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1.
Nat Commun ; 12(1): 5725, 2021 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-34593796

RESUMO

Although psycho-social stress is a well-known factor that contributes to the development of cancer, it remains largely unclear whether and how environmental eustress influences malignant diseases and regulates cancer-related therapeutic responses. Using an established eustress model, we demonstrate that mice living in an enriched environment (EE) are protected from carcinogen-induced liver neoplasia and transplantable syngeneic liver tumors, owning to a CD8+ T cell-dependent tumor control. We identify a peripheral Neuro-Endocrine-Immune pathway in eustress, including Sympathetic nervous system (SNS)/ß-adrenergic receptors (ß-ARs)/CCL2 that relieves tumor immunosuppression and overcomes PD-L1 resistance to immunotherapy. Notably, EE activates peripheral SNS and ß-ARs signaling in tumor cells and tumor infiltrated myeloid cells, leading to suppression of CCL2 expression and activation of anti-tumor immunity. Either blockade of CCL2/CCR2 or ß-AR signaling in EE mice lose the tumor protection capability. Our study reveales that environmental eustress via EE stimulates anti-tumor immunity, resulting in more efficient tumor control and a better outcome of immunotherapy.


Assuntos
Resistencia a Medicamentos Antineoplásicos/imunologia , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neuroimunomodulação , Estresse Psicológico/imunologia , Animais , Antígeno B7-H1/antagonistas & inibidores , Tetracloreto de Carbono/administração & dosagem , Tetracloreto de Carbono/toxicidade , Quimiocina CCL2/antagonistas & inibidores , Quimiocina CCL2/metabolismo , Dietilnitrosamina/administração & dosagem , Dietilnitrosamina/toxicidade , Células Estreladas do Fígado , Hepatócitos , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/patologia , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/imunologia , Neoplasias Hepáticas Experimentais/patologia , Masculino , Camundongos , Organoides , Receptores Adrenérgicos beta/metabolismo , Receptores CCR2/antagonistas & inibidores , Receptores CCR2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Sistema Nervoso Simpático/imunologia , Evasão Tumoral , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
2.
Nat Commun ; 12(1): 5255, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34489438

RESUMO

Monocytes are part of the mononuclear phagocytic system. Monocytes play a central role during inflammatory conditions and a better understanding of their dynamics might open therapeutic opportunities. In the present study, we focused on the characterization and impact of monocytes on brown adipose tissue (BAT) functions during tissue remodeling. Single-cell RNA sequencing analysis of BAT immune cells uncovered a large diversity in monocyte and macrophage populations. Fate-mapping experiments demonstrated that the BAT macrophage pool requires constant replenishment from monocytes. Using a genetic model of BAT expansion, we found that brown fat monocyte numbers were selectively increased in this scenario. This observation was confirmed using a CCR2-binding radiotracer and positron emission tomography. Importantly, in line with their tissue recruitment, blood monocyte counts were decreased while bone marrow hematopoiesis was not affected. Monocyte depletion prevented brown adipose tissue expansion and altered its architecture. Podoplanin engagement is strictly required for BAT expansion. Together, these data redefine the diversity of immune cells in the BAT and emphasize the role of monocyte recruitment for tissue remodeling.


Assuntos
Tecido Adiposo Marrom/citologia , Monócitos/fisiologia , Adiponectina/genética , Tecido Adiposo Marrom/fisiologia , Animais , Diferenciação Celular/genética , Contagem de Leucócitos , Macrófagos/citologia , Macrófagos/fisiologia , Glicoproteínas de Membrana/metabolismo , Camundongos Transgênicos , Monócitos/citologia , Tomografia por Emissão de Pósitrons , Receptores CCR2/genética , Receptores CCR2/metabolismo
3.
Cell Prolif ; 54(10): e13115, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34464477

RESUMO

The chemokine ligand CCL2 and its receptor CCR2 are implicated in the initiation and progression of various cancers. CCL2 can activate tumour cell growth and proliferation through a variety of mechanisms. By interacting with CCR2, CCL2 promotes cancer cell migration and recruits immunosuppressive cells to the tumour microenvironment, favouring cancer development. Over the last several decades, a series of studies have been conducted to explore the CCL2-CCR2 signalling axis function in malignancies. Therapeutic strategies targeting the CCL2- CCR2 axis have also shown promising effects, enriching our approaches for fighting against cancer. In this review, we summarize the role of the CCL2-CCR2 signalling axis in tumorigenesis and highlight recent studies on CCL2-CCR2 targeted therapy, focusing on preclinical studies and clinical trials.


