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1.
PLoS One ; 16(1): e0245924, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33481950

RESUMO

SARS-CoV-2 is a single stranded RNA (ssRNA) virus and contains GU-rich sequences distributed abundantly in the genome. In COVID-19, the infection and immune hyperactivation causes accumulation of inflammatory immune cells, blood clots, and protein aggregates in lung fluid, increased lung alveolar wall thickness, and upregulation of serum cytokine levels. A serum protein called serum amyloid P (SAP) has a calming effect on the innate immune system and shows efficacy as a therapeutic for fibrosis in animal models and clinical trials. Here we show that aspiration of the GU-rich ssRNA oligonucleotide ORN06 into mouse lungs induces all of the above COVID-19-like symptoms. Men tend to have more severe COVID-19 symptoms than women, and in the aspirated ORN06 model, male mice tended to have more severe symptoms than female mice. Intraperitoneal injections of SAP starting from day 1 post ORN06 aspiration attenuated the ORN06-induced increase in the number of inflammatory cells and formation of clot-like aggregates in the mouse lung fluid, reduced ORN06-increased alveolar wall thickness and accumulation of exudates in the alveolar airspace, and attenuated an ORN06-induced upregulation of the inflammatory cytokines IL-1ß, IL-6, IL-12p70, IL-23, and IL-27 in serum. SAP also reduced D-dimer levels in the lung fluid. In human peripheral blood mononuclear cells, SAP attenuated ORN06-induced extracellular accumulation of IL-6. Together, these results suggest that aspiration of ORN06 is a simple model for both COVID-19 as well as cytokine storm in general, and that SAP is a potential therapeutic for diseases with COVID-19-like symptoms and/or a cytokine storm.


Assuntos
/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Pneumonia/tratamento farmacológico , Componente Amiloide P Sérico/uso terapêutico , Animais , /patologia , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/patologia , Modelos Animais de Doenças , Feminino , Humanos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/complicações , Pneumonia/patologia , Componente Amiloide P Sérico/administração & dosagem
2.
PLoS One ; 15(12): e0244762, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33378413

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and type 2 diabetes and is characterized by the accumulation of fat in the liver (steatosis). NAFLD can transition into non-alcoholic steatohepatitis (NASH), with liver cell injury, inflammation, and an increased risk of fibrosis. We previously found that injections of either 1866, a synthetic ligand for the lectin receptor CD209, or DANA, a sialidase inhibitor, can inhibit inflammation and fibrosis in multiple animal models. The methionine and choline-deficient (MCD) diet is a model of NASH which results in the rapid induction of liver steatosis and inflammation. In this report, we show that for C57BL/6 mice on a MCD diet, injections of both 1866 and DANA reversed MCD diet-induced decreases in white fat, decreases in adipocyte size, and white fat inflammation. However, these effects were not observed in type 2 diabetic db/db mice on a MCD diet. In db/db mice on a MCD diet, 1866 decreased liver steatosis, but these effects were not observed in C57BL/6 mice. There was no correlation between the ability of 1866 or DANA to affect steatosis and the effects of these compounds on the density of liver macrophage cells expressing CLEC4F, CD64, F4/80, or Mac2. Together these results indicate that 1866 and DANA modulate adipocyte size and adipose tissue macrophage populations, that 1866 could be useful for modulating steatosis, and that changes in the local density of 4 different liver macrophages cell types do not correlate with effects on liver steatosis.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Moléculas de Adesão Celular/agonistas , Lectinas Tipo C/agonistas , Fígado/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Ácido N-Acetilneuramínico/análogos & derivados , Neuraminidase/antagonistas & inibidores , Receptores de Superfície Celular/agonistas , Tecido Adiposo/metabolismo , Animais , Deficiência de Colina/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Inflamação/metabolismo , Fígado/metabolismo , Macrófagos/metabolismo , Camundongos , Ácido N-Acetilneuramínico/farmacologia , Ácido N-Acetilneuramínico/uso terapêutico , Neuraminidase/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo
3.
Am J Pathol ; 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33039353

RESUMO

High-fat diet (HFD)-induced inflammation and steatosis of adipose tissue and liver are associated with a variety of serious health risks. Sialic acids are found as the distal terminal sugar on glycoproteins, which are removed by sialidases (neuraminidases). In humans and mice, pulmonary fibrosis is associated with up-regulation of sialidases, and injections of sialidase inhibitors attenuate bleomycin-induced pulmonary fibrosis. Sialidase levels are altered in obese rodents and humans. This report shows that for mice on an HFD, injections of the sialidase inhibitor N-acetyl-2,3-dehydro-2-deoxyneuraminic acid inhibit weight gain, reduce steatosis, and decrease adipose tissue and liver inflammation. Compared with control, mice lacking the sialidase neuraminidase 3 have reduced HFD-induced adipose tissue and liver inflammation. These data suggest that sialidases promote adipose and liver inflammation in response to a high-fat diet.

