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1.
Nat Commun ; 11(1): 4909, 2020 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-32999291

RESUMO

Effectively activating macrophages against cancer is promising but challenging. In particular, cancer cells express CD47, a 'don't eat me' signal that interacts with signal regulatory protein alpha (SIRPα) on macrophages to prevent phagocytosis. Also, cancer cells secrete stimulating factors, which polarize tumor-associated macrophages from an antitumor M1 phenotype to a tumorigenic M2 phenotype. Here, we report that hybrid cell membrane nanovesicles (known as hNVs) displaying SIRPα variants with significantly increased affinity to CD47 and containing M2-to-M1 repolarization signals can disable both mechanisms. The hNVs block CD47-SIRPα signaling axis while promoting M2-to-M1 repolarization within tumor microenvironment, significantly preventing both local recurrence and distant metastasis in malignant melanoma models. Furthermore, by loading a stimulator of interferon genes (STING) agonist, hNVs lead to potent tumor inhibition in a poorly immunogenic triple negative breast cancer model. hNVs are safe, stable, drug loadable, and suitable for genetic editing. These properties, combined with the capabilities inherited from source cells, make hNVs an attractive immunotherapy.


Assuntos
Micropartículas Derivadas de Células/imunologia , Imunoterapia/métodos , Macrófagos/imunologia , Melanoma/terapia , Recidiva Local de Neoplasia/prevenção & controle , Neoplasias de Mama Triplo Negativas/terapia , Animais , Antígeno CD47/metabolismo , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Melanoma/imunologia , Melanoma/secundário , Proteínas de Membrana/agonistas , Proteínas de Membrana/imunologia , Camundongos , Nanopartículas/administração & dosagem , Recidiva Local de Neoplasia/imunologia , Nucleotídeos Cíclicos/administração & dosagem , Receptores Imunológicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Evasão Tumoral/efeitos dos fármacos , Evasão Tumoral/imunologia , Microambiente Tumoral/imunologia
2.
J Environ Pathol Toxicol Oncol ; 39(3): 235-245, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32865915

RESUMO

Ulcerative colitis (UC) is an intractable ailment, in which may chronic inflammations/ulcerations may develop in the mucosal lining of the colon with multiple recurrences. Various drugs such as steroids, immunosuppressants, and antibiotics are extensively used to treat UC. The patients suffer from adverse effects of these advanced drugs. So, they need a harmless therapeutic agent from natural sources. The therapeutic D-carvone has an anti-inflammatory action against the investigational colon cancer models. Therefore, we analyzed the effect of D-carvone on dextran sulfate sodium (DSS) provoked colitis model in mice as follows: Group I: noncolitis healthy control mice; Group II: ulcerative colitis mice models; Group III: D-carvone (40 mg/kg) + ulcerative colitis models; Group IV: sulfasalazine (50 mg/kg) + ulcerative colitis models. On the 8th day, the experimental study was terminated and serum samples and colon tissues were processed for further analysis. The effect of D-carvone at different concentration was studied on the LPS challenged RAW 264.7 cell lines. The D-carvone (40 mg/kg) treatment maintained the colon length and decreased disease activity index (DAI) score in UC animals. The increased antioxidant enzymes status and decreased oxidative stress and pro-inflammatory markers were noted in the D-carvone (40 mg/ kg) + UC mice. Histopathological study of colon tissue of D-carvone (40 mg/kg) treated UC mice displayed less mucosal damage and improved crypt integrity and goblet cells compared with DSS only provoked mice. The im-munohistochemical expression of iNOS and COX-2 was drastically diminished in the D-carvone treated UC mice. D-carvone (40 mg/kg) treatment appreciably diminished the LPS provoked NO production and pro-inflammatory modulators in the RAW 264.7 macrophage cell lines. These findings proved that D-carvone has a potential therapeutic effect to prevent LPS induced inflammation in in vitro cells and chemically induced ulcerative colitis in vivo models.


