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1.
Nat Commun ; 12(1): 2299, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33863908

RESUMO

Mycobacterial cell-wall glycolipids elicit an anti-mycobacterial immune response via FcRγ-associated C-type lectin receptors, including Mincle, and caspase-recruitment domain family member 9 (CARD9). Additionally, mycobacteria harbor immuno-evasive cell-wall lipids associated with virulence and latency; however, a mechanism of action is unclear. Here, we show that the DAP12-associated triggering receptor expressed on myeloid cells 2 (TREM2) recognizes mycobacterial cell-wall mycolic acid (MA)-containing lipids and suggest a mechanism by which mycobacteria control host immunity via TREM2. Macrophages respond to glycosylated MA-containing lipids in a Mincle/FcRγ/CARD9-dependent manner to produce inflammatory cytokines and recruit inducible nitric oxide synthase (iNOS)-positive mycobactericidal macrophages. Conversely, macrophages respond to non-glycosylated MAs in a TREM2/DAP12-dependent but CARD9-independent manner to recruit iNOS-negative mycobacterium-permissive macrophages. Furthermore, TREM2 deletion enhances Mincle-induced macrophage activation in vitro and inflammation in vivo and accelerates the elimination of mycobacterial infection, suggesting that TREM2-DAP12 signaling counteracts Mincle-FcRγ-CARD9-mediated anti-mycobacterial immunity. Mycobacteria, therefore, harness TREM2 for immune evasion.


Assuntos
Evasão da Resposta Imune , Tuberculose Latente/imunologia , Glicoproteínas de Membrana/metabolismo , Mycobacterium tuberculosis/imunologia , Ácidos Micólicos/metabolismo , Receptores Imunológicos/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Parede Celular/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Feminino , Glicolipídeos/metabolismo , Humanos , Tuberculose Latente/microbiologia , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Masculino , Glicoproteínas de Membrana/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Mycobacterium tuberculosis/metabolismo , Mycobacterium tuberculosis/patogenicidade , Cultura Primária de Células , Receptores de IgG/metabolismo , Receptores Imunológicos/genética , Fatores de Virulência/metabolismo
2.
Life Sci ; 276: 119422, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33781833

RESUMO

AIMS: Inflammation plays a key role in peripheral nerve adhesion and often leads to severe pain and nerve dysfunction. Minocycline was reported to have potent anti-inflammatory effects and might be a promising drug to prevent or attenuate peripheral nerve adhesion. The present study aimed to clarify whether minocycline contributes to nerve adhesion protection and its underlying mechanism. MATERIALS AND METHODS: Rats with sciatic nerve adhesion induced by glutaraldehyde glue (GG) were intraperitoneally injected with minocycline or saline every 12 h for 7 consecutive days. After that, the adhesion score, Ashcroft score, demyelination, macrophage polarization and inflammatory factors in peripheral nerve adhesion tissues or tissues in sham group were determined with histological staining, western blot and real time-PCR. Murine macrophage RAW264.7 cells were stimulated by LPS alone or together with minocycline at different concentrations and time duration to study the mechanism of minocycline in alleviating nerve adhesion. KEY FINDINGS: We found that minocycline treatment reduced the adhesion score, Ashcroft score, the growth of scar tissue, demyelination, and macrophage recruitment. Moreover, minocycline significantly and dose-dependently promoted regulatory macrophage polarization but decreased pro-inflammatory macrophage polarization. Furthermore, mechanism studies showed that TAK1 and its downstream pathway p38/JNK/ERK1/2/p65 were inhibited by minocycline, which led to lower IL-1ß and TNFα expression, but increased IL-10 expression. SIGNIFICANCE: Altogether, these results suggest that minocycline is highly effective against peripheral nerve adhesion through anti-fibrosis, anti-inflammation, and myelination protection, making it a highly promising candidate for treating adhesion-related disorders.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , MAP Quinase Quinase Quinases/metabolismo , Ativação de Macrófagos/imunologia , Minociclina/farmacologia , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Neuropatia Ciática/tratamento farmacológico , Aderências Teciduais/prevenção & controle , Animais , Antibacterianos/farmacologia , Modelos Animais de Doenças , Feminino , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , MAP Quinase Quinase Quinases/genética , Ativação de Macrófagos/efeitos dos fármacos , Doenças do Sistema Nervoso Periférico/imunologia , Doenças do Sistema Nervoso Periférico/metabolismo , Doenças do Sistema Nervoso Periférico/patologia , Ratos , Ratos Sprague-Dawley , Neuropatia Ciática/imunologia , Neuropatia Ciática/metabolismo , Neuropatia Ciática/patologia
3.
Microb Pathog ; 153: 104799, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33609650

