Abstract
Macrophages are key innate immune cells that mediate implant acceptance or rejection. Titanium implants degrade over time inside the body, which results in the release of implant wear-off particles. Titanium nanoparticles (TiNPs) favor pro-inflammatory macrophage polarization (M1) and lower tolerogenic activation (M2). GDF-15 regulates immune tolerance and fibrosis and is endocytosed by stabilin-1. How TiNPs affect the healing activities of macrophages and their release of circulating cytokines is an open question in regenerative medicine. In this study for the first time, we identified the transcriptional program induced and suppressed by TiNPs in human pro-inflammatory and healing macrophages. Microarray analysis revealed that TiNPs altered the expression of 5098 genes in M1 (IFN-γ-stimulated) and 4380 genes in M2 (IL-4–stimulated) macrophages. 1980 genes were differentially regulated in both M1 and M2. Affymetrix analysis, confirmed by RT-PCR, demonstrated that TiNPs upregulate expression of GDF-15 and suppress stabilin-1, scavenger receptor of GDF-15. TiNPs also significantly stimulated GDF-15 protein secretion in inflammatory and healing macrophages. Flow cytometry demonstrated, that scavenging activity of stabilin-1 was significantly suppressed by TiNPs. Confocal microscopy analysis showed that TiNPs impair internalization of stabilin-1 ligand acLDL and its transport to the endocytic pathway. Our data demonstrate that TiNPs have a dual effect on the GDF-15/stabilin-1 interaction in macrophage system, by increasing the production of GDF-15 and suppressing stabilin-1-mediated clearance function. In summary, this process can result in a significant increase of GDF-15 in the extracellular space and in circulation leading to unbalanced pro-fibrotic reactions and implant complications.
Highlights
Implantation of biomedical devices is one of the most frequently performed procedures in fields such as orthopedics and dentistry [1, 2]
We found that Titanium nanoparticles (TiNPs) stimulate all subtypes of macrophages to produce growth differentiation factor 15 (GDF-15), a cytokine involved in the regulation of tissue remodeling, healing, and angiogenesis, with growing evidence about its implication in pathology
The analysis revealed a significant downregulation of the multifunctional scavenger receptor stabilin-1 under TiNPs in M1 and M2
Summary
Implantation of biomedical devices is one of the most frequently performed procedures in fields such as orthopedics and dentistry [1, 2]. Monocytes are recruited from the circulation to differentiate into macrophages and react against the foreign body. The recognition of the material as a foreign body in the tissue encompasses macrophage interaction with the implant surface. This interaction favors the release of chemokines, which recruit additional macrophages and other immune cells leading to acute inflammation [4]. M2 differentiation occurs in response to interleukin 4 (IL-4) or IL13 and it is associated with healing responses, promoting local tissue remodeling [5]. M0 are unpolarized or uncommitted macrophages that have neither pro-inflammatory nor anti-inflammatory characteristics, and which differentiation is driven by M-CSF [6]. Implant revision negatively affects the patient’s quality of life and aggravates the economic burden due to an increase in hospitalization rates and in the necessity of reintervention [10]
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