Activation of the inflammasome and enhanced migration of microparticle-stimulated dendritic cells to the draining lymph node

Ismail M. Meraz, Brenda Melendez, Jianhua Gu, Stephen T.C. Wong, Xuewu Liu, Helen A. Andersson, Rita E. Serda

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Porous silicon microparticles presenting pathogen-associated molecular patterns mimic pathogens, enhancing internalization of the microparticles and activation of antigen presenting dendritic cells. We demonstrate abundant uptake of microparticles bound by the TLR-4 ligands LPS and MPL by murine bone marrow-derived dendritic cells (BMDC). Labeled microparticles induce concentration-dependent production of IL-1β, with inhibition by the caspase inhibitor Z-VAD-FMK supporting activation of the NLRP3-dependent inflammasome. Inoculation of BALB/c mice with ligand-bound microparticles induces a significant increase in circulating levels of IL-1β, TNF-α, and IL-6. Stimulation of BMDC with ligand-bound microparticles increases surface expression of costimulatory and MHC molecules, and enhances migration of BMDC to the draining lymph node. LPS-microparticles stimulate in vivo C57BL/6 BMDC and OT-1 transgenic T cell interactions in the presence of OVA SIINFEKL peptide in lymph nodes, with intact nodes imaged using two-photon microscopy. Formation of in vivo and in vitro immunological synapses between BMDC, loaded with OVA peptide and LPS-microparticles, and OT-1 T cells are presented, as well as elevated intracellular interferon gamma levels in CD8 + T cells stimulated by BMDC carrying peptide-loaded microparticles. In short, ligand-bound microparticles enhance (1) phagocytosis of microparticles; (2) BMDC inflammasome activation and upregulation of costimulatory and MHC molecules; (3) cellular migration of BMDC to lymphatic tissue; and (4) cellular interactions leading to T cell activation in the presence of antigen.

Original languageEnglish (US)
Pages (from-to)2049-2062
Number of pages14
JournalMolecular pharmaceutics
Volume9
Issue number7
DOIs
StatePublished - Jul 2 2012

Keywords

  • atomic force microscopy
  • dendritic cell
  • LPS
  • microparticle
  • migration
  • monophosphoryl lipid A
  • phagocytosis
  • vaccine

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Molecular Medicine
  • Drug Discovery

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