RESUMO

The outbreak of coronavirus disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, has emerged in China in December 2019 and rapidly spread to more than 196 countries worldwide. The physiopathology of human SARS-CoV-2 has not been completely understood, but its pathogenesis has been linked to a disproportionate response of the immune system. Just as described for SARS and MERS, an uncontrolled systemic inflammatory response, known as cytokine release syndrome (CRS) was observed in severe COVID-19 patients. It results from the release by immune and non-immune effector cells of substantial amounts of pro-inflammatory cytokines and appears to contribute to SARS-CoV-2 pulmonary inflammation and extensive lung damage. In addition, hyper-coagulation and thrombosis resulted from the important release of pro-inflammatory cytokines contribute to the lethality of subjects severely infected with SARS-CoV-2. It is therefore essential to have a deep understanding of the various cytokines involved in this exacerbated immune response, and that could be targeted by potential immunological treatments. The aim of this review was to gather the current knowledge about the role of pro-inflammatory cytokines, namely IL-1ß, IL-6, IL-8, IL-17 and TNFα in SARS-CoV-2 CRS, the probable causes and clinical outcomes of this phenomenon in severe cases of COVID-19.


Assuntos
/patologia , Síndrome da Liberação de Citocina/patologia , Citocinas/sangue , /imunologia , Citocinas/imunologia , Humanos , Ativação de Macrófagos/imunologia , Trombose/patologia
4.
Int J Mol Sci ; 22(2)2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33451052

RESUMO

Lung cancer is currently the first cause of cancer-related death. The major lung cancer subtype is non-small cell lung cancers (NSCLC), which accounts for approximatively 85% of cases. The major carcinogenic associated with lung cancer is tobacco smoke, which produces long-lasting and progressive damage to the respiratory tract. The progressive and diffuse alterations that occur in the respiratory tract of patients with cancer and premalignant lesions have been described as field cancerization. At the level of tumor cells, adjacent tumor microenvironment (TME) and cancerized field are taking place dynamic interactions through direct cell-to-cell communication or through extracellular vesicles. These molecular messages exchanged between tumor and nontumor cells are represented by proteins, noncoding RNAs (ncRNAs) and microRNAs (miRNAs). In this paper, we analyze the miRNA roles in the macrophage polarization at the level of TME and cancerized field in NSCLC. Identifying molecular players that can influence the phenotypic states at the level of malignant cells, tumor microenvironment and cancerized field can provide us new insights into tumor regulatory mechanisms that can be further modulated to restore the immunogenic capacity of the TME. This approach could revert alterations in the cancerized field and could enhance currently available therapy approaches.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/etiologia , Transformação Celular Neoplásica/genética , Suscetibilidade a Doenças , Neoplasias Pulmonares/etiologia , Ativação de Macrófagos/genética , Macrófagos/metabolismo , MicroRNAs/genética , Animais , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Interferência de RNA , Microambiente Tumoral/imunologia
5.
Life Sci ; 266: 118903, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33340526

RESUMO

AIMS: We will investigate the anti-inflammatory activities of berberine (BBR) in treating chronic atrophic gastritis (CAG) induced by Helicobacter pylori (H. pylori). Furthermore, the underlying molecular mechanisms of BBR also will be explored systematically. MATERIALS AND METHODS: Rats were infected by H. pylori. Lipopolysaccharide (LPS) and H. pylori were applied to induce M1 Mφs polarization, interleukin 4 (IL-4) and BBR were used to induce M2 Mφs polarization. Supernatants of polarized Mφs were collected as conditioned media (CM) for investigating the impact of Mφs and its' secreted cytokine on gastric epithelial cells (GES-1). Cell viability, morphology, proliferation, and quantitative analysis of RAW 264.7 cells and GES-1 cells were detected by high-content screening (HCS) imaging assay. To further investigate the potential mechanisms of BBR, relative mRNA, immunohistochemistry and protein expression were measured. KEY FINDINGS: BBR inhibited M1-polarized Mφs, which was induced by H. pylori and LPS, and advocated M2-polarized Mφs. The M1-specific markers (TNF-α and IFN-γ) in supernatants were reduced significantly and M2 specific markers (TGF-ß and IL-10) were increased obviously under BBR intervention. In addition, BBR significantly protected GES-1 from M1-polarized Mφs injury. The mRNA expression of M1-polarized Mφs, including TNF-α, NOS2, CCR7, and IRF-8, were suppressed by BBR administration and the mRNA expression of M2-polarized Mφs, including IL-4, STAT6, IL-10 and Chil3, were increased by BBR intervention. Meanwhile, BBR activated IL-4-STAT6 signaling pathway in vivo and in vitro when H. pylori infection and presented anti-inflammatory activities. SIGNIFICANCE: BBR promotes M2-polarized Mφs when H. pylori infection. The anti-inflammatory properties of BBR tightly related to M1-polarized Mφs inhibition and M2-polarized Mφs promotion. BBR activates IL-4-STAT6 signaling pathway, which is crucial exceedingly in M2 Mφs activation and anti-inflammatory response.


