International Journal of Nanomedicine (Jul 2022)
Phosphonate-Modified Cellulose Nanocrystals Potentiate the Th1 Polarising Capacity of Monocyte-Derived Dendritic Cells via GABA-B Receptor
Abstract
Marina Bekić,1 Miloš Vasiljević,2 Dušica Stojanović,3 Vanja Kokol,4 Dušan Mihajlović,2 Dragana Vučević,2 Petar Uskoković,3 Miodrag Čolić,1,2,5 Sergej Tomić1 1Department for Immunology and Immunoparasitology, Institute for the Application of Nuclear Energy, University of Belgrade, Belgrade, Serbia; 2Center for Biomedical Sciences, Medical Faculty Foča, University of East Sarajevo, Foča, Bosnia and Herzegovina; 3Department for Construction and Special Materials, Faculty for Technology and Metallurgy, University in Belgrade, Belgrade, Serbia; 4Department of Textile Materials and Design, Faculty of Mechanical Engineering, University of Maribor, Maribor, Slovenia; 5Serbian Academy of Sciences and Arts, Belgrade, SerbiaCorrespondence: Sergej Tomić, Institute for the Application of Nuclear Energy, University of Belgrade, Banatska 31b, Belgrade, Zemun, 11080, Serbia, Tel +381 11 2610 126, Fax +381 11 2618 724, Email [email protected]: Phosphonates, like 3-AminoPropylphosphonic Acid (ApA), possess a great potential for the therapy of bone tumours, and their delivery via cellulose nanocrystals (CNCs) seems a promising approach for their increased efficacy in target tissues. However, the immunological effects of CNC-phosphonates have not been investigated thoroughly. The main aim was to examine how the modification of CNCs with phosphonate affects their immunomodulatory properties in human cells.Methods: Wood-based native (n) CNCs were modified via oxidation (ox-CNCs) and subsequent conjugation with ApA (ApA-CNCs). CNCs were characterised by atomic force microscopy (AFM) and nanoindentation. Cytotoxicity and immunomodulatory potential of CNCs were investigated in cultures of human peripheral blood mononuclear cells (PBMCs) and monocyte-derived dendritic cells (MoDCs)/T cells co-cultures by monitoring phenotype, cytokines production, allostimulatory and Th/Treg polarisation capacity.Results: AFM showed an increase in CNCs’ thickens, elasticity modulus and hardness during the modification with ApA. When applied at non-toxic doses, nCNCs showed a tolerogenic potential upon internalisation by MoDCs, as judged by their increased capacity to up-regulate tolerogenic markers and induce regulatory T cells (Treg), especially when present during the differentiation of MoDCs. In contrast, ox- and ApA-CNCs induced oxidative stress and autophagy in MoDCs, which correlated with their stimulatory effect on the maturation of MoDCs, but also inhibition of MoDCs differentiation. ApA-CNC-treated MoDCs displayed the highest allostimulatory and Th1/CTL polarising activity in co-cultures with T cells. These effects of ApA-CNCs were mediated via GABA-B receptor-induced lowering of cAMP levels in MoDCs, and they could be blocked by GABA-B receptor inhibitor. Moreover, the Th1 polarising and allostimulatory capacity of MoDCs differentiated with ApA-CNC were largely preserved upon the maturation of MoDCs, whereas nCNC- and ox-CNC-differentiated MoDCs displayed an increased tolerogenic potential.Conclusion: The delivery of ApA via CNCs induces potent DC-mediated Th1 polarisation, which could be beneficial in their potential application in tumour therapy.Keywords: cellulose nanocrystals, phosphonates, dendritic cells, immunomodulation, GABA-B receptor
