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1.
Eur J Immunol ; 49(5): 801-811, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30779113

RESUMO

Macrophage plasticity is the ability of mononuclear phagocytes to change phenotype, function, and genetic reprogramming upon encounter of specific local stimuli. In the tumor microenvironment, Tumor-Associated Macrophages (TAMs) acquire an immune-suppressive and tumor-promoting phenotype. With the aim to re-educate TAMs to antitumor effectors, in this study, we used two immunestimulatory compounds: the TLR7 agonist Imiquimod (IMQ) and the TLR3 agonist Poly(I:C). To better mimic in vitro the response of TAMs, we used Tumor-Conditioned Macrophages (TC-Mϕ) differentiated in the presence of tumor cell supernatants. Our results show that TC-Mϕ respond differently from conventional M2-polarized macrophages. Upon stimulation with IMQ, TC-Mϕ did not upregulate major histocompatibility complex (MHC II) molecules and unexpectedly expressed increased CD206. With both compounds, TC-Mϕ produced higher levels of inflammatory cytokines than M2 macrophages. IMQ and Poly(I:C) differed in the types of regulated genes and secreted mediators. Reflecting their signaling pathways, only IMQ significantly induced IL-1ß and IL-6, while only Poly(I:C) stimulated CXCL10, and both upregulated CCL5. Of note, using a novel cytotoxicity assay, Poly(I:C), but not IMQ, was effective in triggering the cytotoxic activity of TC-Mϕ against cancer cells. Overall, the results demonstrate that Poly(I:C) stimulation of TC-Mϕ is superior than IMQ in terms of macrophage re-education toward antitumor effectors.


Assuntos
Antineoplásicos/farmacologia , Imiquimode/farmacologia , Macrófagos/imunologia , Neoplasias/imunologia , Poli I-C/farmacologia , Linhagem Celular Tumoral , Membrana Celular/imunologia , Membrana Celular/metabolismo , Citocinas/metabolismo , Humanos , Imiquimode/imunologia , Imunomodulação , Macrófagos/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Poli I-C/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
2.
Sci Rep ; 8(1): 1115, 2018 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-29348435

RESUMO

Carbon-based nanomaterials including carbon nanotubes (CNTs) have been shown to trigger inflammation. However, how these materials are 'sensed' by immune cells is not known. Here we compared the effects of two carbon-based nanomaterials, single-walled CNTs (SWCNTs) and graphene oxide (GO), on primary human monocyte-derived macrophages. Genome-wide transcriptomics assessment was performed at sub-cytotoxic doses. Pathway analysis of the microarray data revealed pronounced effects on chemokine-encoding genes in macrophages exposed to SWCNTs, but not in response to GO, and these results were validated by multiplex array-based cytokine and chemokine profiling. Conditioned medium from SWCNT-exposed cells acted as a chemoattractant for dendritic cells. Chemokine secretion was reduced upon inhibition of NF-κB, as predicted by upstream regulator analysis of the transcriptomics data, and Toll-like receptors (TLRs) and their adaptor molecule, MyD88 were shown to be important for CCL5 secretion. Moreover, a specific role for TLR2/4 was confirmed by using reporter cell lines. Computational studies to elucidate how SWCNTs may interact with TLR4 in the absence of a protein corona suggested that binding is guided mainly by hydrophobic interactions. Taken together, these results imply that CNTs may be 'sensed' as pathogens by immune cells.


Assuntos
Macrófagos/fisiologia , Nanotubos de Carbono , Receptores Toll-Like/metabolismo , Células Cultivadas , Quimiocinas/metabolismo , Citotoxicidade Imunológica , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Interações Hospedeiro-Patógeno/imunologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Macrófagos/ultraestrutura , Modelos Moleculares , Conformação Molecular , Nanotubos de Carbono/química , Reprodutibilidade dos Testes , Transdução de Sinais , Receptores Toll-Like/química , Transcriptoma
3.
Nanoscale ; 6(12): 6974-83, 2014 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-24835568

RESUMO

Neutrophils extrude neutrophil extracellular traps (NETs) consisting of a network of chromatin decorated with antimicrobial proteins to enable non-phagocytic killing of microorganisms. Here, utilizing a model of ex vivo activated human neutrophils, we present evidence of entrapment and degradation of carboxylated single-walled carbon nanotubes (SWCNTs) in NETs. The degradation of SWCNTs was catalyzed by myeloperoxidase (MPO) present in purified NETs and the reaction was facilitated by the addition of H2O2 and NaBr. These results show that SWCNTs can undergo acellular, MPO-mediated biodegradation and imply that the immune system may deploy similar strategies to rid the body of offending microorganisms and engineered nanomaterials.


Assuntos
Armadilhas Extracelulares/imunologia , Imunidade Inata/imunologia , Nanotubos de Carbono/química , Ativação de Neutrófilo/imunologia , Neutrófilos/química , Neutrófilos/imunologia , Células Cultivadas , Humanos
4.
Small ; 9(16): 2721-9, 2720, 2013 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-23447468

RESUMO

Eosinophil peroxidase (EPO) is one of the major oxidant-producing enzymes during inflammatory states in the human lung. The degradation of single-walled carbon nanotubes (SWCNTs) upon incubation with human EPO and H2O2 is reported. Biodegradation of SWCNTs is higher in the presence of NaBr, but neither EPO alone nor H2O2 alone caused the degradation of nanotubes. Molecular modeling reveals two binding sites for SWCNTs on EPO, one located at the proximal side (same side as the catalytic site) and the other on the distal side of EPO. The oxidized groups on SWCNTs in both cases are stabilized by electrostatic interactions with positively charged residues. Biodegradation of SWCNTs can also be executed in an ex vivo culture system using primary murine eosinophils stimulated to undergo degranulation. Biodegradation is proven by a range of methods including transmission electron microscopy, UV-visible-NIR spectroscopy, Raman spectroscopy, and confocal Raman imaging. Thus, human EPO (in vitro) and ex vivo activated eosinophils mediate biodegradation of SWCNTs: an observation that is relevant to pulmonary responses to these materials.


Assuntos
Nanotubos de Carbono/química , Animais , Biodegradação Ambiental , Peroxidase de Eosinófilo/metabolismo , Eosinófilos/metabolismo , Humanos , Camundongos
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