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1.
PLoS Comput Biol ; 15(7): e1007172, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31365522

RESUMO

In an inflammatory setting, macrophages can be polarized to an inflammatory M1 phenotype or to an anti-inflammatory M2 phenotype, as well as existing on a spectrum between these two extremes. Dysfunction of this phenotypic switch can result in a population imbalance that leads to chronic wounds or disease due to unresolved inflammation. Therapeutic interventions that target macrophages have therefore been proposed and implemented in diseases that feature chronic inflammation such as diabetes mellitus and atherosclerosis. We have developed a model for the sequential influx of immune cells in the peritoneal cavity in response to a bacterial stimulus that includes macrophage polarization, with the simplifying assumption that macrophages can be classified as M1 or M2. With this model, we were able to reproduce the expected timing of sequential influx of immune cells and mediators in a general inflammatory setting. We then fit this model to in vivo experimental data obtained from a mouse peritonitis model of inflammation, which is widely used to evaluate endogenous processes in response to an inflammatory stimulus. Model robustness is explored with local structural and practical identifiability of the proposed model a posteriori. Additionally, we perform sensitivity analysis that identifies the population of apoptotic neutrophils as a key driver of the inflammatory process. Finally, we simulate a selection of proposed therapies including points of intervention in the case of delayed neutrophil apoptosis, which our model predicts will result in a sustained inflammatory response. Our model can therefore provide hypothesis testing for therapeutic interventions that target macrophage phenotype and predict outcomes to be validated by subsequent experimentation.


Assuntos
Inflamação/imunologia , Macrófagos/imunologia , Modelos Imunológicos , Animais , Apoptose/imunologia , Biologia Computacional , Simulação por Computador , Modelos Animais de Doenças , Humanos , Mediadores da Inflamação/imunologia , Ativação de Macrófagos , Macrófagos/classificação , Macrófagos Peritoneais/classificação , Macrófagos Peritoneais/imunologia , Camundongos , Neutrófilos/citologia , Neutrófilos/imunologia , Fenótipo
2.
Braz. J. Pharm. Sci. (Online) ; 55: e17561, 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1039065

RESUMO

Obesity is a chronic inflammatory disease that affects millions of people worldwide. Most studies observe the effects of a high-fat diet (HFD) in 10-12 weeks. This work investigated the effects induced by a HFD administered for 6 weeks on the nutritional status of mice and some aspects of the inflammatory response in mouse peritoneal macrophages. Male Swiss Webster mice, 2-3 months of age, were fed a control diet or HFD for 6 weeks. After this period, the mice were euthanized, and peritoneal macrophages were collected for immunoassays and assessment of biochemical parameters. A HFD was associated with increased cholesterol, insulin resistance, C-reactive protein (CRP), leptin, and serum resistin levels. Lipopolysaccharide (LPS)- stimulated adipocyte cultures of animals subjected to a HFD showed increased production of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6). However, peritoneal macrophages of the HFD group showed no changes in the levels of these cytokines. LPS-stimulated peritoneal macrophages from HFD-treated animals showed a reduction in mRNA expression of TNF-α and IL-6, as well as a decrease in expression of the transcription factor nuclear factor-kappa B (NF-kB). In conclusion, HFD treatment for 6 weeks induces similar signs to metabolic syndrome and decreases the capacity of peritoneal macrophages to develop an appropriate inflammatory response to a bacterial component


Assuntos
Animais , Masculino , Camundongos , Macrófagos Peritoneais/classificação , Dieta Hiperlipídica/efeitos adversos , NF-kappa B/farmacocinética , Síndrome Metabólica
3.
Int Immunopharmacol ; 65: 44-49, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30273916

RESUMO

Exposure to an enriched environment (EE) affects not only brain functions but also immune responses upon viral or bacterial infections. In this study, we examined changes in the phagocytic response and chemokine production of resident peritoneal macrophages after mice had been housed under EE conditions for 6 or 8 weeks, and then explored the possibility that EE could cause a change in the macrophage phenotype by means of flow cytometry as well as quantitative RT-PCR. The percentages of EE macrophages phagocytosing S. aureus and apoptotic neutrophils were significantly larger than those of standard environment (SE) macrophages. After coculturing with S. aureus, EE macrophages tended to produce greater amounts of chemokines such as MIP-2, KC and MCP-1 than SE ones, although the increases for MIP-2 and KC were not statistically significant. As compared with SE macrophages, EE macrophages included more CD40-positive cells (M1 marker), and expressed more mRNAs of IL-6 (M1 marker) and IRF4 (M2 marker), and less mRNA of CD38 (M1 marker), suggesting either the possibility that EE macrophages are a mixed population of M1 and M2 macrophages or the possibility that they are a unique population with a mixed M1 and M2 macrophage phenotype.


