Phosphonate-modified cellulose nanocrystals potentiate the Th1 polarising capacity of monocyte-derived dendritic cells via GABA-B receptorBekić, Marina (Avtor) Vasiljević, Miloš (Avtor) Stojanović, Dušica (Avtor) Kokol, Vanja (Avtor) Mihajlović, Dušan (Avtor) Vučević, Dragana (Avtor) Uskoković, Petar S. (Avtor) Čolić, Miodrag (Avtor) Tomić, Sergej (Avtor) cellulose nanocrystalsphosphonatesdendritic cellsregulatory T-cell subsetsimmunomodulationGABA-B receptorPurpose: 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.20222023-08-17 08:47:16Znanstveno delo85047UDK: 677.46:620.3COBISS_ID: 117195779DOI: 10.2147/IJN.S362038ISSN pri članku: 1178-2013sl