Assuntos
Quimiocina CCL2/metabolismo , Neoplasias/metabolismo , Receptores CCR2/metabolismo , Transdução de Sinais/fisiologia , Animais , Carcinogênese/metabolismo , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Humanos
4.
Cells ; 10(8)2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34440839

RESUMO

Uncontrolled inflammation is associated with neurodegenerative conditions in central nervous system tissues, including the retina and brain. We previously found that the neural retina (NR) plays an important role in retinal immunity. Tumor necrosis factor Receptor-Associated Factor 3 (TRAF3) is a known immune regulator expressed in the retina; however, whether TRAF3 regulates retinal immunity is unknown. We have generated the first conditional NR-Traf3 knockout mouse model (Chx10-Cre/Traf3f/f) to enable studies of neuronal TRAF3 function. Here, we evaluated NR-Traf3 depletion effects on whole retinal TRAF3 protein expression, visual acuity, and retinal structure and function. Additionally, to determine if NR-Traf3 plays a role in retinal immune regulation, we used flow cytometry to assess immune cell infiltration following acute local lipopolysaccharide (LPS) administration. Our results show that TRAF3 protein is highly expressed in the NR and establish that NR-Traf3 depletion does not affect basal retinal structure or function. Importantly, NR-Traf3 promoted LPS-stimulated retinal immune infiltration. Thus, our findings propose NR-Traf3 as a positive regulator of retinal immunity. Further, the NR-Traf3 mouse provides a tool for investigations of neuronal TRAF3 as a novel potential target for therapeutic interventions aimed at suppressing retinal inflammatory disease and may also inform treatment approaches for inflammatory neurodegenerative brain conditions.


Assuntos
Proteínas de Homeodomínio/genética , Neurônios/metabolismo , Retina/metabolismo , Fator 3 Associado a Receptor de TNF/genética , Fatores de Transcrição/genética , Animais , Modelos Animais de Doenças , Eletrorretinografia , Imunidade/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Macrófagos/citologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Neurônios/imunologia , Receptores CCR2/genética , Receptores CCR2/metabolismo , Retina/fisiologia , Fator 3 Associado a Receptor de TNF/deficiência , Fator 3 Associado a Receptor de TNF/metabolismo , Fatores de Transcrição/deficiência , Uveíte/etiologia , Uveíte/imunologia , Uveíte/metabolismo , Acuidade Visual
5.
Sci Rep ; 11(1): 16438, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34385589

RESUMO

Macrophages expressing C-C chemokine receptor type 2 (CCR2) infiltrate the central and peripheral neural tissues of amyotrophic lateral sclerosis (ALS) patients. To identify the functional role of CCR2+ macrophages in the pathomechanisms of ALS, we used an ALS animal model, mutant Cu/Zn superoxide dismutase 1G93A (mSOD1)-transgenic (Tg) mice. To clarify the CCR2 function in the model, we generated SOD1G93A/CCR2Red fluorescence protein (RFP)/Wild type (WT)/CX3CR1Green fluorescence protein (GFP)/WT-Tg mice, which heterozygously express CCR2-RFP and CX3CR1-GFP, and SOD1G93A/CCR2RFP/RFP-Tg mice, which lack CCR2 protein expression and present with a CCR2-deficient phenotype. In mSOD1-Tg mice, mSOD1 accumulated in the sciatic nerve earlier than in the spinal cord. Furthermore, spinal cords of SOD1G93A/CCR2RFP/WT/CX3CR1GFP/WT mice showed peripheral macrophage infiltration that emerged at the end-stage, whereas in peripheral nerves, macrophage infiltration started from the pre-symptomatic stage. Before disease onset, CCR2+ macrophages harboring mSOD1 infiltrated sciatic nerves earlier than the lumbar cord. CCR2-deficient mSOD1-Tg mice showed an earlier onset and axonal derangement in the sciatic nerve than CCR2-positive mSOD1-Tg mice. CCR2-deficient mSOD1-Tg mice showed an increase in deposited mSOD1 in the sciatic nerve compared with CCR2-positive mice. These findings suggest that CCR2+ and CX3CR1+ macrophages exert neuroprotective functions in mSOD1 ALS via mSOD1 clearance from the peripheral nerves.