Assuntos
Abrigo para Animais , Macrófagos Peritoneais , Animais , Biomarcadores , Quimiocinas/genética , Quimiocinas/metabolismo , Técnicas de Cocultura , Regulação da Expressão Gênica , Macrófagos Peritoneais/classificação , Macrófagos Peritoneais/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos , Fagocitose , Fenótipo , Staphylococcus aureus
4.
J Virol ; 92(10)2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29491152

RESUMO

We found previously that altering macrophage polarization toward M2 responses by injection of colony-stimulating factor 1 (CSF-1) was more effective in reducing both primary and latent infections in mice ocularly infected with herpes simplex virus 1 (HSV-1) than M1 polarization by gamma interferon (IFN-γ) injection. Cytokines can coordinately regulate macrophage and T helper (TH) responses, with interleukin-4 (IL-4) inducing type 2 TH (TH2) as well as M2 responses and IFN-γ inducing TH1 as well as M1 responses. We have now differentiated the contributions of these immune compartments to protection against latency reactivation and corneal scarring by comparing the effects of infection with recombinant HSV-1 in which the latency-associated transcript (LAT) gene was replaced with either the IL-4 (HSV-IL-4) or IFN-γ (HSV-IFN-γ) gene using infection with the parental (LAT-negative) virus as a control. Analysis of peritoneal macrophages in vitro established that the replacement of LAT with the IL-4 or IFN-γ gene did not affect virus infectivity and promoted polarization appropriately. Protection against corneal scarring was significantly higher in mice ocularly infected with HSV-IL-4 than in those infected with HSV-IFN-γ or parental virus. Levels of primary virus replication in the eyes and trigeminal ganglia (TG) were similar in the three groups of mice, but the numbers of gC+ cells were lower on day 5 postinfection in the eyes of HSV-IL-4-infected mice than in those infected with HSV-IFN-γ or parental virus. Latency and explant reactivation were lower in both HSV-IL-4- and HSV-IFN-γ-infected mice than in those infected with parental virus, with the lowest level of latency being associated with HSV-IL-4 infection. Higher latency correlated with higher levels of CD8, PD-1, and IFN-γ mRNA, while reduced latency and T-cell exhaustion correlated with lower gC+ expression in the TG. Depletion of macrophages increased the levels of latency in all ocularly infected mice compared with their undepleted counterparts, with macrophage depletion increasing latency in the HSV-IL-4 group greater than 3,000-fold. Our results suggest that shifting the innate macrophage immune responses toward M2, rather than M1, responses in HSV-1 infection would improve protection against establishment of latency, reactivation, and eye disease.IMPORTANCE Ocular HSV-1 infections are among the most frequent serious viral eye infections in the United States and a major cause of virus-induced blindness. As establishment of a latent infection in the trigeminal ganglia results in recurrent infection and is associated with corneal scarring, prevention of latency reactivation is a major therapeutic goal. It is well established that absence of latency-associated transcripts (LATs) reduces latency reactivation. Here we demonstrate that recombinant HSV-1 expressing IL-4 (an inducer of TH2/M2 responses) or IFN-γ (an inducer of TH1/M1 responses) in place of LAT further reduced latency, with HSV-IL-4 showing the highest overall protective efficacy. In naive mice, this higher protective efficacy was mediated by innate rather than adaptive immune responses. Although both M1 and M2 macrophage responses were protective, shifting macrophages toward an M2 response through expression of IL-4 was more effective in curtailing ocular HSV-1 latency reactivation.


Assuntos
Herpes Simples/imunologia , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 1/fisiologia , Interleucina-4/imunologia , Macrófagos Peritoneais/imunologia , Células Th2/imunologia , Ativação Viral/imunologia , Animais , Células Cultivadas , Lesões da Córnea/imunologia , Lesões da Córnea/prevenção & controle , Lesões da Córnea/virologia , Olho/imunologia , Olho/virologia , Oftalmopatias/virologia , Infecções Oculares/imunologia , Infecções Oculares/virologia , Feminino , Herpes Simples/virologia , Interferon gama/genética , Interleucina-4/biossíntese , Interleucina-4/genética , Macrófagos Peritoneais/classificação , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Coelhos , Gânglio Trigeminal/imunologia , Gânglio Trigeminal/virologia , Latência Viral/fisiologia , Replicação Viral/imunologia
5.
Oncogene ; 35(15): 1996-2002, 2016 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-26119930