4.
bioRxiv ; 2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32869032

RESUMO

SARS-CoV-2 is a single stranded RNA (ssRNA) virus and contains GU-rich sequences distributed abundantly in the genome. In COVID-19, the infection and immune hyperactivation causes accumulation of inflammatory immune cells, blood clots, and protein aggregates in lung fluid, increased lung alveolar wall thickness, and upregulation of serum cytokine levels. A serum protein called serum amyloid P (SAP) has a calming effect on the innate immune system and shows efficacy as a therapeutic for fibrosis in animal models and clinical trials. In this report, we show that aspiration of the GU-rich ssRNA oligonucleotide ORN06 into mouse lungs induces all of the above COVID-19-like symptoms. Men tend to have more severe COVID-19 symptoms than women, and in the aspirated ORN06 model, male mice tended to have more severe symptoms than female mice. Intraperitoneal injections of SAP starting from day 1 post ORN06 aspiration attenuated the ORN06-induced increase in the number of inflammatory cells and formation of clot-like aggregates in the mouse lung fluid, reduced ORN06-increased alveolar wall thickness and accumulation of exudates in the alveolar airspace, and attenuated an ORN06-induced upregulation of the inflammatory cytokines IL-1ß, IL-6, IL-12p70, IL-23, and IL-27 in serum. Together, these results suggest that aspiration of ORN06 is a simple model for both COVID-19 as well as cytokine storm in general, and that SAP is a potential therapeutic for diseases with COVID-19-like symptoms as well as diseases that generate a cytokine storm.

5.
Am J Pathol ; 189(12): 2400-2413, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31539521

RESUMO

High-fat diet (HFD)-induced inflammation is associated with a variety of health risks. The systemic pentraxin serum amyloid P (SAP) inhibits inflammation. SAP activates the high-affinity IgG receptor Fcγ receptor I (FcγRI; CD64) and the lectin receptor dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN; CD209). Herein, we show that for mice on an HFD, injections of SAP and a synthetic CD209 ligand (1866) reduced HFD-increased adipose and liver tissue inflammation, adipocyte differentiation, and lipid accumulation in adipose tissue. HFD worsened glucose tolerance test results and caused increased adipocyte size; for mice on an HFD, SAP improved glucose tolerance test results and reduced adipocyte size. Mice on an HFD had elevated serum levels of IL-1ß, IL-23, interferon (IFN)-ß, IFN-γ, monocyte chemoattractant protein 1 [MCP-1; chemokine (C-C motif) ligand 2 (CCL2)], and tumor necrosis factor-α. SAP reduced serum levels of IL-23, IFN-ß, MCP-1, and tumor necrosis factor-α, whereas 1866 reduced IFN-γ. In vitro, SAP, but not 1866, treated cells isolated from white fat tissue (stromal vesicular fraction) produced the anti-inflammatory cytokine IL-10. HFD causes steatosis, and both SAP and 1866 reduced it. Conversely, compared with control mice, SAP knockout mice fed on a normal diet had increased white adipocyte cell sizes, increased numbers of inflammatory cells in adipose and liver tissue, and steatosis; and these effects were exacerbated on an HFD. SAP and 1866 may inhibit some, but not all, of the effects of a high-fat diet.


Assuntos
Tecido Adiposo/patologia , Moléculas de Adesão Celular/metabolismo , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/prevenção & controle , Hepatite/prevenção & controle , Lectinas Tipo C/metabolismo , Obesidade/complicações , Receptores de Superfície Celular/metabolismo , Componente Amiloide P Sérico/metabolismo , Tecido Adiposo/metabolismo , Animais , Moléculas de Adesão Celular/genética , Fígado Gorduroso/etiologia , Fígado Gorduroso/patologia , Hepatite/etiologia , Hepatite/patologia , Resistência à Insulina , Lectinas Tipo C/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Superfície Celular/genética , Componente Amiloide P Sérico/genética
6.
J Immunol ; 203(2): 493-499, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31160533

RESUMO

Fibrocytes are monocyte-derived fibroblast like cells that participate in wound healing, but little is known about what initiates fibrocyte differentiation. Blood platelets contain 60-100-mer polymers of phosphate groups called polyphosphate, and when activated, platelets induce blood clotting (the first step in wound healing) in part by the release of polyphosphate. We find that activated platelets release a factor that promotes fibrocyte differentiation. The factor is abolished by treating the crude platelet factor with the polyphosphate-degrading enzyme polyphosphatase, and polyphosphate promotes fibrocyte differentiation. Macrophages and recruited neutrophils also potentiate wound healing, and polyphosphate also promotes macrophage differentiation and induces chemoattraction of neutrophils. In support of the hypothesis that polyphosphate is a signal that affects leukocytes, we observe saturable binding of polyphosphate to these cells. Polyphosphate also inhibits leukocyte proliferation and proteasome activity. These results suggest new roles for extracellular polyphosphate as a mediator of wound healing and inflammation and also provide a potential link between platelet activation and the progression of fibrosing diseases.


