title: Macrophage activation status determines the internalization of mesoporous silica particles of different sizes: Exploring the role of different pattern recognition receptors.
abstract: Mesoporous silica-based particles are promising candidates for biomedical applications. Here, we address the importance of macrophage activation status for internalization of AMS6 (approx. 200 nm in diameter) versus AMS8 (approx. 2 μm) mesoporous silica particles and the role of different phagocytosis receptors for particle uptake. To this end, FITC-conjugated silica particles were used. AMS8 were found to be non-cytotoxic both for M-CSF-stimulated (anti-inflammatory) and GM-CSF-stimulated (pro-inflammatory) macrophages, whereas AMS6 exhibited cytotoxicity towards M-CSF-stimulated, but not GM-CSF-stimulated macrophages; this toxicity was, however, mitigated in the presence of serum. AMS8 triggered the secretion of pro-inflammatory cytokines in M-CSF-activated cells. Class A scavenger receptor (SR-A) expression was noted in both M-CSF and GM-CSF-stimulated macrophages, although the expression was higher in the former case, and gene silencing of SR-A resulted in a decreased uptake of AMS6 in the absence of serum. GM-CSF-stimulated macrophages expressed higher levels of the mannose receptor CD206 compared to M-CSF-stimulated cells, and uptake of AMS6, but not AMS8, was reduced following the downregulation of CD206 in GM-CSF-stimulated cells; particle uptake was also suppressed by mannan, a competitive ligand. These studies demonstrate that macrophage activation status is an important determinant of particle uptake and provide evidence for a role of different macrophage receptors for cell uptake of silica particles.
authors.affiliation: Nanosafety & Nanomedicine Laboratory, Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, 171 77, Stockholm, Sweden.
authors.forename: Audrey
authors.initials: A
authors.lastname: Gallud
authors.affiliation: Nanosafety & Nanomedicine Laboratory, Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, 171 77, Stockholm, Sweden.
authors.forename: Olesja
authors.initials: O
authors.lastname: Bondarenko
authors.affiliation: Nanosafety & Nanomedicine Laboratory, Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, 171 77, Stockholm, Sweden.
authors.forename: Neus
authors.initials: N
authors.lastname: Feliu
authors.affiliation: Department of Materials and Environmental Chemistry, Stockholm University, 106 91, Stockholm, Sweden.
authors.forename: Natalia
authors.initials: N
authors.lastname: Kupferschmidt
authors.affiliation: Nanologica AB, 114 28, Stockholm, Sweden.
authors.forename: Rambabu
authors.initials: R
authors.lastname: Atluri
authors.affiliation: Department of Chemistry and Biomolecular Science, Macquarie University, Sydney, NSW, 2109, Australia.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Garcia-Bennett
authors.affiliation: Nanosafety & Nanomedicine Laboratory, Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, 171 77, Stockholm, Sweden. Electronic address: Bengt.Fadeel@ki.se.
authors.forename: Bengt
authors.initials: B
authors.lastname: Fadeel
mesh_terms: D002478:Cells, Cultured; D006801:Humans; D008262:Macrophage Activation / Q000187:drug effects* / Q000276:immunology*; D008264:Macrophages / Q000737:chemistry* / Q000276:immunology*; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry* / Q000648:ultrastructure*; D058608:Nanopores / Q000648:ultrastructure; D010316:Particle Size; D016062:Porosity; D012822:Silicon Dioxide / Q000008:administration & dosage / Q000737:chemistry*
chemical_list: D012822:Silicon Dioxide
keywords: Human macrophages; Mannose receptors; Scavenger receptors; Silica particles