Assuntos
Anti-Inflamatórios/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Monoterpenos Cicloexânicos/uso terapêutico , Ciclo-Oxigenase 2/metabolismo , Macrófagos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fator de Necrose Tumoral alfa/sangue , Animais , Anti-Inflamatórios/administração & dosagem , Sobrevivência Celular/efeitos dos fármacos , Colite Ulcerativa/imunologia , Colite Ulcerativa/patologia , Colo/efeitos dos fármacos , Colo/imunologia , Colo/patologia , Monoterpenos Cicloexânicos/administração & dosagem , Sulfato de Dextrana , Modelos Animais de Doenças , Lipopolissacarídeos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7
3.
Mem Inst Oswaldo Cruz ; 115: e200140, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32965329

RESUMO

Although Leishmania infantum is well-known as the aethiological agent of visceral leishmaniasis (VL), in some Central American countries it may cause atypical non-ulcerated cutaneous leishmaniasis (NUCL). However, the mechanisms favoring its establishment in the skin are still unknown. Lipophosphoglycan (LPG) is the major Leishmania multivirulence factor involved in parasite-host interaction. In the case of viscerotropic L. infantum, it causes an immunosuppression during the interaction with macrophages. Here, we investigated the biochemical and functional roles of LPGs from four dermotropic L. infantum strains from Honduras during in vitro interaction with murine macrophages. LPGs were extracted, purified and their repeat units analysed. They did not have side chains consisting of Gal(ß1,4)Man(α1)-PO4 common to all LPGs. Peritoneal macrophages from BALB/c and C57BL/6 were exposed to LPG for nitric oxide (NO) and cytokine (TNF-α and, IL-6) production. LPGs from dermotropic strains from Honduras triggered higher NO and cytokine levels compared to those from viscerotropic strains. In conclusion, LPGs from dermotropic strains are devoid of side-chains and exhibit high pro-inflammatory activity.


Assuntos
Glicoesfingolipídeos , Leishmania infantum/fisiologia , Animais , América Central , Honduras , Humanos , Macrófagos/imunologia , Masculino , Camundongos
4.
Vaccine ; 38(42): 6487-6499, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32907757

RESUMO

The many carbohydrate chains on Covid-19 coronavirus SARS-CoV-2 and its S-protein form a glycan-shield that masks antigenic peptides and decreases uptake of inactivated virus or S-protein vaccines by APC. Studies on inactivated influenza virus and recombinant gp120 of HIV vaccines indicate that glycoengineering of glycan-shields to present α-gal epitopes (Galα1-3Galß1-4GlcNAc-R) enables harnessing of the natural anti-Gal antibody for amplifying vaccine efficacy, as evaluated in mice producing anti-Gal. The α-gal epitope is the ligand for the natural anti-Gal antibody which constitutes ~1% of immunoglobulins in humans. Upon administration of vaccines presenting α-gal epitopes, anti-Gal binds to these epitopes at the vaccination site and forms immune complexes with the vaccines. These immune complexes are targeted for extensive uptake by APC as a result of binding of the Fc portion of immunocomplexed anti-Gal to Fc receptors on APC. This anti-Gal mediated effective uptake of vaccines by APC results in 10-200-fold higher anti-viral immune response and in 8-fold higher survival rate following challenge with a lethal dose of live influenza virus, than same vaccines lacking α-gal epitopes. It is suggested that glycoengineering of carbohydrate chains on the glycan-shield of inactivated SARS-CoV-2 or on S-protein vaccines, for presenting α-gal epitopes, will have similar amplifying effects on vaccine efficacy. α-Gal epitope synthesis on coronavirus vaccines can be achieved with recombinant α1,3galactosyltransferase, replication of the virus in cells with high α1,3galactosyltransferase activity as a result of stable transfection of cells with several copies of the α1,3galactosyltransferase gene (GGTA1), or by transduction of host cells with replication defective adenovirus containing this gene. In addition, recombinant S-protein presenting multiple α-gal epitopes on the glycan-shield may be produced in glycoengineered yeast or bacteria expression systems containing the corresponding glycosyltransferases. Prospective Covid-19 vaccines presenting α-gal epitopes may provide better protection than vaccines lacking this epitope because of increased uptake by APC.