Assuntos
Diferenciação Celular/fisiologia , Proliferação de Células/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Leucócitos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Polifosfatos/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Coagulação Sanguínea/fisiologia , Fibroblastos/metabolismo , Humanos , Leucócitos/metabolismo , Macrófagos/metabolismo , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Neutrófilos/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Cicatrização/fisiologia
7.
mBio ; 10(2)2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30862745

RESUMO

In patients with invasive fungal diseases, there is often little cellular inflammatory response. We tested the idea that binding of the human constitutive plasma protein serum amyloid P component (SAP) (also called PTX2) to Candida albicans dampens the innate immune response to this fungus. Many pathogenic fungi have cell surface amyloid-like structures important for adhesion and biofilm formation. Human SAP bound to fungi that expressed functional cell surface amyloid, but SAP had minimal binding to fungi with reduced expression of cell surface amyloid. In the absence of SAP, phagocytosis of fungi by human macrophages was potentiated by expression of amyloid on the fungi. SAP binding to fungi inhibited their phagocytosis by macrophages. Macrophages pretreated with SAP displayed reduced fungal phagocytosis, reduced secretion of inflammatory cytokines (IFN-γ, IL-6, and TNF-α), and increased secretion of the anti-inflammatory cytokine IL-10. SAP bound to fungi or added to the medium upregulated the expression of the anti-inflammatory receptor CD206 on macrophages. These findings suggest that SAP bound to amyloid-like structures on fungal cells dampens the host cellular immune response in fungal diseases such as invasive candidiasis.IMPORTANCE Macrophages are a key part of our innate immune system and are responsible for recognizing invading microbes, ingesting them, and sending appropriate signals to other immune cells. We have found that human macrophages can recognize invading yeast pathogens that have a specific molecular pattern of proteins on their surfaces: these proteins have structures similar to the structures of amyloid aggregates in neurodegenerative diseases like Alzheimer's disease. However, this surface pattern also causes the fungi to bind a serum protein called serum amyloid P component (SAP). In turn, the SAP-coated yeasts are poorly recognized and seldom ingested by the macrophages, and the macrophages have a more tolerant and less inflammatory response in the presence of SAP. Therefore, we find that surface structures on the yeast can alter how the macrophages react to invading microbes.


Assuntos
Candida albicans/imunologia , Candidíase/microbiologia , Citocinas/metabolismo , Proteínas Fúngicas/metabolismo , Macrófagos/imunologia , Fagocitose/efeitos dos fármacos , Componente Amiloide P Sérico/metabolismo , Candidíase/imunologia , Células Cultivadas , Humanos , Macrófagos/efeitos dos fármacos
8.
J Immunol ; 202(1): 239-248, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30510066

RESUMO

The movement of neutrophils between blood and tissues appears to be regulated by chemoattractants and chemorepellents. Compared with neutrophil chemoattractants, relatively little is known about neutrophil chemorepellents. Slit proteins are endogenously cleaved into a variety of N- and C-terminal fragments, and these fragments are neuronal chemorepellents and inhibit chemoattraction of many cell types, including neutrophils. In this report, we show that the ∼140-kDa N-terminal Slit2 fragment (Slit2-N) is a chemoattractant and the ∼110-kDa N-terminal Slit2 fragment (Slit2-S) is a chemorepellent for human neutrophils. The effects of both Slit2 fragments were blocked by Abs to the Slit2 receptor Roundabout homolog 1 or the Slit2 coreceptor Syndecan-4. Slit2-N did not appear to activate Ras but increased phosphatidylinositol 3,4,5-triphosphate levels. Slit2-N-induced chemoattraction was unaffected by Ras inhibitors, reversed by PI3K inhibitors, and blocked by Cdc42 and Rac inhibitors. In contrast, Slit2-S activated Ras but did not increase phosphatidylinositol 3,4,5-triphosphate levels. Slit2-S-induced chemorepulsion was blocked by Ras and Rac inhibitors, not affected by PI3K inhibitors, and reversed by Cdc42 inhibitors. Slit2-N, but not Slit2-S, increased neutrophil adhesion, myosin L chain 2 phosphorylation, and polarized actin formation and single pseudopods at the leading edge of cells. Slit2-S induced multiple pseudopods. These data suggest that Slit2 isoforms use similar receptors but different intracellular signaling pathways and have different effects on the cytoskeleton and pseudopods to induce neutrophil chemoattraction or chemorepulsion.


