title: Polyhydroxylated metallofullerenols stimulate IL-1β secretion of macrophage through TLRs/MyD88/NF-κB pathway and NLRP₃ inflammasome activation.
abstract: Polyhydroxylated fullerenols especially gadolinium endohedral metallofullerenols (Gd@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 inﬂammasomes, 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@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@C82(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@C82(OH)22 had stronger ability C60(OH)22 due to the different electron affinity on the surface of carbon cage induced by the encaged gadolinium ion.
authors.affiliation: CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology of China and Institute of High Energy Physics, Chinese Academy of Science, Beijing, 100190, China.
authors.forename: Zhiyun
authors.initials: Z
authors.lastname: Chen
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Baoyun
authors.initials: B
authors.lastname: Sun
authors.forename: Han
authors.initials: H
authors.lastname: Li
authors.forename: Jinquan
authors.initials: J
authors.lastname: Dong
authors.forename: Lijuan
authors.initials: L
authors.lastname: Zhang
authors.forename: Liming
authors.initials: L
authors.lastname: Wang
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.forename: Yuliang
authors.initials: Y
authors.lastname: Zhao
authors.forename: Chunying
authors.initials: C
authors.lastname: Chen
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D037741:Fullerenes / Q000737:chemistry / Q000494:pharmacology*; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D015398:Signal Transduction / Q000187:drug effects; D051193:Toll-Like Receptors / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D002352:Carrier Proteins; D037741:Fullerenes; D058847:Inflammasomes; D053583:Interleukin-1beta; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D051193:Toll-Like Receptors; C108127:fullerenol
keywords: IL-1β; NLRP3 inflammasome; TLRs/MyD88/NF-κB Pathway; macrophages; metallofullerenols