Assuntos
Berberina/farmacologia , Gastrite Atrófica/tratamento farmacológico , Infecções por Helicobacter/complicações , Helicobacter pylori/isolamento & purificação , Interleucina-4/metabolismo , Ativação de Macrófagos/imunologia , Fator de Transcrição STAT6/metabolismo , Animais , Gastrite Atrófica/etiologia , Gastrite Atrófica/patologia , Regulação da Expressão Gênica , Infecções por Helicobacter/microbiologia , Humanos , Interleucina-4/genética , Ativação de Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Ratos , Fator de Transcrição STAT6/genética
6.
Medicine (Baltimore) ; 99(42): e22438, 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33080678

RESUMO

BACKGROUND: Myeloid cell leukemia-1 (Mcl-1) plays an important role in the clearance of Mycobacterium tuberculosis (MTB) infection. It has the effect of anti-apoptosis, protecting macrophages that have engulfed pathogens and preventing pathogen clearance. Meanwhile, the MAPK signaling pathway plays a significant role in regulating Mcl-1 expression during tuberculosis infection. In the case of latent infection and active infection, the apoptosis and polarization of macrophages have a great influence during MTB infection, so we discussed the effect of Mcl-1 on apoptosis and polarization. Then, further discussed its mechanism. METHODS: An infected RAW264.7 macrophage model was established to investigate the regulatory role and mechanism of the Mcl-1 pathway inhibition during apoptosis and polarization of H37Rv infection. First, Mcl-1 protein and mRNA was identified by western blotting and Real-Time Polymerase Chain Reaction (RT-PCR). RAW264.7 macrophage apoptosis was detected by flow cytometry. RT-PCR was utilized to detect Bax, Caspase-3, Cyt-c and Bcl-2 mRNA expression. Next, Then the expression levels of inflammation factors CD86, CD206, iNOS, Fizz1, IL-6, IL-10, TNF-α, and TGF-ß was detected by ELISA. SEM was used to observe macrophages phenotype. Finally, Bax, Bcl-2 and Bcl-xl the expression was detected by western blotting. Confocal microscopy was used to analyze mitochondrial membrane potential using the JC-10 kit. RESULTS: In this study, we found that inhibiting the Mcl-1 expression signaling pathway led to infection by different virulence Mycobacterium tuberculosis, as well as changes in Mcl-1 protein and mRNA expression. Concomitantly macrophage apoptosis rate also changed, While, two phenotypic states of M1 and M2 appeared in the infected cells. We also found that the mitochondrial pathway was activated, the expression of its related genes Bax, casepase3, and Cyt-c, increased, whereas that of Bcl-2 decreased, and the mitochondrial membrane depolarization function was changed. CONCLUSIONS: We found that Mcl-1 affected the apoptosis and polarization of macrophages infected by Mycobacterium tuberculosis, mainly M1 in the early stage and M2 in the later stage. In addition, mitochondria played a crucial role in this process.


Assuntos
Proteínas Reguladoras de Apoptose/imunologia , Hidrolases/imunologia , Sistema de Sinalização das MAP Quinases/imunologia , Ativação de Macrófagos/imunologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/imunologia , Células Cultivadas , Regulação para Baixo , Ativação Enzimática , Humanos , Macrófagos/imunologia , Potenciais da Membrana , Fenótipo , Virulência
7.
Nanotoxicology ; 14(8): 1137-1155, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32916084