Assuntos
Citoesqueleto de Actina/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neutrófilos/fisiologia , Isoformas de Proteínas/metabolismo , Pseudópodes/metabolismo , Anticorpos Bloqueadores/metabolismo , Orientação de Axônios , Adesão Celular , Células Cultivadas , Quimiotaxia/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/imunologia , Fosfatos de Fosfatidilinositol/metabolismo , Ligação Proteica , Isoformas de Proteínas/genética , Pseudópodes/ultraestrutura , Transdução de Sinais , Sindecana-4/metabolismo , Proteína cdc42 de Ligação ao GTP/metabolismo , Proteínas ras/metabolismo
9.
Front Immunol ; 9: 2328, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30459752

RESUMO

Pentraxins such as serum amyloid P (SAP; also known as PTX2) regulate several aspects of the innate immune system. SAP inhibits the differentiation of monocyte-derived fibroblast-like cells called fibrocytes, promotes the formation of immuno-regulatory macrophages, and inhibits neutrophil adhesion to extracellular matrix proteins. In this minireview, we describe how these effects of SAP have led to its possible use as a therapeutic, and how modulating SAP effects might be used for other therapeutics. Fibrosing diseases such as pulmonary fibrosis, cardiac fibrosis, liver fibrosis, and renal fibrosis are associated with 30-45% of deaths in the US. Fibrosis involves both fibrocyte differentiation and profibrotic macrophage differentiation, and possibly because SAP inhibits both of these processes, in 9 different animal models, SAP inhibited fibrosis. In Phase 1B and Phase 2 clinical trials, SAP injections reduced the decline in lung function in pulmonary fibrosis patients, and in a small Phase 2 trial SAP injections reduced fibrosis in myelofibrosis patients. Acute respiratory distress syndrome/ acute lung injury (ARDS/ALI) involves the accumulation of neutrophils in the lungs, and possibly because SAP inhibits neutrophil adhesion, SAP injections reduced the severity of ARDS in an animal model. Conversely, depleting SAP is a potential therapeutic for amyloidosis, topically removing SAP from wound fluid speeds wound healing in animal models, and blocking SAP binding to one of its receptors makes cultured macrophages more aggressive toward tuberculosis bacteria. These results suggest that modulating pentraxin signaling might be useful for a variety of diseases.


Assuntos
Componente Amiloide P Sérico/farmacologia , Amiloidose/tratamento farmacológico , Amiloidose/etiologia , Amiloidose/metabolismo , Amiloidose/patologia , Animais , Ensaios Clínicos como Assunto , Fibroblastos/efeitos dos fármacos , Fibroblastos/imunologia , Fibroblastos/metabolismo , Fibrose/tratamento farmacológico , Fibrose/etiologia , Fibrose/metabolismo , Humanos , Imunomodulação/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Família Multigênica , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Componente Amiloide P Sérico/genética , Componente Amiloide P Sérico/metabolismo , Componente Amiloide P Sérico/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia , Cicatrização/efeitos dos fármacos
10.
J Leukoc Biol ; 103(1): 119-128, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29345066

RESUMO

Compared to neutrophil chemoattractants, relatively little is known about the mechanism neutrophils use to respond to chemorepellents. We previously found that the soluble extracellular protein dipeptidyl peptidase IV (DPPIV) is a neutrophil chemorepellent. In this report, we show that an inhibitor of the protease activated receptor 2 (PAR2) blocks DPPIV-induced human neutrophil chemorepulsion, and that PAR2 agonists such as trypsin, tryptase, 2f-LIGRL, SLIGKV, and AC55541 induce human neutrophil chemorepulsion. Several PAR2 agonists in turn block the ability of the chemoattractant fMLP to attract neutrophils. Compared to neutrophils from male and female C57BL/6 mice, neutrophils from male and female mice lacking PAR2 are insensitive to the chemorepulsive effects of DPPIV or PAR2 agonists. Acute respiratory distress syndrome (ARDS) involves an insult-mediated influx of neutrophils into the lungs. In a mouse model of ARDS, aspiration of PAR2 agonists starting 24 h after an insult reduce neutrophil numbers in the bronchoalveolar lavage (BAL) fluid, as well as the post-BAL lung tissue. Together, these results indicate that the PAR2 receptor mediates DPPIV-induced chemorepulsion, and that PAR2 agonists might be useful to induce neutrophil chemorepulsion.