Assuntos
Macrófagos/patologia , Doença dos Neurônios Motores/patologia , Mutação , Nervos Periféricos/metabolismo , Receptores CCR2/metabolismo , Animais , Receptor 1 de Quimiocina CX3C/genética , Progressão da Doença , Humanos , Camundongos , Camundongos Transgênicos , Receptores CCR2/genética , Medula Espinal/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
6.
Sci Rep ; 11(1): 16801, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34413352

RESUMO

The lymphatic network of mammalian heart is an important regulator of interstitial fluid compartment and immune cell trafficking. We observed a remodeling of the cardiac lymphatic vessels and a reduced lymphatic efficiency during heart hypertrophy and failure induced by transverse aortic constriction. The lymphatic endothelial cell number of the failing hearts was positively correlated with cardiac function and with a subset of cardiac macrophages. This macrophage population distinguished by LYVE-1 (Lymphatic vessel endothelial hyaluronic acid receptor-1) and by resident macrophage gene expression signature, appeared not replenished by CCR2 mediated monocyte infiltration during pressure overload. Isolation of macrophage subpopulations showed that the LYVE-1 positive subset sustained in vitro and in vivo lymphangiogenesis through the expression of pro-lymphangiogenic factors. In contrast, the LYVE-1 negative macrophage subset strongly expressed MMP12 and decreased the endothelial LYVE-1 receptors in lymphatic endothelial cells, a feature of cardiac lymphatic remodeling in failing hearts. The treatment of mice with a CCR2 antagonist during pressure overload modified the proportion of macrophage subsets within the pathological heart and preserved lymphatic network from remodeling. This study reports unknown and differential functions of macrophage subpopulations in the regulation of cardiac lymphatic during pathological hypertrophy and may constitute a key mechanism underlying the progression of heart failure.


Assuntos
Vasos Linfáticos/metabolismo , Macrófagos/metabolismo , Miocárdio/patologia , Pressão , Animais , Benzoxazinas/farmacologia , Células CHO , Polaridade Celular/efeitos dos fármacos , Cricetulus , Eletrocardiografia , Células Endoteliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Linfangiogênese/efeitos dos fármacos , Vasos Linfáticos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Monócitos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores CCR2/metabolismo , Compostos de Espiro/farmacologia , Transcriptoma , Proteínas de Transporte Vesicular/metabolismo
7.
Biochem Biophys Res Commun ; 572: 171-177, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34371259

RESUMO

Chemokine receptors are generally sulfated at tyrosine residues of the N-terminal region. Tyrosine sulfation of the C-C chemokine receptor type 2 (CCR2) enhances its interaction with the chemokine ligand CCL2. Here, we generated a recombinant sulfated CCR2 peptide trap (mCCR2-S2) and investigated its effects on retinal degeneration in mice. Treatment with mCCR2-S2 reduced choroidal neovascularization (CNV) in a laser-induced CNV mouse model. In NaIO3-injected mice, treatment with mCCR2-S2 increased the outer nuclear layer thickness and rhodopsin expression in the retinas compared to that in mice treated with mCCR2-wild-type or glutathione S-transferase controls. Furthermore, glial fibrillary acidic protein (GFAP) expression and macrophage infiltration were decreased in mCCR2-S2-treated retinas. Recombinant mCCR2-S2 suppressed CNV development and retinal degeneration, possibly by regulating macrophage infiltration. Thus, the sulfated form of the CCR2 peptide trap may be a useful tool for treating patients with retinal degeneration, such as those with age-related macular degeneration and intraocular inflammatory disorders.