RESUMO

Bystander effects in biological systems are the responses shown by nontargeted neighboring cells, and critical to the bio-nano interface interactions. In addition to direct effects, bystander effects also determine the design, applications and safety of nanomaterials, although the related information of nanomaterial-induced bystander effects remain largely unknown. A coculture system of A549 and THP-1 was established to mimic the lung microenvironment to study the bystander effects of WS2 nanosheets (representative transition-metal dichalcogenide nanosheets) on microenvironment macrophages during the inhalation exposure or the nanomaterial biomedical application in the lung. Lung cells exposed to WS2 nanosheet resulted in an increase in reactive oxygen species and the depolarization of mitochondrial membrane potential in neighboring macrophages. Bystander exposure also induced macrophage polarization toward the anti-inflammatory M2 phenotype, which is adverse to disease therapy. Metabolomics showed that WS2 nanosheets disturbed the energy metabolism and amino acid metabolism of macrophages, consistent with the metabolic characteristics of M2 macrophages. Nitric oxide-transforming growth factor-ß1 played an important mediator in the bystander effects. Importantly, WS2 nanosheet bystander exposure affected macrophage phagocytosis and migration and altered the macrophage immune response to endotoxin. This study improves the current understanding of bio-nano interactions and highlights the importance of neighboring cell responses, allowing us to use the maximum benefits of nanomaterials while limiting their adverse bystander effects.


Assuntos
Efeito Espectador/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Nanoestruturas/toxicidade , Sulfetos/toxicidade , Compostos de Tungstênio/toxicidade , Células A549 , Animais , Efeito Espectador/imunologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Cocultura , Humanos , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Nanoestruturas/química , Óxido Nítrico/metabolismo , Tamanho da Partícula , Fagocitose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Sulfetos/química , Propriedades de Superfície , Células THP-1 , Compostos de Tungstênio/química
8.
PLoS Biol ; 18(9): e3000813, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32991574

RESUMO

Short-chain fatty acids (SCFAs) produced by gastrointestinal microbiota regulate immune responses, but host molecular mechanisms remain unknown. Unbiased screening using SCFA-conjugated affinity nanobeads identified apoptosis-associated speck-like protein (ASC), an adaptor protein of inflammasome complex, as a noncanonical SCFA receptor besides GPRs. SCFAs promoted inflammasome activation in macrophages by binding to its ASC PYRIN domain. Activated inflammasome suppressed survival of Salmonella enterica serovar Typhimurium (S. Typhimurium) in macrophages by pyroptosis and facilitated neutrophil recruitment to promote bacterial elimination and thus inhibit systemic dissemination in the host. Administration of SCFAs or dietary fibers, which are fermented to SCFAs by gut bacteria, significantly prolonged the survival of S. Typhimurium-infected mice through ASC-mediated inflammasome activation. SCFAs penetrated into the inflammatory region of the infected gut mucosa to protect against infection. This study provided evidence that SCFAs suppress Salmonella infection via inflammasome activation, shedding new light on the therapeutic activity of dietary fiber.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/metabolismo , Ácidos Graxos Voláteis/metabolismo , Inflamassomos/imunologia , Inflamassomos/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Infecções por Salmonella/prevenção & controle , Animais , Proteínas Adaptadoras de Sinalização CARD/genética , Feminino , Microbioma Gastrointestinal/imunologia , Células HEK293 , Humanos , Imunidade Inata/fisiologia , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ligação Proteica , Receptores Acoplados a Proteínas-G/genética , Infecções por Salmonella/genética , Infecções por Salmonella/imunologia , Infecções por Salmonella/metabolismo , Salmonella typhimurium/imunologia , Células U937
9.
Zhongguo Xue Xi Chong Bing Fang Zhi Za Zhi ; 32(4): 432-435, 2020 Feb 24.
Artigo em Chinês | MEDLINE | ID: mdl-32935525

RESUMO

Macrophages are important members of innate immunity and play an extremely important role in the host defense against pathogenic infections, tumors, and allergic diseases. Macrophages have a high degree of plasticity, and may be polarized into classical activated macrophages (M1 macrophages) and alternative activated macrophages (M2 macrophages) under the stimulation of different environments. M1 macrophages are found to promote inflammatory responses, which facilitates the clearance of pathogens, while M2 macrophages may inhibit inflammatory responses, which facilitates the survival and reproduction of pathogens. This review summarizes the role of macrophage polarization in parasitic infections, so as to provide insights into the prevention and treatment of parasitic diseases.


Assuntos
Ativação de Macrófagos , Doenças Parasitárias , Humanos , Ativação de Macrófagos/imunologia , Macrófagos/citologia , Macrófagos/imunologia , Doenças Parasitárias/imunologia
10.
PLoS One ; 15(8): e0233818, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32857777