Assuntos
Dipeptidil Peptidase 4/farmacologia , Pulmão/imunologia , Neutrófilos/imunologia , Receptor PAR-2/fisiologia , Tripsina/farmacologia , Triptases/farmacologia , Animais , Células Cultivadas , Quimiotaxia de Leucócito , Modelos Animais de Doenças , Feminino , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , /metabolismo
11.
BMC Immunol ; 18(1): 47, 2017 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-29202702

RESUMO

BACKGROUND: Pentraxins are a family of highly conserved secreted proteins that regulate the innate immune system, including monocytes and macrophages. C-reactive protein (CRP) is a plasma protein whose levels can rise to 1000 µg/ml from the normal <3 µg/ ml during inflammation. RESULTS: We find that CRP inhibits proliferation of the human myeloid leukemia cell line Mono Mac 6 with an IC50 of 75 µg/ ml by inducing apoptosis of these cells. The related proteins serum amyloid P (SAP) and pentraxin 3 (PTX3) do not inhibit Mono Mac 6 proliferation. CRP has no significant effect on the proliferation of other leukemia cell lines such as HL-60, Mono Mac 1, K562, U937, or THP-1, or the survival of normal peripheral blood cells. The effect of CRP appears to be dependent on the CRP receptor FcγRI, and is negatively regulated by a phosphatidylinositol -3-kinase pathway. CONCLUSION: These data reveal differential signaling by pentraxins on immune cells, and suggest that CRP can regulate the proliferation of some myeloid leukemia cells.


Assuntos
Apoptose/efeitos dos fármacos , Proteína C-Reativa/farmacologia , Leucemia Mieloide Aguda/fisiopatologia , Componente Amiloide P Sérico/farmacologia , Antígenos CD/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Leucócitos Mononucleares/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Receptores Fc/genética , Receptores Fc/metabolismo , Receptores de IgG/metabolismo , Receptores Imunológicos/genética , Transdução de Sinais/efeitos dos fármacos
12.
Exp Lung Res ; 43(9-10): 395-406, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29220597

RESUMO

PURPOSE: High levels of NaCl in the diet are associated with both cardiac and renal fibrosis, but whether salt intake affects pulmonary fibrosis has not been examined. AIM OF THE STUDY: To test the hypothesis that salt intake might affect pulmonary fibrosis. MATERIALS AND METHODS: Mice were fed low, normal, or high salt diets for 2 weeks, and then treated with oropharyngeal bleomycin to induce pulmonary fibrosis, or oropharyngeal saline as a control. RESULTS: As determined by collagen staining of lung sections, and protein levels and cell numbers in the bronchoalveolar lavage (BAL) fluid at 21 days after bleomycin, the high salt diet did not exacerbate bleomycin-induced fibrosis, while the low salt diet attenuated fibrosis. For the bleomycin-treated mice, staining of the post-BAL lung sections indicated that compared to the regular salt diet, high salt increased the number of Ly6c-positive macrophages and decreased the number of CD11c and CD206-positive macrophages and dendritic cells. The low salt diet caused bleomycin-induced leukocyte numbers to be similar to control saline-treated mice, but reduced numbers of CD45/collagen-VI positive fibrocytes. In the saline controls, low dietary salt decreased CD11b and CD11c positive cells in lung sections, and high dietary salt increased fibrocytes. CONCLUSIONS: Together, these data suggest the possibility that a low salt diet might attenuate pulmonary fibrosis.


Assuntos
Dieta Hipossódica , Fibrose Pulmonar/induzido quimicamente , Cloreto de Sódio na Dieta/farmacologia , Animais , Bleomicina , Líquido da Lavagem Broncoalveolar/citologia , Camundongos , Cloreto de Sódio na Dieta/efeitos adversos
13.
Sci Rep ; 7(1): 15069, 2017 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-29118338

RESUMO

Fibrosis involves increasing amounts of scar tissue appearing in a tissue, but what drives this is unclear. In fibrotic lesions in human and mouse lungs, we found extensive desialylation of glycoconjugates, and upregulation of sialidases. The fibrosis-associated cytokine TGF-ß1 upregulates sialidases in human airway epithelium cells, lung fibroblasts, and immune system cells. Conversely, addition of sialidases to human peripheral blood mononuclear cells induces accumulation of extracellular TGF-ß1, forming what appears to be a sialidase - TGF-ß1 - sialidase positive feedback loop. Monocyte-derived cells called fibrocytes also activate fibroblasts, and we found that sialidases potentiate fibrocyte differentiation. A sialylated glycoprotein called serum amyloid P (SAP) inhibits fibrocyte differentiation, and sialidases attenuate SAP function. Injections of the sialidase inhibitors DANA and oseltamivir (Tamiflu) starting either 1 day or 10 days after bleomycin strongly attenuate pulmonary fibrosis in the mouse bleomycin model, and by breaking the feedback loop, cause a downregulation of sialidase and TGF-ß1 accumulation. Together, these results suggest that a positive feedback loop involving sialidases potentiates fibrosis, and suggest that sialidase inhibitors could be useful for the treatment of fibrosis.