RESUMO

Germline BAP1 mutations predispose to several cancers, in particular malignant mesothelioma. Mesothelioma is an aggressive malignancy generally associated with professional exposure to asbestos. However, to date, we found that none of the mesothelioma patients carrying germline BAP1 mutations were professionally exposed to asbestos. We hypothesized that germline BAP1 mutations might influence the asbestos-induced inflammatory response that is linked to asbestos carcinogenesis, thereby increasing the risk of developing mesothelioma after minimal exposure. Using a BAP1(+/-) mouse model, we found that, compared with their wild-type littermates, BAP1(+/-) mice exposed to low-dose asbestos fibers showed significant alterations of the peritoneal inflammatory response, including significantly higher levels of pro-tumorigenic alternatively polarized M2 macrophages, and lower levels of several chemokines and cytokines. Consistent with these data, BAP1(+/-) mice had a significantly higher incidence of mesothelioma after exposure to very low doses of asbestos, doses that rarely induced mesothelioma in wild-type mice. Our findings suggest that minimal exposure to carcinogenic fibers may significantly increase the risk of malignant mesothelioma in genetically predisposed individuals carrying germline BAP1 mutations, possibly via alterations of the inflammatory response.


Assuntos
Asbesto Crocidolita/toxicidade , Mesotelioma/etiologia , Neoplasias Peritoneais/etiologia , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Animais , Asbesto Crocidolita/administração & dosagem , Líquido Ascítico/química , Quimiocinas/análise , Citocinas/análise , Relação Dose-Resposta a Droga , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Heterozigoto , Leucócitos/patologia , Macrófagos Peritoneais/classificação , Macrófagos Peritoneais/fisiologia , Masculino , Mesotelioma/genética , Camundongos , Camundongos Endogâmicos C57BL , Fibras Minerais/toxicidade , Neoplasias Peritoneais/genética , Peritonite/etiologia , Peritonite/genética , Distribuição Aleatória , Proteínas Supressoras de Tumor/deficiência , Proteínas Supressoras de Tumor/fisiologia , Ubiquitina Tiolesterase/deficiência , Ubiquitina Tiolesterase/fisiologia
6.
Int J Mol Sci ; 14(5): 10369-82, 2013 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-23685870

RESUMO

It has been confirmed that alternatively activated macrophages (M2) participate in tissue remodeling and fibrosis occurrence, but the effect of M2 on peritoneal fibrosis related to peritoneal dialysis (PD) hasn't been elucidated. This study was therefore conducted to assess the association between M2 and peritoneal fibrosis related to PD. In this study, peritoneal fibrosis was induced by intraperitoneal (i.p.) injection of Lactate-4.25% dialysate (100 mL/kg) to C57BL/6J mice for 28 days, and liposome-encapsulated clodronate (LC, the specific scavenger of macrophages) was used to treat the peritoneal fibrosis mice model by i.p. injection at day 18 and day 21. All animals were sacrificed at day 29. Parietal peritonea were stained with Masson's trichrome, and the expression of type I collagen (Col-I), fibronectin, mannose receptor (CD206), transforming growth factor beta (TGF-ß), chemokine receptor 7 (CCR7), chitinase 3-like 3 (Ym-1) and arginase-1 (Arg-1) was determined by Western blotting, immunofluorescence and quantitative real-time PCR. Our results revealed that peritoneal thickness, Col-I, fibronectin, CD206, TGF-ß, Ym-1 and Arg-1 were upregulated in the peritoneal fibrosis mice model, and all of these indexes were downregulated in those treated with LC. Additionally, there was no difference in the level of CCR7 between the model and treatment group. Our study indicated that peritoneal M2 played an important role in the process of peritoneal fibrosis related to PD and might be a potential target for intervention therapy of peritoneal fibrosis.


Assuntos
Ativação de Macrófagos , Macrófagos Peritoneais/metabolismo , Diálise Peritoneal , Fibrose Peritoneal/metabolismo , Animais , Arginase/genética , Arginase/metabolismo , Western Blotting , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Feminino , Fibronectinas/genética , Fibronectinas/metabolismo , Lectinas/genética , Lectinas/metabolismo , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Macrófagos Peritoneais/classificação , Receptor de Manose , Lectinas de Ligação a Manose/genética , Lectinas de Ligação a Manose/metabolismo , Camundongos Endogâmicos C57BL , Microscopia Confocal , Fibrose Peritoneal/genética , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , beta-N-Acetil-Hexosaminidases/genética , beta-N-Acetil-Hexosaminidases/metabolismo
7.
J Immunol ; 187(12): 6208-16, 2011 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-22075699