RESUMO

Macrophages serve as a first line of defense against infection with the facultative intracellular pathogen, Cryptococcus neoformans (Cn). However, the ability of these innate phagocytic cells to destroy ingested Cn is strongly influenced by polarization state with classically (M1) activated macrophages better able to control cryptococcal infections than alternatively (M2) activated cells. While earlier studies have demonstrated that intracellular Cn minimally affects the expression of M1 and M2 markers, the impact on the broader transcriptome associated with these states remains unclear. To investigate this, an in vitro cell culture model of intracellular infection together with RNA sequencing-based transcriptome profiling was used to measure the impact of Cn infection on gene expression in both polarization states. The gene expression profile of both M1 and M2 cells was extensively altered to become more like naive (M0) macrophages. Gene ontology analysis suggested that this involved changes in the activity of the Janus kinase-signal transducers and activators of transcription (JAK-STAT), p53, and nuclear factor-κB (NF-κB) pathways. Analyses of the principle polarization markers at the protein-level also revealed discrepancies between the RNA- and protein-level responses. In contrast to earlier studies, intracellular Cn was found to increase protein levels of the M1 marker iNos. In addition, common gene expression changes were identified that occurred post-Cn infection, independent of polarization state. This included upregulation of the transcriptional co-regulator Cited1, which was also apparent at the protein level in M1-polarized macrophages. These changes constitute a transcriptional signature of macrophage Cn infection and provide new insights into how Cn impacts gene expression and the phenotype of host phagocytes.


Assuntos
Cryptococcus neoformans/patogenicidade , Macrófagos/metabolismo , Macrófagos/microbiologia , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Cryptococcus neoformans/imunologia , Ontologia Genética , Redes Reguladoras de Genes , Imunidade Inata/genética , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Camundongos , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7 , Transativadores/genética , Transativadores/metabolismo , Transcriptoma
11.
Front Immunol ; 11: 1580, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32670297

RESUMO

SARS-CoV-2 might directly activate NLRP3 inflammasome resulting in an endogenous adjuvant activity necessary to mount a proper adaptive immune response against the virus. Heterogeneous response of COVID-19 patients could be attributed to differences in not being able to properly downregulate NLRP3 inflammasome activation. This relates to the fitness of the immune system of the individual challenged by the virus. Patients with a reduced immune fitness can demonstrate a dysregulated NLRP3 inflammasome activity resulting in severe COVID-19 with tissue damage and a cytokine storm. We sketch the outlines of five possible scenarios for COVID-19 in medical practice and provide potential treatment options targeting dysregulated endogenous adjuvant activity in severe COVID-19 patients.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Proteína HMGB1/metabolismo , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus/patologia , Citocinas/metabolismo , Humanos , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Infiltração de Neutrófilos/imunologia , Neutrófilos/imunologia , Pandemias , Pneumonia Viral/patologia
12.
Mol Immunol ; 125: 104-114, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32659595

RESUMO

Leishmania are obligate protozoan parasites responsible for substantial public health problems in tropical and subtropical regions around the world, with L. braziliensis being one of the causative agents of American Tegumentary Leishmaniasis. Macrophages, fundamental cells in the innate inflammatory response against Leishmania, constitute a heterogeneous group with multiple activation phenotypes and functions. The outcome of this infection depends largely on the activation status of macrophages, the first line of mammalian defense and the major target cells for parasite replication. The importance of lipids, the major components of cell membranes, goes beyond their basic structural functions. Lipid bioactive molecules have been described in Leishmania spp., and in the recent years the knowledge about the biological relevance of lipids in particular and their relationship with the immune response is expanding. The present work analyzes the biological effects of L. braziliensis lipids from lysed promastigotes (PRO) to mimic rapid modulatory processes that could occur in the initial steps of infection or the effects of lipids from lysed and incubated promastigotes (PROinc), simulating the parasite lipid degradation processes triggered after parasite lysis that might occur in the mammalian host. To perform these studies, lipid profiles of PRO and PROinc were compared with lipids from amastigotes under similar conditions (AMA and AMAinc), and the effect of these lipid extracts were analyzed on the induction of an inflammatory response in murine peritoneal macrophages: LB induction, COX-2, iNOS and Arginase expression, TNF-α, IL-10 and NO production, Arginase activity and M1/M2 markers mRNA induction.


Assuntos
Antígenos de Protozoários/imunologia , Leishmania braziliensis/imunologia , Leishmaniose/imunologia , Lipídeos/imunologia , Ativação de Macrófagos/imunologia , Animais , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C
14.
PLoS One ; 15(6): e0234484, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32511271

