Macrophage metabolic profile is altered by hydroxyapatite particle size.

Autor: Shanley LC; School of Biochemistry & Immunology, Trinity College, The University of Dublin, Dublin 2, Ireland; Centre for Advanced Materials and Bioengineering Research Amber., Mahon OR; School of Biochemistry & Immunology, Trinity College, The University of Dublin, Dublin 2, Ireland; Centre for Advanced Materials and Bioengineering Research Amber; Health Research Institute and the Bernal Institute, University of Limerick, Limerick, V94 T9PX, Ireland., O'Rourke SA; School of Biochemistry & Immunology, Trinity College, The University of Dublin, Dublin 2, Ireland; Department of Mechanical, Manufacturing and Biomedical Engineering, School of Engineering, Trinity College Dublin, Dublin, Ireland., Neto NGB; Department of Mechanical, Manufacturing and Biomedical Engineering, School of Engineering, Trinity College Dublin, Dublin, Ireland., Monaghan MG; Centre for Advanced Materials and Bioengineering Research Amber; Department of Mechanical, Manufacturing and Biomedical Engineering, School of Engineering, Trinity College Dublin, Dublin, Ireland., Kelly DJ; Centre for Advanced Materials and Bioengineering Research Amber; Department of Mechanical, Manufacturing and Biomedical Engineering, School of Engineering, Trinity College Dublin, Dublin, Ireland., Dunne A; School of Biochemistry & Immunology, Trinity College, The University of Dublin, Dublin 2, Ireland; Centre for Advanced Materials and Bioengineering Research Amber; School of Medicine, Trinity College, The University of Dublin, Dublin 2, Ireland. Electronic address: aidunne@tcd.ie.
Jazyk: angličtina
Zdroj: Acta biomaterialia [Acta Biomater] 2023 Apr 01; Vol. 160, pp. 311-321. Date of Electronic Publication: 2023 Feb 07.
DOI: 10.1016/j.actbio.2023.01.058
Abstrakt: Since the recent observation that immune cells undergo metabolic reprogramming upon activation, there has been immense research in this area to not only understand the basis of such changes, but also to exploit metabolic rewiring for therapeutic benefit. In a resting state, macrophages preferentially utilise oxidative phosphorylation to generate energy; however, in the presence of immune cell activators, glycolytic genes are upregulated, and energy is generated through glycolysis. This facilitates the rapid production of biosynthetic intermediates and a pro-inflammatory macrophage phenotype. While this is essential to mount responses to infectious agents, more evidence is accumulating linking dysregulated metabolism to inappropriate immune responses. Given that certain biomaterials are known to promote an inflammatory macrophage phenotype, this prompted us to investigate if biomaterial particulates can impact on macrophage metabolism. Using micron and nano sized hydroxyapatite (HA), we demonstrate for the first time that these biomaterials can indeed drive changes in metabolism, and that this occurs in a size-dependent manner. We show that micronHA, but not nanoHA, particles upregulate surrogate markets of glycolysis including the glucose transporter (GLUT1), hexokinase 2 (HK2), GAPDH, and PKM2. Furthermore, we demonstrate that micronHA alters mitochondrial morphology and promotes a bioenergetic shift to favour glycolysis. Finally, we demonstrate that glycolytic gene expression is dependent on particle uptake and that targeting glycolysis attenuates the pro-inflammatory profile of micronHA-treated macrophages. These results not only further our understanding of biomaterial-based macrophage activation, but also implicate immunometabolism as a new area for consideration in intelligent biomaterial design and therapeutic targeting. STATEMENT OF SIGNIFICANCE: Several recent studies have reported that immune cell activation occurs concurrently with metabolic reprogramming. Furthermore, metabolic reprogramming of innate immune cells plays a prominent role in determining cellular phenotype and function. In this study we demonstrate that hydroxyapatite particle size alters macrophage metabolism, in turn driving their functional phenotype. Specifically, the pro-inflammatory phenotype promoted by micron-sized HA-particles is accompanied by changes in mitochondrial dynamics and a bioenergetic shift favouring glycolysis. This effect is not seen with nano-HA particles and can be attenuated upon inhibition of glycolysis. This study therefore not only identifies immunometabolism as a useful tool for characterising the immune response to biomaterials, but also highlights immunometabolism as a targetable aspect of the host response for therapeutic benefit.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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