PMID- 28645296 OWN - NLM STAT- MEDLINE DCOM- 20180425 LR - 20240326 IS - 1743-8977 (Electronic) IS - 1743-8977 (Linking) VI - 14 IP - 1 DP - 2017 Jun 23 TI - MyD88-dependent pro-interleukin-1beta induction in dendritic cells exposed to food-grade synthetic amorphous silica. PG - 21 LID - 10.1186/s12989-017-0202-8 [doi] LID - 21 AB - BACKGROUND: Dendritic cells (DCs) are specialized first-line sensors of foreign materials invading the organism. These sentinel cells rely on pattern recognition receptors such as Nod-like or Toll-like receptors (TLRs) to launch immune reactions against pathogens, but also to mediate tolerance to self-antigens and, in the intestinal milieu, to nutrients and commensals. Since inappropriate DC activation contributes to inflammatory diseases and immunopathologies, a key question in the evaluation of orally ingested nanomaterials is whether their contact with DCs in the intestinal mucosa disrupts this delicate homeostatic balance between pathogen defense and tolerance. Here, we generated steady-state DCs by incubating hematopoietic progenitors with feline McDonough sarcoma-like tyrosine kinase 3 ligand (Flt3L) and used the resulting immature DCs to test potential biological responses against food-grade synthetic amorphous silica (SAS) representing a common nanomaterial generally thought to be safe. RESULTS: Interaction of immature and unprimed DCs with food-grade SAS particles and their internalization by endocytic uptake fails to elicit cytotoxicity and the release of interleukin (IL)-1alpha or tumor necrosis factor-alpha, which were identified as master regulators of acute inflammation in lung-related studies. However, the display of maturation markers on the cell surface shows that SAS particles activate completely immature DCs. Also, the endocytic uptake of SAS particles into these steady-state DCs leads to induction of the pro-IL-1beta precursor, subsequently cleaved by the inflammasome to secrete mature IL-1beta. In contrast, neither pro-IL-1beta induction nor mature IL-1beta secretion occurs upon internalization of TiO(2) or FePO(4) nanoparticles. The pro-IL-1beta induction is suppressed by pharmacologic inhibitors of endosomal TLR activation or by genetic ablation of MyD88, a downstream adapter of TLR pathways, indicating that endosomal pattern recognition is responsible for the observed cytokine response to food-grade SAS particles. CONCLUSIONS: Our results unexpectedly show that food-grade SAS particles are able to directly initiate the endosomal MyD88-dependent pathogen pattern recognition and signaling pathway in steady-state DCs. The ensuing activation of immature DCs with de novo induction of pro-IL-1beta implies that the currently massive use of SAS particles as food additive should be reconsidered. FAU - Winkler, Hans Christian AU - Winkler HC AD - Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Winterthurerstrasse 260, 8057, Zurich, Switzerland. AD - Present address: Institute of Food, Nutrition and Health, Laboratory of Human Nutrition, ETH Zurich, Schmelzbergstrasse 7, 8092, Zurich, Switzerland. FAU - Kornprobst, Julian AU - Kornprobst J AD - Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Winterthurerstrasse 260, 8057, Zurich, Switzerland. FAU - Wick, Peter AU - Wick P AD - Laboratory for Particles-Biology Interactions, Empa Swiss Laboratories for Materials and Technology, Lerchenfeldstrasse 5, 9014, St. Gallen, Switzerland. FAU - von Moos, Lea Maria AU - von Moos LM AD - Department of Health Sciences and Technology, ETH Zurich, Schmelzbergstrasse 9, 8092, Zurich, Switzerland. FAU - Trantakis, Ioannis AU - Trantakis I AD - Department of Health Sciences and Technology, ETH Zurich, Schmelzbergstrasse 9, 8092, Zurich, Switzerland. FAU - Schraner, Elisabeth Maria AU - Schraner EM AD - Electron Microscopy, Institutes of Veterinary Anatomy and Virology, Winterthurerstrasse 260, 8057, Zurich, Switzerland. FAU - Bathke, Barbara AU - Bathke B AD - Department of Research, Bavarian Nordic GmbH, 82152, Martinsried, Germany. FAU - Hochrein, Hubertus AU - Hochrein H AD - Department of Research, Bavarian Nordic GmbH, 82152, Martinsried, Germany. FAU - Suter, Mark AU - Suter M AD - Immunology Division, Vetsuisse Faculty, University of Zurich, Winterthurerstrasse 204, 8057, Zurich, Switzerland. FAU - Naegeli, Hanspeter AU - Naegeli H AD - Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Winterthurerstrasse 260, 8057, Zurich, Switzerland. naegelih@vetpharm.uzh.ch. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20170623 PL - England TA - Part Fibre Toxicol JT - Particle and fibre toxicology JID - 101236354 RN - 0 (Food Additives) RN - 0 (IL1B protein, mouse) RN - 0 (Inflammasomes) RN - 0 (Interleukin-1beta) RN - 0 (Myd88 protein, mouse) RN - 0 (Myeloid Differentiation Factor 88) RN - 0 (Protein Precursors) RN - 0 (Receptors, Pattern Recognition) RN - 0 (Toll-Like Receptors) RN - 7631-86-9 (Silicon Dioxide) SB - IM MH - Animals MH - Cells, Cultured MH - Dendritic Cells/*drug effects/metabolism/ultrastructure MH - Dose-Response Relationship, Drug MH - Endocytosis MH - Endosomes/drug effects/metabolism/ultrastructure MH - Food Additives/chemical synthesis/metabolism/*toxicity MH - Food Safety MH - Inflammasomes/metabolism MH - Interleukin-1beta/*metabolism MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Myeloid Differentiation Factor 88/deficiency/genetics/*metabolism MH - Nanoparticles MH - Protein Precursors/*metabolism MH - Protein Processing, Post-Translational MH - Receptors, Pattern Recognition/metabolism MH - Risk Assessment MH - Signal Transduction/drug effects MH - Silicon Dioxide/chemical synthesis/metabolism/*toxicity MH - Time Factors MH - Toll-Like Receptors/genetics/metabolism MH - Up-Regulation PMC - PMC5481969 OTO - NOTNLM OT - E 551 OT - Food additive OT - Food toxicology OT - Gut-associated lymphoid tissue OT - Inflammatory bowel disease OT - Nanomaterial OT - Silicon dioxide OT - Synthetic amorphous silica EDAT- 2017/06/25 06:00 MHDA- 2018/04/26 06:00 PMCR- 2017/06/23 CRDT- 2017/06/25 06:00 PHST- 2017/01/16 00:00 [received] PHST- 2017/06/18 00:00 [accepted] PHST- 2017/06/25 06:00 [entrez] PHST- 2017/06/25 06:00 [pubmed] PHST- 2018/04/26 06:00 [medline] PHST- 2017/06/23 00:00 [pmc-release] AID - 10.1186/s12989-017-0202-8 [pii] AID - 202 [pii] AID - 10.1186/s12989-017-0202-8 [doi] PST - epublish SO - Part Fibre Toxicol. 2017 Jun 23;14(1):21. doi: 10.1186/s12989-017-0202-8.