Assuntos
Receptores CCR2/metabolismo , Degeneração Retiniana/metabolismo , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Recombinantes/metabolismo
8.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299260

RESUMO

The CD73 pathway is an important anti-inflammatory mechanism in various disease settings. Observations in mouse models suggested that CD73 might have a protective role in kidney damage; however, no direct evidence of its role in human kidney disease has been described to date. Here, we hypothesized that podocyte injury in human kidney diseases alters CD73 expression that may facilitate the diagnosis of podocytopathies. We assessed the expression of CD73 and one of its functionally important targets, the C-C chemokine receptor type 2 (CCR2), in podocytes from kidney biopsies of 39 patients with podocytopathy (including focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranous glomerulonephritis (MGN) and amyloidosis) and a control group. Podocyte CD73 expression in each of the disease groups was significantly increased in comparison to controls (p < 0.001-p < 0.0001). Moreover, there was a marked negative correlation between CD73 and CCR2 expression, as confirmed by immunohistochemistry and immunofluorescence (Pearson r = -0.5068, p = 0.0031; Pearson r = -0.4705, p = 0.0313, respectively), thus suggesting a protective role of CD73 in kidney injury. Finally, we identify CD73 as a novel potential diagnostic marker of human podocytopathies, particularly of MCD that has been notorious for the lack of pathological features recognizable by light microscopy and immunohistochemistry.


Assuntos
5'-Nucleotidase/genética , Nefropatias/metabolismo , Podócitos/metabolismo , 5'-Nucleotidase/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Humanos , Rim/metabolismo , Rim/patologia , Nefropatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Podócitos/fisiologia , Proteinúria , Receptores CCR2/genética , Receptores CCR2/metabolismo
9.
Science ; 373(6550)2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34210853

RESUMO

The mechanisms by which macrophages regulate energy storage remain poorly understood. We identify in a genetic screen a platelet-derived growth factor (PDGF)/vascular endothelial growth factor (VEGF)-family ortholog, Pvf3, that is produced by macrophages and is required for lipid storage in fat-body cells of Drosophila larvae. Genetic and pharmacological experiments indicate that the mouse Pvf3 ortholog PDGFcc, produced by adipose tissue-resident macrophages, controls lipid storage in adipocytes in a leptin receptor- and C-C chemokine receptor type 2-independent manner. PDGFcc production is regulated by diet and acts in a paracrine manner to control lipid storage in adipose tissues of newborn and adult mice. At the organismal level upon PDGFcc blockade, excess lipids are redirected toward thermogenesis in brown fat. These data identify a macrophage-dependent mechanism, conducive to the design of pharmacological interventions, that controls energy storage in metazoans.


Assuntos
Adipócitos/imunologia , Dieta Hiperlipídica , Proteínas de Drosophila/metabolismo , Metabolismo Energético , Linfocinas/metabolismo , Macrófagos/imunologia , Obesidade/imunologia , Fator de Crescimento Derivado de Plaquetas/metabolismo , Termogênese , Tecido Adiposo Marrom/imunologia , Animais , Proteínas de Drosophila/genética , Drosophila melanogaster , Feminino , Hemócitos/imunologia , Fígado/imunologia , Linfocinas/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator de Crescimento Derivado de Plaquetas/genética , Receptores CCR2/genética , Receptores CCR2/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
10.
Sci Rep ; 11(1): 14950, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34294770

RESUMO

The inflammatory chemokines, monocyte chemoattractant protein (MCP)-1 and IL-8, are produced by normal trabecular meshwork cells (TM) and elevated in the aqueous humor of primary open angle glaucoma (POAG) and hypertensive anterior uveitis associated with viral infection. However, their role in TM cells and aqueous humor outflow remains unclear. Here, we explored the possible involvement of MCP-1 and IL-8 in the physiology of TM cells in the context of aqueous outflow, and the viral anterior uveitis. We found that the stimulation of human TM cells with MCP-1 and IL-8 induced significant increase in the formation of actin stress fibers and focal adhesions, myosin light chain phosphorylation, and the contraction of TM cells. MCP-1 and IL-8 also demonstrated elevation of extracellular matrix proteins, and the migration of TM cells. When TM cells were infected with HSV-1 and CMV virus, there was a significant increase in cytoskeletal contraction and Rho-GTPase activation. Viral infection of TM cells revealed significantly increased expression of MCP-1 and IL-8. Taken together, these results indicate that MCP-1 and IL-8 induce TM cell contractibility, fibrogenic activity, and plasticity, which are presumed to increase resistance to aqueous outflow in viral anterior uveitis and POAG.