Assuntos
Antígenos Virais/genética , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Glicoproteína da Espícula de Coronavírus/genética , Trissacarídeos/imunologia , Vacinas Virais/imunologia , Animais , Anticorpos Antivirais/biossíntese , Antígenos Virais/imunologia , Antígenos Virais/metabolismo , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/genética , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/virologia , Engenharia Genética , Proteína do Núcleo p24 do HIV/química , Proteína do Núcleo p24 do HIV/genética , Proteína do Núcleo p24 do HIV/imunologia , Proteína gp120 do Envelope de HIV/química , Proteína gp120 do Envelope de HIV/genética , Proteína gp120 do Envelope de HIV/imunologia , Humanos , Imunogenicidade da Vacina , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/virologia , Camundongos , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Trissacarídeos/química , Vacinas Virais/administração & dosagem , Vacinas Virais/biossíntese , Vacinas Virais/genética
5.
J Toxicol Sci ; 45(9): 569-579, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32879256

RESUMO

Indoxyl, a derivative of indole originating from tryptophan, may undergo phase-II sulfate-conjugation pathway, thereby forming indoxyl sulfate (IS) in vivo. We previously reported that IS, a well-known uremic toxin, can increase the intracellular oxidation level and decrease the phagocytic activity in a differentiated HL-60 human macrophage cell model. Using the same cell model, the current study aimed to investigate whether indole and indoxyl (the metabolic precursors of indoxyl and IS, respectively) may cause macrophage immune dysfunction. Results obtained indicated that intracellular oxidation level and cytotoxicity markedly increased upon treatment with indole and indoxyl, in comparison with IS. Incubation of the cells with indole and indoxyl also resulted in attenuated phagocytic activity. Human serum albumin (HSA)-binding assay confirmed that tryptophan and IS, but not indole and indoxyl, could selectively bind to the site II in HSA. Collectively, the results indicated that indole and indoxyl may strongly down-regulate the phagocytic immune function of macrophages, whereas IS, formed upon sulfate conjugation of indoxyl, may exhibit enhanced HSA-binding capability, thereby reducing the adverse effects of indoxyl.


Assuntos
Indóis/efeitos adversos , Macrófagos/imunologia , Macrófagos/metabolismo , Oxirredução/efeitos dos fármacos , Fagocitose/efeitos dos fármacos , Fagocitose/imunologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Células HL-60 , Humanos , Indicã/metabolismo , Macrófagos/efeitos dos fármacos , Ligação Proteica , Albumina Sérica/metabolismo , Triptofano/metabolismo
6.
DNA Cell Biol ; 39(10): 1838-1849, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32876480

RESUMO

The breast cancer gene 1 (BRCA1) is a tumor suppressor, and mutations or epigenetic inactivation will increase the risk of breast cancer oncogenesis. The current research aimed to explore the relationship between BRCA1 expression, prognosis, and tumor immunity in hepatocellular carcinoma (HCC). In this study, BRCA1 expression was analyzed via multiple online databases and its association with clinical characteristics, prognosis and genetic alterations was identified using the original The Cancer Genome Atlas-liver hepatocellular carcinoma cohorts. DNA methylation sites and their prognostic values were analyzed using MethSurv. The correlations between BRCA1 and immune infiltration were investigated via Tumor Immune Estimation Resource. As results, BRCA1 was significantly upregulated in tumor tissues in multiple HCC cohorts. Besides, high BRCA1 expression was correlated with race, advanced T stage, clinical stage, poor tumor grade, MSI status, and worse prognosis. Notably, BRCA1 expression was positively correlated with infiltration levels of B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells. The current findings imply that BRCA1 is associated with prognosis and immune infiltration, laying foundations for in-depth research on the role of BRCA1 in HCC.