RESUMO

Inflammation plays a crucial role in the defense response of the innate immune system against pathogen infection. In this study, we selected 4 compounds for their potential or proven anti-inflammatory and/or anti-microbial properties to test on our in vitro model of bacteria-infected THP-1-derived macrophages. We first compared the capacity of sulforaphane (SFN), wogonin (WG), oltipraz (OTZ), and dimethyl fumarate (DMF) to induce the nuclear factor erythroid 2-related factor 2 (Nrf2), a key regulator of the antioxidant, anti-inflammatory response pathways. Next, we performed a comparative evaluation of the antioxidant and anti-inflammatory efficacies of the 4 selected compounds. THP-1-derived macrophages and LPS-stimulated macrophages were treated with each compound and expression levels of genes coding for inflammatory cytokines IL-1ß, IL-6, and TNF-α were quantified by RT-qPCR. Moreover, expression levels of genes coding for M1 (IL-23, CCR7, IL-1ß, IL-6, and TNF-α) and M2 (PPARγ, MRC1, CCL22, and IL-10) markers were determined in classically-activated M1 macrophages treated with each compound. Finally, the effects of each compound on the intracellular bacterial survival of gram-negative E. coli and gram-positive S. aureus in THP-1-derived macrophages and PBMC-derived macrophages were examined. Our data confirmed the anti-inflammatory and antioxidant effects of SFN, WG, and DMF on LPS-stimulated THP-1-derived macrophages. In addition, SFN or WG treatment of classically-activated THP-1-derived macrophages reduced expression levels of M1 marker genes, while SFN or DMF treatment upregulated the M2 marker gene MRC1. This decrease in expression of M1 marker genes may be correlated with the decrease in intracellular S. aureus load in SFN- or DMF-treated macrophages. Interestingly, an increase in intracellular survival of E. coli in SFN-treated THP-1-derived macrophages that was not observed in PBMC-derived macrophages. Conversely, OTZ exhibited pro-oxidant and proinflammatory properties, and affected intracellular survival of E. coli in THP-1-derived macrophages. Altogether, we provide new potential therapeutic alternatives in treating inflammation and bacterial infection.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Infecções por Escherichia coli/tratamento farmacológico , Inflamação/tratamento farmacológico , Ativação de Macrófagos/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/imunologia , Estresse Oxidativo/efeitos dos fármacos , Infecções Estafilocócicas/tratamento farmacológico , Fumarato de Dimetilo/farmacologia , Escherichia coli/efeitos dos fármacos , Infecções por Escherichia coli/imunologia , Flavanonas/farmacologia , Humanos , Inflamação/imunologia , Isotiocianatos/farmacologia , Leucócitos Mononucleares , Ativação de Macrófagos/imunologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Estresse Oxidativo/imunologia , Pirazinas/farmacologia , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/efeitos dos fármacos , Células THP-1 , Tionas , Tiofenos
15.
J Autoimmun ; 114: 102506, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32563547

RESUMO

Coronavirus disease 2019 (COVID-19) has been categorized as evolving in overlapping phases. First, there is a viral phase that may well be asymptomatic or mild in the majority, perhaps 80% of patients. The pathophysiological mechanisms resulting in minimal disease in this initial phase are not well known. In the remaining 20% of cases, the disease may become severe and/or critical. In most patients of this latter group, there is a phase characterized by the hyperresponsiveness of the immune system. A third phase corresponds to a state of hypercoagulability. Finally, in the fourth stage organ injury and failure occur. Appearance of autoinflammatory/autoimmune phenomena in patients with COVID-19 calls attention for the development of new strategies for the management of life-threatening conditions in critically ill patients. Antiphospholipid syndrome, autoimmune cytopenia, Guillain-Barré syndrome and Kawasaki disease have each been reported in patients with COVID-19. Here we present a scoping review of the relevant immunological findings in COVID-19 as well as the current reports about autoinflammatory/autoimmune conditions associated with the disease. These observations have crucial therapeutic implications since immunomodulatory drugs are at present the most likely best candidates for COVID-19 therapy. Clinicians should be aware of these conditions in patients with COVID-19, and these observations should be considered in the current development of vaccines.


Assuntos
Doenças Autoimunes/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Pneumonia Viral/imunologia , Imunidade Adaptativa/genética , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/terapia , Doenças Autoimunes/virologia , Betacoronavirus/isolamento & purificação , Técnicas de Laboratório Clínico , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/terapia , Estado Terminal , Síndrome da Liberação de Citocina/diagnóstico , Síndrome da Liberação de Citocina/terapia , Síndrome da Liberação de Citocina/virologia , Feminino , Predisposição Genética para Doença , Humanos , Imunidade Inata/genética , Imunização Passiva/métodos , Mediadores da Inflamação/sangue , Mediadores da Inflamação/imunologia , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Masculino , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/epidemiologia , Pneumonia Viral/terapia , Fatores de Risco , Índice de Gravidade de Doença , Fatores Sexuais
16.
Cancer Immunol Immunother ; 69(8): 1409-1421, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32242260