RESUMO

Age-related adiposity has been linked to chronic inflammatory diseases in late life. To date, the studies on adipose tissue leukocytes and aging have not taken into account the heterogeneity of adipose tissue macrophages (ATMs), nor have they examined how age impacts other leukocytes such as T cells in fat. Therefore, we have performed a detailed examination of ATM subtypes in young and old mice using state of the art techniques. Our results demonstrate qualitative changes in ATMs with aging that generate a decrease in resident type 2 (M2) ATMs. The profile of ATMs in old fat shifts toward a proinflammatory environment with increased numbers of CD206(-)CD11c(-) (double-negative) ATMs. The mechanism of this aging-induced shift in the phenotypic profile of ATMs was found to be related to a decrease in peroxisome proliferator-activated receptor-γ expression in ATMs and alterations in chemokine/chemokine receptor expression profiles. Furthermore, we have revealed a profound and unexpected expansion of adipose tissue T cells in visceral fat with aging that includes a significant induction of regulatory T cells in fat. Our findings demonstrate a unique inflammatory cell signature in the physiologic context of aging adipose tissue that differs from those induced in setting of diet-induced obesity.


Assuntos
Envelhecimento/imunologia , Envelhecimento/patologia , Senescência Celular/imunologia , Gordura Intra-Abdominal/imunologia , Gordura Intra-Abdominal/patologia , Leucócitos Mononucleares/imunologia , Animais , Separação Celular/métodos , Imunofenotipagem , Inflamação/imunologia , Inflamação/patologia , Gordura Intra-Abdominal/citologia , Contagem de Leucócitos , Leucócitos Mononucleares/classificação , Leucócitos Mononucleares/patologia , Contagem de Linfócitos , Macrófagos Peritoneais/classificação , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/citologia , Monócitos/imunologia , Baço/citologia , Baço/imunologia , Subpopulações de Linfócitos T/classificação , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/patologia
8.
Atherosclerosis ; 219(2): 475-83, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21982410

RESUMO

OBJECTIVE: Peritoneal macrophages are used in many studies related to atherosclerosis. In situ, they are non-adherent and upon culturing, they adhere and function as scavengers of modified lipoproteins and dead apoptotic cells. They also produce growth factors, suggesting that they may provide life-supporting function as well. In this study, we propose that macrophage adherence plays a major role in their function and propose a novel concept that non-adherent macrophages are poor scavengers and may delay the process of apoptosis by secretion of growth factors. METHODS AND RESULTS: We analyzed non-adherent and adherent macrophages for changes in receptor expression, growth factor production and function by microarrays, real-time PCR, and western blot analyses. Our results indicate that adherent macrophages have increased expression of scavenger receptors as compared to fresh peritoneal cells. While genes for many growth factors were expressed in both non-adherent and adherent macrophages, the milk fat globule-epidermal growth factor 8 protein (MFG-E8) that recognizes and takes up apoptotic cells was specifically enhanced in non-adherent cells. Furthermore, early apoptotic endothelial cells demonstrated signs of delayed apoptosis when incubated in the presence of peritoneal lavage fluid that was shown to contain MFG-E8. Functional arrays indicated that peritoneal non-adherent macrophages represent a class of macrophages, distinct from either blood monocytes or adherent cultured macrophages. CONCLUSIONS: These results suggest that the adherence status of macrophages may play a major role in their functions.


Assuntos
Adesão Celular , Macrófagos Peritoneais/classificação , Macrófagos/classificação , Monócitos/classificação , Animais , Apoptose , Líquido Ascítico/metabolismo , Western Blotting , Células Cultivadas , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Macrófagos Peritoneais/metabolismo , Macrófagos Peritoneais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/metabolismo , Monócitos/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Lavagem Peritoneal , Reação em Cadeia da Polimerase em Tempo Real , Receptores Depuradores/genética , Receptores Depuradores/metabolismo , Fatores de Tempo
9.
Klin Lab Diagn ; (6): 42-4, 2011 Jun.
Artigo em Russo | MEDLINE | ID: mdl-21851011

RESUMO

According to the etiology of acute pancreatitis, the authors identified the most common phenotypes of superficial antigens of peritoneal macrophages: CD14(+) CD25(-)CD64(-)HLA-DR(-) in acute biliary pancreatitis, CD14(+) CD25(+)CD64(+)HLA-DR(+) in nonbiliary pancreatitis; moreover, all the patients were found to have increased expression of early (CD25+) and late (HLA-DR+) markers of cell activation. A comparative study was conducted and the most informative tools to evaluate the adhesive, cytokine-producing, phagocytic, and oxygen-dependent activities of peritoneal macrophages were recognized.