Assuntos
Proteína BRCA1/genética , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Proteína BRCA1/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Movimento Celular , Metilação de DNA , Células Dendríticas/imunologia , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Linfócitos/imunologia , Macrófagos/imunologia
7.
Theranostics ; 10(21): 9591-9600, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32863947

RESUMO

Cytokine storms, defined by the dysregulated and excessive production of multiple pro-inflammatory cytokines, are closely associated with the pathology and mortality of several infectious diseases, including coronavirus disease 2019 (COVID-19). Effective therapies are urgently needed to block the development of cytokine storms to improve patient outcomes, but approaches that target individual cytokines may have limited effect due to the number of cytokines involved in this process. Dysfunctional macrophages appear to play an essential role in cytokine storm development, and therapeutic interventions that target these cells may be a more feasible approach than targeting specific cytokines. Nanomedicine-based therapeutics that target macrophages have recently been shown to reduce cytokine production in animal models of diseases that are associated with excessive proinflammatory responses. In this mini-review, we summarize important studies and discuss how macrophage-targeted nanomedicines can be employed to attenuate cytokine storms and their associated pathological effects to improve outcomes in patients with severe infections or other conditions associated with excessive pro-inflammatory responses. We also discuss engineering approaches that can improve nanocarriers targeting efficiency to macrophages, and key issues should be considered before initiating such studies.


Assuntos
Anti-Infecciosos/uso terapêutico , Citocinas/imunologia , Infecções/imunologia , Macrófagos/imunologia , Nanomedicina/tendências , Animais , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Humanos , Infecções/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia
8.
Nat Commun ; 11(1): 4498, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32908142

RESUMO

The androgen receptor (AR) is the master regulator of prostate cancer (PCa) development, and inhibition of AR signalling is the most effective PCa treatment. AR is expressed in PCa cells and also in the PCa-associated stroma, including infiltrating macrophages. Macrophages have a decisive function in PCa initiation and progression, but the role of AR in macrophages remains largely unexplored. Here, we show that AR signalling in the macrophage-like THP-1 cell line supports PCa cell line migration and invasion in culture via increased Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) signalling and expression of its downstream cytokines. Moreover, AR signalling in THP-1 and monocyte-derived macrophages upregulates IL-10 and markers of tissue residency. In conclusion, our data suggest that AR signalling in macrophages may support PCa invasiveness, and blocking this process may constitute one mechanism of anti-androgen therapy.


Assuntos
Macrófagos/metabolismo , Neoplasias da Próstata/patologia , Receptores Androgênicos/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Idoso , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/uso terapêutico , Anilidas/farmacologia , Anilidas/uso terapêutico , Biópsia , Buffy Coat/citologia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Quimioterapia Adjuvante , Técnicas de Cocultura , Intervalo Livre de Doença , Humanos , Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Invasividade Neoplásica/imunologia , Invasividade Neoplásica/prevenção & controle , Nitrilos/farmacologia , Nitrilos/uso terapêutico , Intervalo Livre de Progressão , Próstata/patologia , Próstata/cirurgia , Prostatectomia , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/terapia , Procedimentos Cirúrgicos Robóticos , Transdução de Sinais/imunologia , Análise de Célula Única , Células THP-1 , Compostos de Tosil/farmacologia , Compostos de Tosil/uso terapêutico
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.
Front Immunol ; 11: 2056, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32973814