Assuntos
Quimiocina CCL2/metabolismo , Infecções Oculares Virais/imunologia , Interleucina-8/metabolismo , Malha Trabecular/citologia , Uveíte Anterior/virologia , Adulto , Humor Aquoso/imunologia , Movimento Celular , Células Cultivadas , Citomegalovirus/patogenicidade , Proteínas da Matriz Extracelular/metabolismo , Infecções Oculares Virais/patologia , Herpesvirus Humano 1/patogenicidade , Humanos , Pessoa de Meia-Idade , Cultura Primária de Células , Receptores CCR2/metabolismo , Receptores de Interleucina-8A/metabolismo , Malha Trabecular/imunologia , Malha Trabecular/virologia , Uveíte Anterior/imunologia , Uveíte Anterior/patologia
11.
Nat Commun ; 12(1): 3543, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112803

RESUMO

Metastatic spread of a cancer to secondary sites is a coordinated, non-random process. Cancer cell-secreted vesicles, especially exosomes, have recently been implicated in the guidance of metastatic dissemination, with specific surface composition determining some aspects of organ-specific localization. Nevertheless, whether the tumor microenvironment influences exosome biodistribution has yet to be investigated. Here, we show that microenvironmental cytokines, particularly CCL2, decorate cancer exosomes via binding to surface glycosaminoglycan side chains of proteoglycans, causing exosome accumulation in specific cell subsets and organs. Exosome retention results in changes in the immune landscape within these organs, coupled with a higher metastatic burden. Strikingly, CCL2-decorated exosomes are directed to a subset of cells that express the CCL2 receptor CCR2, demonstrating that exosome-bound cytokines are a crucial determinant of exosome-cell interactions. In addition to the finding that cytokine-conjugated exosomes are detected in the blood of cancer patients, we discovered that healthy subjects derived exosomes are also associated with cytokines. Although displaying a different profile from exosomes isolated from cancer patients, it further indicates that specific combinations of cytokines bound to exosomes could likewise affect other physiological and disease settings.


Assuntos
Neoplasias da Mama/sangue , Quimiocina CCL2/metabolismo , Exossomos/metabolismo , Receptores CCR2/metabolismo , Microambiente Tumoral , Animais , Neoplasias da Mama/patologia , Citocinas/metabolismo , Exossomos/imunologia , Exossomos/patologia , Feminino , Glicosaminoglicanos/metabolismo , Humanos , Células Matadoras Naturais/imunologia , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Metástase Neoplásica , Proteoglicanas/metabolismo , Receptores de Citocinas/metabolismo , Baço/imunologia , Baço/metabolismo , Baço/patologia , Linfócitos T/imunologia , Microambiente Tumoral/imunologia
12.
J Am Heart Assoc ; 10(12): e019521, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34056918

RESUMO

Background The opening of mitochondrial permeability transition pore and inflammation cooperatively progress myocardial ischemia-reperfusion (IR) injury, which hampers therapeutic effects of primary reperfusion therapy for acute myocardial infarction. We examined the therapeutic effects of nanoparticle-mediated medicine that simultaneously targets mitochondrial permeability transition pore and inflammation during IR injury. Methods and Results We used mice lacking cyclophilin D (CypD, a key molecule for mitochondrial permeability transition pore opening) and C-C chemokine receptor 2 and found that CypD contributes to the progression of myocardial IR injury at early time point (30-45 minutes) after reperfusion, whereas C-C chemokine receptor 2 contributes to IR injury at later time point (45-60 minutes) after reperfusion. Double deficiency of CypD and C-C chemokine receptor 2 enhanced cardioprotection compared with single deficiency regardless of the durations of ischemia. Deletion of C-C chemokine receptor 2, but not deletion of CypD, decreased the recruitment of Ly-6Chigh monocytes after myocardial IR injury. In CypD-knockout mice, administration of interleukin-1ß blocking antibody reduced the recruitment of these monocytes. Combined administration of polymeric nanoparticles composed of poly-lactic/glycolic acid and encapsulating nanoparticles containing cyclosporine A or pitavastatin, which inhibit mitochondrial permeability transition pore opening and monocyte-mediated inflammation, respectively, augmented the cardioprotection as compared with single administration of nanoparticles containing cyclosporine A or pitavastatin after myocardial IR injury. Conclusions Nanoparticle-mediated simultaneous targeting of mitochondrial injury and inflammation could be a novel therapeutic strategy for the treatment of myocardial IR injury.