RESUMO

MMP12 is mainly secreted by macrophages, is involved in macrophage development, and decomposes the extracellular matrix. Herein, we investigated whether macrophages would change in the intestinal tumor microenvironment after MMP12 knockout. ApcMin/+;MMP12-/-mice were obtained by crossbreeding ApcMin/+ mice with MMP12 knockout mice (MMP12-/- mice). The data showed that the number and volume of intestinal tumors were significantly increased in ApcMin/+;MMP12-/- mice compared with ApcMin/+ mice. Additionally, the tumor biomarkers CA19-9, CEA, and ß-catenin appeared relatively early in intestinal tumors in ApcMin/+;MMP12-/- mice. The results demonstrated that knocking out MMP12 accelerated the tumor growth and pathological process. On further investigation of its mechanism, the proportions of M2 macrophages in the spleen and among peritoneal macrophages were significantly up-regulated in ApcMin/+;MMP12-/- mice. Expression of M2 macrophage-related genes was up-regulated in tumor and peritoneal macrophages. The M2-related cytokine levels of IL-4 and IL-13 were increased in the serum of ApcMin/+;MMP12-/-mice. In vitro, bone marrow-derived M2 macrophages were obtained by treating bone marrow cells with IL-4 and IL-13, and these M2 macrophages secreted cytokines being changed. This finding reveals the crucial role of MMP12 in macrophage development and provides a new target for the control of macrophage polarization. Knocking out MMP12 causes intestinal M2 macrophage accumulation in tumor microenvironment, promoting the growth of intestinal tumors in ApcMin/+ mice.


Assuntos
Neoplasias Intestinais/imunologia , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Macrófagos/patologia , Metaloproteinase 12 da Matriz/fisiologia , Microambiente Tumoral/imunologia , Animais , Citocinas/metabolismo , Feminino , Neoplasias Intestinais/enzimologia , Neoplasias Intestinais/patologia , Macrófagos/enzimologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
17.
PLoS Pathog ; 16(4): e1008474, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32315358

RESUMO

Trypanosoma cruzi (T. cruzi) is the etiological agent of Chagas cardiomyopathy. In the present study, we investigated the role of extracellular vesicles (Ev) in shaping the macrophage (Mφ) response in progressive Chagas disease (CD). We purified T. cruzi Ev (TcEv) from axenic parasite cultures, and T. cruzi-induced Ev (TEv) from the supernatants of infected cells and plasma of acutely and chronically infected wild-type and Parp1-/- mice. Cultured (Raw 264.7) and bone-marrow Mφ responded to TcEV and TEv with a profound increase in the expression and release of TNF-α, IL-6, and IL-1ß cytokines. TEv produced by both immune (Mφ) and non-immune (muscle) cells were proinflammatory. Chemical inhibition or genetic deletion of PARP1 (a DNA repair enzyme) significantly depressed the TEv-induced transcriptional and translational activation of proinflammatory Mφ response. Oxidized DNA encapsulated by TEv was necessary for PARP1-dependent proinflammatory Mφ response. Inhibition studies suggested that DNA-sensing innate immune receptors (cGAS>>TLR9) synergized with PARP1 in signaling the NFκB activation, and inhibition of PARP1 and cGAS resulted in >80% inhibition of TEv-induced NFκB activity. Histochemical studies showed intense inflammatory infiltrate associated with profound increase in CD11b+CD68+TNF-α+ Mφ in the myocardium of CD wild-type mice. In comparison, chronically infected Parp1-/- mice exhibited low-to-moderate tissue inflammation, >80% decline in myocardial infiltration of TNF-α+ Mφ, and no change in immunoregulatory IL-10+ Mφ. We conclude that oxidized DNA released with TEv signal the PARP1-cGAS-NF-κB pathway of proinflammatory Mφ activation and worsens the chronic inflammatory pathology in CD. Small molecule antagonists of PARP1-cGAS signaling pathway would potentially be useful in reprogramming the Mφ activation and controlling the chronic inflammation in CD.