RESUMO

The pandemic of coronavirus disease 2019 (COVID-19), a disease which causes severe lung injury and multiple organ damage, presents an urgent need for new drugs. The case severity and fatality of COVID-19 are associated with excessive inflammation, namely, a cytokine storm. Metformin, a widely used drug to treat type 2 diabetes (T2D) mellitus and metabolic syndrome, has immunomodulatory activity that reduces the production of proinflammatory cytokines using macrophages and causes the formation of neutrophil extracellular traps (NETs). Metformin also inhibits the cytokine production of pathogenic Th1 and Th17 cells. Importantly, treatment with metformin alleviates various lung injuries in preclinical animal models. In addition, a recent proteomic study revealed that metformin has the potential to directly inhibit SARS-CoV-2 infection. Furthermore, retrospective clinical studies have revealed that metformin treatment reduces the mortality of T2D with COVID-19. Therefore, metformin has the potential to be repurposed to treat patients with COVID-19 at risk of developing severe illness. This review summarizes the immune pathogenesis of SARS-CoV-2 and addresses the effects of metformin on inhibiting cytokine storms and preventing SARS-CoV-2 infection, as well as its side effects.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Lesão Pulmonar/tratamento farmacológico , Metformina/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Animais , Antivirais/efeitos adversos , Antivirais/farmacologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Citocinas/antagonistas & inibidores , Reposicionamento de Medicamentos/métodos , Armadilhas Extracelulares/efeitos dos fármacos , Humanos , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/farmacologia , Inflamação/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Metformina/efeitos adversos , Metformina/farmacologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia
11.
Anim Sci J ; 91(1): e13436, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32761774

RESUMO

Probiotics are growing alternatives to antibiotics, and can contribute to the prevention and treatment of diseases and enhance livestock production. Lactobacillus (L.) ingluviei is a novel probiotic species with growth-enhancement effects; however, this species remains poorly understood, and there have been (to our knowledge) no studies focusing on its immunological effects. Here, we isolated L. ingluviei C37 (LIC37) from chicken and evaluated the bacterium's immunomodulatory properties to explore its probiotic potential. Real-time quantitative PCR and ELISA showed that in vitro exposure of inflammation-stimulated mouse peritoneal macrophages to heat-killed LIC37 led to decreases in tumor necrosis factor-α and interleukin (IL)-6 levels and an increase in IL-10. These findings suggested that LIC37 exerts anti-inflammatory effects by modulating cytokine profiles. This species may be an attractive probiotic bacterial strain for use in animal production.


Assuntos
Galinhas/microbiologia , Inflamação/prevenção & controle , Lactobacillus , Lipopolissacarídeos , Macrófagos/imunologia , Animais , Imunomodulação , Camundongos
12.
Nat Commun ; 11(1): 3924, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32764665

RESUMO

Several studies show that the immunosuppressive drugs targeting the interleukin-6 (IL-6) receptor, including tocilizumab, ameliorate lethal inflammatory responses in COVID-19 patients infected with SARS-CoV-2. Here, by employing single-cell analysis of the immune cell composition of two severe-stage COVID-19 patients prior to and following tocilizumab-induced remission, we identify a monocyte subpopulation that contributes to the inflammatory cytokine storms. Furthermore, although tocilizumab treatment attenuates the inflammation, immune cells, including plasma B cells and CD8+ T cells, still exhibit robust humoral and cellular antiviral immune responses. Thus, in addition to providing a high-dimensional dataset on the immune cell distribution at multiple stages of the COVID-19, our work also provides insights into the therapeutic effects of tocilizumab, and identifies potential target cell populations for treating COVID-19-related cytokine storms.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Citocinas/imunologia , Monócitos/imunologia , Pneumonia Viral/imunologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Biologia Computacional , Infecções por Coronavirus/sangue , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Citocinas/sangue , Humanos , Inflamação/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Receptores de Interleucina-6/imunologia , Análise de Célula Única/métodos
13.
Anim Sci J ; 91(1): e13439, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32779289