Assuntos
Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Neuraminidase/antagonistas & inibidores , Fibrose Pulmonar/prevenção & controle , Células A549 , Animais , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Neuraminidase/metabolismo , Fibrose Pulmonar/metabolismo , Componente Amiloide P Sérico/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
14.
BMC Immunol ; 18(1): 30, 2017 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-28619036

RESUMO

BACKGROUND: Circulating bone marrow-derived monocytes can leave the blood, enter a tissue, and differentiate into M1 inflammatory, M2a remodeling/fibrotic, or M2c/Mreg resolving/immune-regulatory macrophages. Macrophages can also convert from one of the above types to another. Pentraxins are secreted proteins that bind to, and promote efficient clearance of, microbial pathogens and cellular debris during infection, inflammation, and tissue damage. The pentraxins C-reactive protein (CRP), serum amyloid P (SAP), and pentraxin-3 (PTX3) can also bind a variety of endogenous ligands. As monocytes and macrophages are exposed to differing concentrations of pentraxins and their ligands during infection, inflammation, and tissue damage, we assessed what effect pentraxins and their ligands have on these cells. RESULTS: We found that many polarization markers do not discriminate between the effects of pentraxins and their ligands on macrophages. However, pentraxins, their ligands, and cytokines differentially regulate the expression of the hemoglobin-haptoglobin complex receptor CD163, the sialic acid-binding lectin CD169, and the macrophage mannose receptor CD206. CRP, a pentraxin generally thought of as being pro-inflammatory, increases the extracellular accumulation of the anti-inflammatory cytokine IL-10, and this effect is attenuated by GM-CSF, mannose-binding lectin, and factor H. CONCLUSIONS: These results suggest that the presence of pentraxins and their ligands regulate macrophage differentiation in the blood and tissues, and that CRP may be a potent inducer of the anti-inflammatory cytokine IL-10.


Assuntos
Proteína C-Reativa/metabolismo , Inflamação/imunologia , Interleucina-10/metabolismo , Macrófagos/fisiologia , Monócitos/fisiologia , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Diferenciação Celular , Células Cultivadas , Fator H do Complemento/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Ativação de Macrófagos , Lectinas de Ligação a Manose/metabolismo , Ácido N-Acetilneuramínico/metabolismo , Receptores de Superfície Celular/metabolismo , Componente Amiloide P Sérico/metabolismo , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo
15.
J Exp Med ; 213(9): 1723-40, 2016 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-27481130

RESUMO

Primary myelofibrosis (PMF) is a fatal neoplastic disease characterized by clonal myeloproliferation and progressive bone marrow (BM) fibrosis thought to be induced by mesenchymal stromal cells stimulated by overproduced growth factors. However, tissue fibrosis in other diseases is associated with monocyte-derived fibrocytes. Therefore, we sought to determine whether fibrocytes play a role in the induction of BM fibrosis in PMF. In this study, we show that BM from patients with PMF harbors an abundance of clonal, neoplastic collagen- and fibronectin-producing fibrocytes. Immunodeficient mice transplanted with myelofibrosis patients' BM cells developed a lethal myelofibrosis-like phenotype. Treatment of the xenograft mice with the fibrocyte inhibitor serum amyloid P (SAP; pentraxin-2) significantly prolonged survival and slowed the development of BM fibrosis. Collectively, our data suggest that neoplastic fibrocytes contribute to the induction of BM fibrosis in PMF, and inhibiting fibrocyte differentiation with SAP may interfere with this process.


Assuntos
Fibroblastos/fisiologia , Monócitos/citologia , Mielofibrose Primária/etiologia , Animais , Medula Óssea/patologia , Transplante de Medula Óssea , Células Cultivadas , Fibroblastos/efeitos dos fármacos , Fibrose , Proteínas de Homeodomínio/farmacologia , Humanos , Camundongos , Camundongos SCID , Mielofibrose Primária/patologia , Pirazóis/farmacologia , Proteínas Recombinantes/farmacologia , Componente Amiloide P Sérico/farmacologia
16.
Proc Natl Acad Sci U S A ; 112(38): 11929-34, 2015 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-26351669