Assuntos
Doença de Chagas/metabolismo , Vesículas Extracelulares/metabolismo , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , NF-kappa B/metabolismo , Nucleotidiltransferases/metabolismo , Poli(ADP-Ribose) Polimerase-1/metabolismo , Animais , Cardiomiopatia Chagásica/imunologia , Cardiomiopatia Chagásica/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Interleucina-6/imunologia , Interleucina-6/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Knockout , NF-kappa B/imunologia , Nucleotidiltransferases/imunologia , Poli(ADP-Ribose) Polimerase-1/imunologia , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/imunologia , Trypanosoma cruzi/metabolismo , Trypanosoma cruzi/patogenicidade , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo
18.
Parasite Immunol ; 42(7): e12712, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32187690

RESUMO

The ability of Toxoplasma gondii to cause clinical disease in immune-competent and immune-deficient hosts coupled with its ease of use in vitro and availability of murine models has led to its use as a model organism to study how the immune system controls an intracellular infection. This article reviews the studies that established the role of the cytokine IFN-γ in the activation of macrophages to control T gondii and the events that lead to the mobilization and expansion of macrophage populations and their ability to limit parasite replication. Macrophages also have pro-inflammatory functions that promote protective NK and T-cell activities as well as regulatory properties that facilitate the resolution of inflammation. Nevertheless, while macrophages are important in determining the outcome of infection, T gondii has evolved mechanisms to subvert macrophage activation and can utilize their migratory activities to promote dissemination and these two properties underlie the ability of this parasite to persist and cause disease.


Assuntos
Interferon gama/imunologia , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Toxoplasma/imunologia , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Interações Hospedeiro-Parasita/imunologia , Evasão da Resposta Imune/fisiologia , Interferon gama/metabolismo , Células Matadoras Naturais/imunologia , Ativação Linfocitária/imunologia , Camundongos , Linfócitos T/imunologia
19.
Am J Physiol Endocrinol Metab ; 318(6): E1004-E1013, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32208002

RESUMO

Macrophage polarization contributes to obesity-induced insulin resistance. Glucose-regulated protein 94 (GRP94) is an endoplasmic reticulum (ER) chaperone specialized for folding and quality control of secreted and membrane proteins. To determine the role of GRP94 in macrophage polarization and insulin resistance, macrophage-specific GRP94 conditional knockout (KO) mice were challenged with a high-fat diet (HFD). Glucose tolerance, insulin sensitivity, and macrophage composition were compared with control mice. KO mice showed better glucose tolerance and increased insulin sensitivity. Adipose tissues from HFD-KO mice contained lower numbers of M1 macrophages, with lower expression of M1 macrophage markers, than wild-type (WT) mice. In vitro, WT adipocytes cocultured with KO macrophages retained insulin sensitivity, whereas those cultured with WT macrophages did not. In addition, compared with WT bone marrow-derived macrophages (BMDMs), BMDMs from GRP94 KO mice exhibited lower expression of M1 macrophage marker genes following stimulation with LPS or IFN-γ, and exhibited partially increased expression of M2 macrophage marker genes following stimulation with interleukin-4. These findings identify GRP94 as a novel regulator of M1 macrophage polarization and insulin resistance and inflammation.


Assuntos
Dieta Hiperlipídica , Resistência à Insulina/genética , Ativação de Macrófagos/genética , Macrófagos/imunologia , Glicoproteínas de Membrana/genética , Obesidade/imunologia , Células 3T3-L1 , Adipócitos/metabolismo , Animais , Técnicas de Cocultura , Citocinas/genética , Citocinas/imunologia , Teste de Tolerância a Glucose , Inflamação/genética , Inflamação/imunologia , Resistência à Insulina/imunologia , Interferon gama/farmacologia , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/imunologia , Macrófagos/efeitos dos fármacos , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Knockout , Obesidade/genética , Obesidade/metabolismo , RNA Mensageiro/metabolismo
20.
Pathog Dis ; 78(1)2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-32068828

RESUMO

Macrophages play an integral role in host defenses against intracellular bacterial pathogens. A remarkable plasticity allows for adaptation to the needs of the host to orchestrate versatile innate immune responses to a variety of microbial threats. Several bacterial pathogens have adapted to macrophage plasticity and modulate the classical (M1) or alternative (M2) activation bias towards a polarization state that increases fitness for intracellular survival. Here, we summarize the current understanding of the host macrophage and intracellular bacterial interface; highlighting the roles of M1/M2 polarization in host defense and the mechanisms employed by several important intracellular pathogens to modulate macrophage polarization to favor persistence or proliferation. Understanding macrophage polarization in the context of disease caused by different bacterial pathogens is important for the identification of targets for therapeutic intervention.


Assuntos
Infecções Bacterianas/imunologia , Infecções Bacterianas/microbiologia , Interações Hospedeiro-Patógeno/imunologia , Ativação de Macrófagos/imunologia , Macrófagos/microbiologia , Macrófagos/fisiologia , Animais , Infecções Bacterianas/metabolismo , Citocinas/metabolismo , Humanos , Imunidade Inata , Imunomodulação
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