RESUMO

Lactobacillus rhamnosus GG (LGG) is increasingly applied in functional food products and acts as a probiotic model in nutritious and clinical studies. Increasing evidences have revealed the immune modulation of LGG on macrophages. The aim of this study is to investigate the effect of LGG on macrophage polarization of murine bone marrow-derived macrophages (BMDMs). BMDMs were treated with 108 colony-forming units (CFU)/ml LGG for 1.5, 3, and 6 hr. Results showed that LGG obviously upregulated the mRNA expression of M1-associated cytokines (p < .05), including interleukin-1 beta (IL-1ß), IL-6, tumor necrosis factor-alpha (TNF-α), and inducible nitric oxide synthase (iNOS), whereas had no effect on the expression of M2-associated markers (p > .05), including arginase 1 (Arg1), mannose receptor, and chitinase-like protein 3 (YM1). Furthermore, LGG markedly increased the expression of pro-inflammatory cytokines (IL-12p40, cyclooxygenase-2 [COX-2], and interferon-γ [IFN-γ]) (p < .05) and anti-inflammatory cytokines (IL-10, IL-4, and transforming growth factor-ß [TGF-ß]) (p < .05). In addition, we also found that TLR2/MyD88/MAPK signaling pathway was required for LGG-induced M1 macrophage polarization and M1-related cytokines expression. Together, these findings demonstrate that probiotic LGG facilitates M1 polarization of BMDMs, suggesting that LGG may have an immunotherapeutic potential in regulating the host defense against pathogen invasion.


Assuntos
Células da Medula Óssea , Lactobacillus rhamnosus/química , Sistema de Sinalização das MAP Quinases/imunologia , Macrófagos/imunologia , Fator 88 de Diferenciação Mieloide/imunologia , Receptor 2 Toll-Like/imunologia , Animais , Camundongos
14.
Medicina (Kaunas) ; 56(9)2020 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-32825011

RESUMO

It is proposed that the bioactive lipid, arachidonic acid (AA, 20:4 n-6), can inactivate severe acute respiratory syndrome(SARS-CoV-2), facilitate M1 and M2 macrophage generation, suppress inflammation, prevent vascular endothelial cell damage, and regulate inflammation resolution processes based on the timely formation of prostaglandin E2 (PGE2) and lipoxin A4 (LXA4) based on the context. Thus, AA may be useful both to prevent and manage coronavrus disease-2019(COVID-19).


Assuntos
Ácido Araquidônico/uso terapêutico , Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Citocinas/imunologia , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ácido Eicosapentaenoico/uso terapêutico , Humanos , Inflamação , Macrófagos/imunologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Inativação de Vírus
15.
PLoS One ; 15(8): e0236212, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32797100

RESUMO

Although an impact of processing on immunogenicity of food proteins has clearly been demonstrated, the underlying mechanisms are still unclear. We applied 3 different processing methods: wet heating (60 °C) and low- or high-temperature (50 °C or 130 °C, respectively) dry-heating in absence or presence of reducing sugars, to ß-lactoglobulin (BLG), lysozyme and thyroglobulin, which represent dietary proteins with different pI or molecular weight. Uptake of the soluble fraction of the samples was tested in two types of, genetically homogeneous, antigen-presenting cells (macrophages and dendritic cells derived from THP-1 monocytes). This revealed a strong correlation between the uptake of the different protein samples by macrophages and dendritic cells, and confirmed the key role of hydrophobicity, over aggregation, in determining the uptake. Several uptake routes were shown to contribute to the uptake of BLG by macrophages. However, cytokine responses following exposure of macrophages to BLG samples were not related to the levels of uptake. Together, our results demonstrate that heat-treatment-induced increased hydrophobicity is the prime driving factor in uptake, but not in cytokine production, by THP-1 macrophages.


