Abstract
Bone healing is thought to be influenced by the cross-talk between bone forming and immune cells. In particular, macrophages play a crucial role in the regulation of osteogenesis. Curcumin, the major bioactive polyphenolic ingredient of turmeric, has been shown to regulate inflammatory response and osteogenic activities. However, whether curcumin could regulate macrophage polarization and subsequently influence osteogenesis remain to be elucidated. In this study, the potential immunomodulatory capability of curcumin on inflammatory response and phenotype switch of macrophages and the subsequent impact on osteogenic differentiation of MSCs are investigated. We demonstrated that curcumin exhibited significant anti-inflammatory effect by polarizing the macrophages toward anti-inflammatory phenotype, with increased expression of IL-4, IL-10, and CD206, and decreased expression of IL-1β, TNF-α, CCR7, and iNOS. In addition, curcumin could improve the osteo-immune microenvironment via promoting osteogenesis-related regenerative cytokine BMP-2 and TGF-β production. Moreover, the co-cultured test of macrophages and BMSCs showed that curcumin-modulated macrophages conditioned medium could promote osteogenic differentiation of BMSCs with increased gene (ALP, Runx-2, OCN, and OPN) and protein (Runx-2 and OCN) expression levels, enhanced ALP activity, and obvious formation of mineralized nodules. Taken together, with the interaction between curcumin-conditioned macrophage and curcumin-stimulated BMSCs, curcumin could remarkably enhance the osteogenic differentiation of BMSCs in LPS-activated inflammatory macrophage-BMSCs coculture system.
Highlights
Macrophages have been shown to play an essential role in innate immunity and maintain homeostasis and tissue regeneration (Sica et al, 2015)
We investigate the influence of curcumin on macrophage polarization and inflammatory response and subsequent effects on osteogenic differentiation of BMSCs
The expression of inflammatory cytokines was evaluated by RT-PCR and Enzyme-linked immunosorbent assay (ELISA), while the phenotype of macrophages was identified by immunofluorescence staining and flow cytometry
Summary
Macrophages have been shown to play an essential role in innate immunity and maintain homeostasis and tissue regeneration (Sica et al, 2015). Throughout the process of tissue regeneration, macrophages exhibit tremendous plasticity and can adapt various intermediate states from pro-inflammatory M1 phenotype to anti-inflammatory M2 phenotype. M2 phenotype macrophages include subtypes such as M2a, M2b, M2c, and M2d These subtypes play relevant but distinct roles during the normal healing process. During the period of bone repair, uncommitted macrophages (M0) become polarized toward an appropriate phenotype to regulate the healing process (Brown et al, 2012). During the acute inflammation period, macrophages exhibit a pro-inflammatory phenotype (M1) to defend against the invasion of pathogens and restore tissue homeostasis. At later stages of healing, M1 macrophages switch to the anti-inflammatory phenotype (M2) to promote bone repair by producing growth factors to recruit progenitor cells and guide the osteo-differentiation. Research has determined that the modulation of the cross-talk between bone forming cells and macrophages and bone precursor cells was critical for bone healing (Walsh et al, 2006; Guder et al, 2020)
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