Assuntos
Testes Imunológicos/métodos , Ativação de Macrófagos , Macrófagos Peritoneais/imunologia , Pancreatite Necrosante Aguda/imunologia , Adulto , Adesão Celular/imunologia , Separação Celular , Citocinas/imunologia , Testes Imunológicos de Citotoxicidade , Antígenos HLA-DR/análise , Humanos , Subunidade alfa de Receptor de Interleucina-2/análise , Receptores de Lipopolissacarídeos/análise , Macrófagos Peritoneais/classificação , Fagocitose , Receptores de IgG/análise
10.
Comp Med ; 57(6): 574-80, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18246870

RESUMO

Primary macrophages from the peritoneal cavities of mice are commonly used ex vivo to produce inflammatory cytokines and test anti-inflammatory agents. Although approximately 1 million peritoneal macrophages can be obtained from an untreated mouse, more than twice that number can be collected 48 to 72 h after intraperitoneal injection of sterile inducing agents such as Brewer thioglycollate broth, casein, and proteose peptone. However, whether 'induced' macrophages are functionally equivalent to 'resident' peritoneal macrophages has been unclear. Flow cytometric analysis revealed significant phenotypic differences between these 2 macrophage types. Resident and induced peritoneal macrophages also demonstrated markedly different capacities to produce the inflammatory cytokines interleukins 6 and 1beta in response to lipopolysaccharide stimulation in vitro. Increased understanding of the differences between resident and induced peritoneal macrophages likely will help investigators decide which macrophage type is appropriate for their in vitro assay needs.


Assuntos
Macrófagos Peritoneais/classificação , Macrófagos Peritoneais/imunologia , Animais , Citocinas/biossíntese , Feminino , Citometria de Fluxo , Separação Imunomagnética , Técnicas In Vitro , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos Peritoneais/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos MRL lpr , Camundongos Endogâmicos NOD , Camundongos Endogâmicos , Fenótipo , Fator de Necrose Tumoral alfa/biossíntese , Zimosan/farmacologia
11.
Am J Reprod Immunol ; 34(5): 317-22, 1995 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-8595131

RESUMO

PROBLEM: Previous studies have established that in vitro proliferation of endometrial cells is enhanced by peripheral blood monocytes (PBM) and suppressed by peritoneal macrophages (PM) from patients with endometriosis but only suppressed by PBM and PM obtained from normal subjects. The functional activity of PBM and PM is influenced by the engagement of numerous cell surface receptors with their respective physiological ligands. METHOD: In this study, PBM and PM from fertile women (Group 1), women with unexplained infertility (Group 2), and women with limited (Group 3) or severe (Group 4) endometriosis were isolated in order to analyze these cells for the expression of CD54, CD58 and HLA-DR (immunoglobulin supergene antigens) CD18 and CD29 (integrins) and CD44 (an addresin). These cell surface antigens are involved in monocyte/macrophage trafficking, activation, signal transduction and/or adhesion. RESULTS: No differences were detected in the percentage of PBM expressing CD18, CD44, CD54, CD58, or HLA-DR among the four groups of subjects. Furthermore, the density of these antigens expressed on PBM was identical in patients and control subjects. In contrast, the percentage of PBM expressing CD29 (also known as VLA beta 1) and the density of CD29 expressed per cell were significantly reduced (P < 0.01) in patients with limited endometriosis compared to controls and patients with severe disease. Interestingly, although the percentage of CD29+ PBM from women with severe endometriosis was not statistically different from the percentage of CD29+ PBM from controls, the density of CD29 expressed per cell was significantly elevated among patients with severe disease. Analysis of PM from the four subject groups revealed no differences in CD29 expression or density. However, the percentage of PM expressing CD18 was significantly decreased in patients with limited (but not severe) endometriosis. CONCLUSION: Since both CD18 and CD29 play a role in cell trafficking and/or adhesion, alterations in their expression among patients with endometriosis suggest that these integrin beta chains may play a role in the pathogenesis of the disease.


Assuntos
Endometriose/imunologia , Integrina beta1/biossíntese , Monócitos/metabolismo , Endometriose/sangue , Endometriose/metabolismo , Feminino , Genes de Imunoglobulinas/imunologia , Humanos , Integrinas/biossíntese , Receptores de Lipopolissacarídeos/análise , Macrófagos Peritoneais/química , Macrófagos Peritoneais/classificação , Monócitos/classificação , Receptores de Retorno de Linfócitos/biossíntese
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