Polyhydroxylated metallofullerenols stimulate IL-1β secretion of macrophage through TLRs/MyD88/NF-κB Pathway and NLRP3 inflammasome activation

Zhiyun Chen, Ying Liu, Baoyun Sun, Han Li, Jinquan Dong, Lijuan Zhang, Liming Wang, Peng Wang, Yuliang Zhao, Chunying Chen

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

Polyhydroxylated fullerenols especially gadolinium endohedral metallofullerenols (Gd at C82(OH)22) are shown as a promising agent for antitumor chemotherapeutics and good immunoregulatory effects with low toxicity. However, their underlying mechanism remains largely unclear. We found for the first time the persistent uptake and subcellular distribution of metallofullerenols in macrophages by taking advantages of synchrotron-based scanning transmission X-ray microscopy (STXM) with high spatial resolution of 30 nm. Gd@C82(OH)22 can significantly activate primary mouse macrophages to produce pro-inflammatory cytokines like IL-1β. Small interfering RNA (siRNA) knockdown shows that NLRP3 in-ammasomes, but not NLRC4, participate in fullerenol-induced IL-1β production. Potassium efflux, activation of P2X7 receptor and intracellular reactive oxygen speciesare also important factors required for fullerenols-induced IL-1β release. Stronger NF-κB signal triggered by Gd at C82(OH)22 is in agreement with higher pro-IL-1β expression than C60(OH)22. Interestingly, TLR4/MyD88 pathway but not TLR2 mediates IL-1β secretion in Gd at C 82(OH)22 exposure confirmed by macrophages from MyD88 -/-/TLR4-/-/TLR2-/- knockout mice, which is different from C60(OH)22. Our work demonstrated that fullerenols can greatly activate macrophage and promote IL-1β production via both TLRs/MyD88/NF-κB pathway and NLRP3 inflammasome activation, while Gd at C82(OH)22 had stronger ability C 60(OH)22 due to the different electron affinity on the surface of carbon cage induced by the encaged gadolinium ion. Metallofullerenols uptaken by macrophages can promote the production of inflammatory cytokines like IL-1β by triggering two signaling pathways indepentently. First, fullerenols prime macrophages to express pro-IL-1β via TLRs/MyD88 pathway and subsequently activate NF-κB. Secondly, they activate NLRP3 inflammasome under the assistance of relative factors including K+ efflux, P2X7 receptor activation and ROS in macrophages, which is required for processing pro-IL-1β into mature IL-1β.

Original languageEnglish (US)
Pages (from-to)2362-2372
Number of pages11
JournalSmall
Volume10
Issue number12
DOIs
StatePublished - Jun 25 2014

Keywords

  • IL-1β
  • macrophages
  • metallofullerenols
  • NLRP3 inflammasome
  • TLRs/MyD88/NF-κB Pathway

ASJC Scopus subject areas

  • Biomaterials
  • Engineering (miscellaneous)
  • Biotechnology

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