Assuntos
Anti-Inflamatórios/farmacologia , Ciclosporina/farmacologia , Portadores de Fármacos , Mitocôndrias Cardíacas/efeitos dos fármacos , Poro de Transição de Permeabilidade Mitocondrial/antagonistas & inibidores , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Nanopartículas , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Quinolinas/farmacologia , Animais , Anti-Inflamatórios/química , Ciclofilina D/genética , Ciclofilina D/metabolismo , Ciclosporina/química , Modelos Animais de Doenças , Combinação de Medicamentos , Composição de Medicamentos , Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Poro de Transição de Permeabilidade Mitocondrial/metabolismo , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Quinolinas/química , Receptores CCR2/genética , Receptores CCR2/metabolismo , Fatores de Tempo
13.
Cells ; 10(5)2021 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-33946919

RESUMO

Osteoarthritis (OA) is the most common form of arthritis and age-related degenerative joint disorder, which adversely affects quality of life and causes disability. However, the pathogenesis of OA remains unclear. This study was performed to examine the effects of Lactobacillus rhamnosus in OA progression. OA was induced in 6-week-old male Wistar rats by monosodium iodoacetate (MIA) injection, and the effects of oral administration of L. rhamnosus were examined in this OA rat model. Pain severity, cartilage destruction, and inflammation were measured in MIA-induced OA rats. The small intestines were isolated from OA rats, and the intestinal structure and inflammation were measured. Protein expression in the dorsal root ganglion was analyzed by immunohistochemistry. The effects of L. rhamnosus on mRNA and protein expression in chondrocytes stimulated with interleukin (IL)-1ß and lipopolysaccharide (LPS) were analyzed by real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Pain severity was decreased in L. rhamnosus-treated MIA-induced OA rats. The levels of expression of MCP-1, a potential inflammatory cytokine, and its receptor, CCR2, were decreased, and GABA and PPAR-γ expression were increased in L. rhamnosus-treated OA rats. The inflammation, as determined by IL-1ß, and cartilage destruction, as determined by MMP3, were also significantly decreased by L. rhamnosus in OA rats. Additionally, intestinal damage and inflammation were improved by L. rhamnosus. In human OA chondrocytes, TIMP1, TIMP3, SOX9, and COL2A1 which are tissue inhibitors of MMP, and IL-10, an anti-inflammatory cytokine, were increased by L. rhamnosus. L. rhamnosus treatment led to decreased pain severity and cartilage destruction in a rat model of OA. Intestinal damage and inflammation were also decreased by L. rhamnosus treatment. Our findings suggested the therapeutic potential of L. rhamnosus in OA.


Assuntos
Terapia Biológica/métodos , Lactobacillus rhamnosus/patogenicidade , Osteoartrite/terapia , Manejo da Dor/métodos , Probióticos , Animais , Células Cultivadas , Quimiocina CCL2/metabolismo , Condrócitos/metabolismo , Colágeno/metabolismo , Gânglios Espinais/metabolismo , Humanos , Interleucina-1beta/metabolismo , Articulações/metabolismo , Articulações/patologia , Osteoartrite/microbiologia , PPAR gama/metabolismo , Ratos , Ratos Wistar , Receptores CCR2/metabolismo , Fatores de Transcrição SOX9/metabolismo , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidor Tecidual de Metaloproteinase-3/metabolismo
14.
Front Immunol ; 12: 621665, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33815375