Assuntos
Citocinas/metabolismo , Células Dendríticas/imunologia , Proteínas na Dieta/imunologia , Macrófagos/imunologia , Receptores de Superfície Celular/metabolismo , Culinária , Células Dendríticas/metabolismo , Proteínas na Dieta/química , Proteínas na Dieta/metabolismo , Temperatura Alta , Humanos , Interações Hidrofóbicas e Hidrofílicas , Macrófagos/metabolismo , Peso Molecular , Células THP-1
16.
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
17.
Nat Commun ; 11(1): 4035, 2020 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-32788578

RESUMO

Polyphosphates are linear polymers and ubiquitous metabolites. Bacterial polyphosphates are long chains of hundreds of phosphate units. Here, we report that mouse survival of peritoneal Escherichia coli sepsis is compromised by long-chain polyphosphates, and improves with bacterial polyphosphatekinase deficiency or neutralization using recombinant exopolyphosphatase. Polyphosphate activities are chain-length dependent, impair pathogen clearance, antagonize phagocyte recruitment, diminish phagocytosis and decrease production of iNOS and cytokines. Macrophages bind and internalize polyphosphates, in which their effects are independent of P2Y1 and RAGE receptors. The M1 polarization driven by E. coli derived LPS is misdirected by polyphosphates in favor of an M2 resembling phenotype. Long-chain polyphosphates modulate the expression of more than 1800 LPS/TLR4-regulated genes in macrophages. This interference includes suppression of hundreds of type I interferon-regulated genes due to lower interferon production and responsiveness, blunted STAT1 phosphorylation and reduced MHCII expression. In conclusion, prokaryotic polyphosphates disturb multiple macrophage functions for evading host immunity.


Assuntos
Infecções por Escherichia coli/imunologia , Infecções por Escherichia coli/microbiologia , Escherichia coli/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata , Polifosfatos/metabolismo , Animais , Apresentação do Antígeno/imunologia , Polaridade Celular , Antígenos de Histocompatibilidade Classe II/metabolismo , Interferon Tipo I/metabolismo , Lipopolissacarídeos , Macrófagos/imunologia , Macrófagos/microbiologia , Camundongos Endogâmicos C57BL , Células Mieloides/imunologia , Fenótipo , Sepse/imunologia , Análise de Sobrevida , Transcriptoma/genética
18.
Curr Med Sci ; 40(4): 618-624, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32767259

RESUMO

The COVID-19 pandemic caused by SARS-CoV2 is characterized by a remarkable variation in clinical severity ranging from a mild illness to a fatal multi-organ disease. Understanding the dysregulated human immune responses in the fatal subjects is critical for management of COVID-19 patients and the pandemic. In this study, we examined the immune cell compositions in the lung tissues and hilar lymph nodes using immunohistochemistry on 6 deceased COVID-19 patients and 4 focal organizing pneumonia (FOP) patients who underwent lung surgery and served as controls. We found a dominant presence of macrophages and a general deficiency of T cells and B cells in the lung tissues from deceased COVID-19 patients. In contrast to the FOP patients, Tfh cells and germinal center formation were largely absent in the draining hilar lymph nodes in the deceased COVID-19 patients. This was correlated with reduced IgM and IgG levels compared to convalescent COVID-19 patients. In summary, our data highlight a defect of germinal center structure in deceased COVID-19 patients leading to an impaired humoral immunity. Understanding the mechanisms of this deficiency will be one of the key points for the management of this epidemic.


Assuntos
Betacoronavirus , Infecções por Coronavirus/imunologia , Centro Germinativo/imunologia , Pneumonia Viral/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Imunidade Adaptativa , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , China/epidemiologia , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/patologia , Evolução Fatal , Feminino , Centro Germinativo/patologia , Humanos , Linfopenia/imunologia , Linfopenia/mortalidade , Linfopenia/patologia , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/mortalidade , Pneumonia Viral/patologia , Linfócitos T Auxiliares-Indutores/patologia
19.
PLoS Pathog ; 16(8): e1008695, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32750090

