Universiteit Utrecht)
Kruyt, M. C. (University Medical Center Utrecht; University of Twente)
Gawlitta, D. (Universiteit Utrecht; University Medical Center Utrecht)
Joosten, L. A.B. (Radboud University Medical Center; University of Medicine and Pharmacy)
Weinans, Harrie (TU Delft Biomaterials & Tissue Biomechanics; University Medical Center Utrecht)
Croes, M. (University Medical Center Utrecht)

2024

Macrophages are key regulators in bone repair and regeneration. Recent studies have shown that long-term epigenetic changes and metabolic shifts occur during specific immune training of macrophages that affect their functional state, resulting in heightened (trained) or reduced (tolerant) responses upon exposure to a second stimulus. This is known as innate immune memory. Here, we study the impact of macrophages’ memory trait on osteoblast differentiation of human mesenchymal stromal cells (hMSCs) and osteoclast differentiation. An in vitro trained immunity protocol of monocyte-derived macrophages was employed using inactivated Candida albicans and Bacillus Calmette–Guérin (BCG) to induce a ‘trained’ state and Pam3CSK4 (PAM) and Lipopolysaccharides (LPS) to induce a ‘tolerance’ state. Macrophages were subsequently cocultured with hMSCs undergoing osteogenic differentiation during either resting (unstimulated) or inflammatory conditions (restimulated with LPS). Alkaline phosphatase activity, mineralization, and cytokine levels (TNF, IL-6, oncostatin M and SDF-1α) were measured. In addition, macrophages underwent osteoclast differentiation. Our findings show that trained and tolerized macrophages induced opposing results. Under resting conditions, BCG-trained macrophages enhanced ALP levels (threefold), while under inflammatory conditions this was found in the LPS-tolerized macrophages (fourfold). Coculture of hMSCs with trained macrophages showed mineralization while tolerized macrophages inhibited the process under both resting and inflammatory conditions. While osteoclast differentiation was not affected in trained-macrophages, this ability was significantly loss in tolerized ones. This study further confirms the intricate cross talk between immune cells and bone cells, highlighting the need to consider this interaction in the development of personalized approaches for bone regenerative medicine. Graphical Abstract: (Figure presented.).

Bone regeneration
Innate immune memory
Macrophage
MSC
Osteoimmunology

http://resolver.tudelft.nl/uuid:d5811855-0b1b-4a3a-a6ea-b0a0a0abd3b5

https://doi.org/10.1007/s12015-024-10711-9

2629-3269

Stem Cell Reviews and Reports, 20 (4), 1121-1134

Institutional Repository

journal article

© 2024 N. R. Rahmani, R. Belluomo, M. C. Kruyt, D. Gawlitta, L. A.B. Joosten, Harrie Weinans, M. Croes