RESUMO

Toll-like receptor 5 (TLR5) is the receptor of bacterial Flagellin. Reportedly, TLR5 engagement helps to combat infections, especially at mucosal sites, by evoking responses from epithelial cells and immune cells. Here we report that TLR5 is expressed on a previously defined bipotent progenitor of macrophages (MΦs) and osteoclasts (OCs) that resides in the mouse bone marrow (BM) and circulates at low frequency in the blood. In vitro, Flagellin promoted the generation of MΦs, but not OCs from this progenitor. In vivo, MΦ/OC progenitors were recruited from the blood into the lung upon intranasal inoculation of Flagellin, where they rapidly differentiated into MΦs. Recruitment of the MΦ/OC progenitors into the lung was likely promoted by the CCL2/CCR2 axis, since the progenitors expressed CCR2 and type 2 alveolar epithelial cells (AECs) produced CCL2 upon stimulation by Flagellin. Moreover, CCR2 blockade reduced migration of the MΦ/OC progenitors toward lung lavage fluid (LLF) from Flagellin-inoculated mice. Our study points to a novel role of the Flagellin/TLR5 axis in recruiting circulating MΦ/OC progenitors into infected tissue and stimulating these progenitors to locally differentiate into MΦs. The progenitor pathway to produce MΦs may act, next to monocyte recruitment, to fortify host protection against bacterial infection at mucosal sites.


Assuntos
Flagelina/metabolismo , Pulmão/imunologia , Macrófagos/fisiologia , Células Progenitoras Mieloides/fisiologia , Osteoclastos/fisiologia , Receptor 5 Toll-Like/metabolismo , Animais , Diferenciação Celular , Movimento Celular , Células Cultivadas , Quimiocina CCL2/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores CCR2/metabolismo , Transdução de Sinais
15.
Cells ; 10(4)2021 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-33918875

RESUMO

Tumor necrosis factor receptor 1 and 2 (TNFR1 and TNFR2) have been found in brain parenchyma of stroke patients, and plasma levels are increased in the acute phase of stroke. We evaluated associations between TNFR1 and TNFR2 plasma levels and stroke severity, infarct size, and functional outcome. Furthermore, we examined cellular expression of TNFR1 and TNFR2 on leukocyte subpopulations to explore the origin of the increased receptor levels. Blood samples were taken from 33 acute ischemic stroke patients and 10 healthy controls. TNFR1 and TNFR2 plasma concentrations were measured and correlated against the Scandinavian Stroke Scale at admission, infarct volume, and the modified Rankin Scale score three months after stroke onset. Classical, intermediate, and non-classical monocytes as well as neutrophils were purified, and cellular expression of TNFR1 and TNFR2 was examined using flow cytometry. TNFR1 and TNFR2 plasma levels were both increased after ischemic stroke, but we found no correlation with patient outcome measurements. Compared to healthy controls, ischemic stroke patients had decreased non-classical monocyte and neutrophil populations expressing TNFR1 and increased neutrophils expressing TNFR2, and decreased non-classical populations co-expressing both TNFR1 and TNFR2. This study supports the hypothesis of an acute immunological response orchestrated by the peripheral immune system following an ischemic stroke. However, the origin of the increased TNFR1 and TNFR2 plasma levels could not be clearly linked to peripheral monocytes or neutrophils. Future studies are needed and will help clarify the potential role as treatment target.


Assuntos
Imunidade , AVC Isquêmico/imunologia , Leucócitos/metabolismo , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Idoso , Estudos de Casos e Controles , Feminino , Proteína Glial Fibrilar Ácida/sangue , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Interleucina-6/sangue , AVC Isquêmico/sangue , AVC Isquêmico/diagnóstico por imagem , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Proteínas de Neurofilamentos/sangue , Neutrófilos/metabolismo , Receptores CCR2/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/sangue , Receptores Tipo II do Fator de Necrose Tumoral/sangue , Índice de Gravidade de Doença , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/imunologia , Resultado do Tratamento
16.
Sci Rep ; 11(1): 8708, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33888841