RESUMO

The NLRP3 inflammasome has emerged as a central immune regulator that senses virulence factors expressed by microbial pathogens for triggering inflammation. Inflammation can be harmful and therefore this response must be tightly controlled. The mechanisms by which immune cells, such as macrophages, discriminate benign from pathogenic microbes to control the NLRP3 inflammasome remain poorly defined. Here we used live cell imaging coupled with a compendium of diverse clinical isolates to define how macrophages respond and activate NLRP3 when faced with the human yeast commensal and pathogen Candida albicans. We show that metabolic competition by C. albicans, rather than virulence traits such as hyphal formation, activates NLRP3 in macrophages. Inflammasome activation is triggered by glucose starvation in macrophages, which occurs when fungal load increases sufficiently to outcompete macrophages for glucose. Consistently, reducing Candida's ability to compete for glucose and increasing glucose availability for macrophages tames inflammatory responses. We define the mechanistic requirements for glucose starvation-dependent inflammasome activation by Candida and show that it leads to inflammatory cytokine production, but it does not trigger pyroptotic macrophage death. Pyroptosis occurs only with some Candida isolates and only under specific experimental conditions, whereas inflammasome activation by glucose starvation is broadly relevant. In conclusion, macrophages use their metabolic status, specifically glucose metabolism, to sense fungal metabolic activity and activate NLRP3 when microbial load increases. Therefore, a major consequence of Candida-induced glucose starvation in macrophages is activation of inflammatory responses, with implications for understanding how metabolism modulates inflammation in fungal infections.


Assuntos
Candida albicans/imunologia , Candidíase/imunologia , Glucose/deficiência , Interações Hospedeiro-Patógeno/imunologia , Inflamação/imunologia , Macrófagos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , Animais , Células 3T3 BALB , Candida albicans/metabolismo , Candidíase/metabolismo , Candidíase/microbiologia , Caspase 1/fisiologia , Caspases Iniciadoras/fisiologia , Feminino , Hifas , Inflamação/metabolismo , Inflamação/microbiologia , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas de Ligação a Fosfato/fisiologia , Piroptose
20.
PLoS Pathog ; 16(8): e1008414, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32776983

RESUMO

The host innate immune system has developed elegant processes for the detection and clearance of invasive fungal pathogens. These strategies may also aid in the spread of pathogens in vivo, although technical limitations have previously hindered our ability to view the host innate immune and endothelial cells to probe their roles in spreading disease. Here, we have leveraged zebrafish larvae as a model to view the interactions of these host processes with the fungal pathogen Candida albicans in vivo. We examined three potential host-mediated mechanisms of fungal spread: movement inside phagocytes in a "Trojan Horse" mechanism, inflammation-assisted spread, and endothelial barrier passage. Utilizing both chemical and genetic tools, we systematically tested the loss of neutrophils and macrophages and the loss of blood flow on yeast cell spread. Both neutrophils and macrophages respond to yeast-locked and wild type C. albicans in our model and time-lapse imaging revealed that macrophages can support yeast spread in a "Trojan Horse" mechanism. Surprisingly, loss of immune cells or inflammation does not alter dissemination dynamics. On the other hand, when blood flow is blocked, yeast can cross into blood vessels but they are limited in how far they travel. Blockade of both phagocytes and circulation reduces rates of dissemination and significantly limits the distance of fungal spread from the infection site. Together, this data suggests a redundant two-step process whereby (1) yeast cross the endothelium inside phagocytes or via direct uptake, and then (2) they utilize blood flow or phagocytes to travel to distant sites.


Assuntos
Candida albicans/imunologia , Candidíase/imunologia , Células Endoteliais/imunologia , Interações Hospedeiro-Patógeno/imunologia , Neutrófilos/imunologia , Fagócitos/imunologia , Peixe-Zebra/microbiologia , Animais , Candidíase/microbiologia , Larva , Macrófagos/imunologia , Macrófagos/microbiologia , Neutrófilos/microbiologia , Fagócitos/microbiologia
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