RESUMO

In healing wounds and fibrotic lesions, fibroblasts and monocyte-derived fibroblast-like cells called fibrocytes help to form scar tissue. Although fibrocytes promote collagen production by fibroblasts, little is known about signaling from fibroblasts to fibrocytes. In this report, we show that fibroblasts stimulated with the fibrocyte-secreted inflammatory signal tumor necrosis factor-α secrete the small leucine-rich proteoglycan lumican, and that lumican, but not the related proteoglycan decorin, promotes human fibrocyte differentiation. Lumican competes with the serum fibrocyte differentiation inhibitor serum amyloid P, but dominates over the fibroblast-secreted fibrocyte inhibitor Slit2. Lumican acts directly on monocytes, and unlike other factors that affect fibrocyte differentiation, lumican has no detectable effect on macrophage differentiation or polarization. α2ß1, αMß2, and αXß2 integrins are needed for lumican-induced fibrocyte differentiation. In lung tissue from pulmonary fibrosis patients with relatively normal lung function, lumican is present at low levels throughout the tissue, whereas patients with advanced disease have pronounced lumican expression in the fibrotic lesions. These data may explain why fibrocytes are increased in fibrotic tissues, suggest that the levels of lumican in tissues may have a significant effect on the decision of monocytes to differentiate into fibrocytes, and indicate that modulating lumican signaling may be useful as a therapeutic for fibrosis.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Fibroblastos/citologia , Fibroblastos/metabolismo , Sulfato de Ceratano/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Animais , Anticorpos Bloqueadores/metabolismo , Bleomicina , Polaridade Celular/efeitos dos fármacos , Fracionamento Químico , Meios de Cultivo Condicionados/farmacologia , Decorina/metabolismo , Modelos Animais de Doenças , Fibroblastos/efeitos dos fármacos , Humanos , Integrina alfa2/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Lumicana , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Peptídeos/metabolismo , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Tripsina/metabolismo
17.
Arthritis Rheumatol ; 67(10): 2634-8, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26138693

RESUMO

OBJECTIVE: To determine whether an intraarticular injection of the neutrophil chemorepellent dipeptidyl peptidase IV (DPPIV; CD26) can attenuate inflammation and decrease the severity of arthritis in a murine model. METHODS: DBA/1 mice were immunized with type II collagen/Freund's complete adjuvant to produce collagen-induced arthritis (CIA). On day 25 postimmunization, recombinant human DPPIV (rhDPPIV) or phosphate buffered saline was injected intraarticularly, and arthritis severity scores were recorded 3 times per week. The hind legs of mice in both groups were fixed, decalcified, paraffin embedded, and sectioned. Pathologic scores for inflammation and neutrophil infiltration were recorded on a scale of 1-8, and the number of neutrophils was determined by morphometric cell counts. In addition, Mac-2-positive macrophages and articular damage were assessed using anti-Mac-2 antibodies and histologic staining, respectively. RESULTS: Injection of rhDPPIV reduced the mean score of arthritis severity in mice with CIA. DPPIV treatment reduced the overall extent of inflammation and articular damage around the arthritic joint and periarticular tissue, and also decreased neutrophil and macrophage infiltration. CONCLUSION: A localized injection of the neutrophil chemorepellent DPPIV reduces inflammation and the severity of the disease in a murine model of arthritis.


Assuntos
Artrite Experimental/tratamento farmacológico , Dipeptidil Peptidase 4/administração & dosagem , Dipeptidil Peptidase 4/uso terapêutico , Modelos Animais de Doenças , Inflamação/prevenção & controle , Animais , Artrite Experimental/patologia , Contagem de Células , Inflamação/patologia , Injeções Intra-Articulares , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos DBA , Neutrófilos/patologia , Índice de Gravidade de Doença , Resultado do Tratamento
18.
Proc Natl Acad Sci U S A ; 112(27): 8385-90, 2015 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-26106150

RESUMO

Fibrosis is caused by scar tissue formation in internal organs and is associated with 45% of deaths in the United States. Two closely related human serum proteins, serum amyloid P (SAP) and C-reactive protein (CRP), strongly affect fibrosis. In multiple animal models, and in Phase 1 and Phase 2 clinical trials, SAP affects several aspects of the innate immune system to reduce fibrosis, whereas CRP appears to potentiate fibrosis. However, SAP and CRP bind the same Fcγ receptors (FcγR) with similar affinities, and why SAP and CRP have opposing effects is unknown. Here, we report that SAP but not CRP binds the receptor DC-SIGN (SIGN-R1) to affect the innate immune system, and that FcγR are not necessary for SAP function. A polycyclic aminothiazole DC-SIGN ligand and anti-DC-SIGN antibodies mimic SAP effects in vitro. In mice, the aminothiazole reduces neutrophil accumulation in a model of acute lung inflammation and, at 0.001 mg/kg, alleviates pulmonary fibrosis by increasing levels of the immunosuppressant IL-10. DC-SIGN (SIGN-R1) is present on mouse lung epithelial cells, and SAP and the aminothiazole potentiate IL-10 production from these cells. Our data suggest that SAP activates DC-SIGN to regulate the innate immune system differently from CRP, and that DC-SIGN is a target for antifibrotics.


Assuntos
Proteína C-Reativa/imunologia , Moléculas de Adesão Celular/imunologia , Imunidade Inata/imunologia , Lectinas Tipo C/imunologia , Fibrose Pulmonar/imunologia , Receptores de Superfície Celular/imunologia , Componente Amiloide P Sérico/imunologia , Animais , Western Blotting , Proteína C-Reativa/metabolismo , Moléculas de Adesão Celular/metabolismo , Células Cultivadas , Células HEK293 , Humanos , Interleucina-10/imunologia , Interleucina-10/metabolismo , Lectinas Tipo C/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Confocal , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Ligação Proteica/imunologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/prevenção & controle , Receptores de Superfície Celular/metabolismo , Receptores de IgG/genética , Receptores de IgG/imunologia , Receptores de IgG/metabolismo , Componente Amiloide P Sérico/metabolismo , Tiazóis/farmacologia
19.
PLoS One ; 10(3): e0119709, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25774777

RESUMO

Monocyte-derived, fibroblast-like cells called fibrocytes are associated with fibrotic lesions. The plasma protein serum amyloid P component (SAP; also known as pentraxin-2, PTX2) inhibits fibrocyte differentiation in vitro, and injections of SAP inhibit fibrosis in vivo. SAP is a member of the pentraxin family of proteins that includes C-reactive protein (CRP; PTX1) and pentraxin-3 (PTX3). All three pentraxins are associated with fibrosis, but only SAP and CRP have been studied for their effects on fibrocyte differentiation. We find that compared to SAP and CRP, PTX3 promotes human and murine fibrocyte differentiation. The effect of PTX3 is dependent on FcγRI. In competition studies, the fibrocyte-inhibitory activity of SAP is dominant over PTX3. Binding competition studies indicate that SAP and PTX3 bind human FcγRI at different sites. In murine models of lung fibrosis, PTX3 is present in fibrotic areas, and the PTX3 distribution is associated with collagen deposition. In lung tissue from pulmonary fibrosis patients, PTX3 has a widespread distribution, both in unaffected tissue and in fibrotic lesions, whereas SAP is restricted to areas adjacent to vessels, and absent from fibrotic areas. These data suggest that the relative levels of SAP and PTX3 present at sites of fibrosis may have a significant effect on the ability of monocytes to differentiate into fibrocytes.


Assuntos
Proteína C-Reativa/metabolismo , Diferenciação Celular , Fibroblastos/metabolismo , Pulmão/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Fibrose Pulmonar/metabolismo , Componente Amiloide P Sérico/metabolismo , Animais , Feminino , Fibroblastos/patologia , Humanos , Pulmão/patologia , Masculino , Camundongos , Monócitos/metabolismo , Monócitos/patologia , Fibrose Pulmonar/patologia , Receptores de IgG/metabolismo
20.
Proc Natl Acad Sci U S A ; 111(51): 18291-6, 2014 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-25489114

RESUMO

Monocytes leave the blood and enter tissues. In healing wounds and fibrotic lesions, some of the monocytes differentiate into fibroblast-like cells called fibrocytes. In healthy tissues, even though monocytes enter the tissue, for unknown reasons, very few monocytes differentiate into fibrocytes. In this report, we show that fibroblasts from healthy human tissues secrete the neuronal guidance protein Slit2 and that Slit2 inhibits human fibrocyte differentiation. In mice, injections of Slit2 inhibit bleomycin-induced lung fibrosis. In lung tissue from pulmonary fibrosis patients with relatively normal lung function, Slit2 has a widespread distribution whereas, in patients with advanced disease, there is less Slit2 in the fibrotic lesions. These data may explain why fibrocytes are rarely observed in healthy tissues, may suggest that the relative levels of Slit2 present in healthy tissue and at sites of fibrosis may have a significant effect on the decision of monocytes to differentiate into fibrocytes, and may indicate that modulating Slit2 signaling may be useful as a therapeutic for fibrosis.


Assuntos
Diferenciação Celular/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Animais , Bleomicina/toxicidade , Linhagem Celular , Fibroblastos/metabolismo , Humanos , Inflamação/induzido quimicamente , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/fisiologia , Fibrose Pulmonar
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