RESUMO

Ductal carcinoma in situ (DCIS) is the most common type of pre-invasive breast cancer diagnosed in women. Because the majority of DCIS cases are unlikely to progress to invasive breast cancer, many women are over-treated for DCIS. By understanding the molecular basis of early stage breast cancer progression, we may identify better prognostic factors and design treatments tailored specifically to the predicted outcome of DCIS. Chemokines are small soluble molecules with complex roles in inflammation and cancer progression. Previously, we demonstrated that CCL2/CCR2 chemokine signaling in breast cancer cell lines regulated growth and invasion through p42/44MAPK and SMAD3 dependent mechanisms. Here, we sought to determine the clinical and functional relevance of CCL2/CCR2 signaling proteins to DCIS progression. Through immunostaining analysis of DCIS and IDC tissues, we show that expression of CCL2, CCR2, phospho-SMAD3 and phospho-p42/44MAPK correlate with IDC. Using PDX models and an immortalized hDCIS.01 breast epithelial cell line, we show that breast epithelial cells with high CCR2 and high CCL2 levels form invasive breast lesions that express phospho-SMAD3 and phospho-p42/44MAPK. These studies demonstrate that increased CCL2/CCR2 signaling in breast tissues is associated with DCIS progression, and could be a signature to predict the likelihood of DCIS progression to IDC.


Assuntos
Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Quimiocina CCL2/metabolismo , Invasividade Neoplásica , Receptores CCR2/metabolismo , Transdução de Sinais , Animais , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Progressão da Doença , Feminino , Xenoenxertos , Humanos , Camundongos , Pessoa de Meia-Idade
17.
J Med Chem ; 64(6): 3367-3380, 2021 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-33683903

RESUMO

Achieving selective inhibition of chemokine activity by structurally well-defined heparan sulfate (HS) or HS mimetic molecules can provide important insights into their roles in individual physiological and pathological cellular processes. Here, we report a novel tailor-made HS mimetic, which furnishes an exclusive iduronic acid (IdoA) scaffold with different sulfation patterns and oligosaccharide chain lengths as potential ligands to target chemokines. Notably, highly sulfated-IdoA tetrasaccharide (I-45) exhibited strong binding to CCL2 chemokine thereby blocking CCL2/CCR2-mediated in vitro cancer cell invasion and metastasis. Taken together, IdoA-based HS mimetics offer an alternative HS substrate to generate selective and efficient inhibitors for chemokines and pave the way to a wide range of new therapeutic applications in cancer biology and immunology.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Heparitina Sulfato/química , Heparitina Sulfato/farmacologia , Ácido Idurônico/química , Ácido Idurônico/farmacologia , Linhagem Celular Tumoral , Quimiocina CCL2/metabolismo , Humanos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Receptores CCR2/metabolismo
18.
Front Immunol ; 12: 628906, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33777013

RESUMO

Chimeric antigen receptor (CAR) T cell therapy faces a number of challenges for the treatment of non-small-cell lung carcinoma (NSCLC), and efficient migration of circulating CAR T cells plays an important role in anti-tumor activity. In this study, a CAR specific for tumor antigen mesothelin (Msln-CAR) was co-expressed with cell chemokine receptors CCR2b or CCR4. Findings showed that CCR2b and CCR4 enhanced the migration of Msln-CAR T cell in vitro by transwell assay. When incubated with mesothelin-positive tumor cells, Msln-CCR2b-CAR and Msln-CCR4-CAR T cell specifically exerted potent cytotoxicity and produced high levels of proinflammatory cytokines, including IL-2, IFN-γ, and TNF-α. Furthermore, NSCLC cell line-derived xenograft (CDX) model was constructed by implanting subcutaneously modified A549 into NSG mice. Compared to conventional Msln-CAR T cells, living imaging indicated that Msln-CCR2b-CAR T cells displayed superior anti-tumor function due to enhanced migration and infiltration into tumor tissue shown by immunohistochemistry (IHC) analysis. In addition, histopathological examinations of mice organs showed that no obvious organic damages were observed. This is the first time that CAR T cell therapy combined with chemokine receptor is applied to NSCLC treatment.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/terapia , Proteínas Ligadas por GPI/metabolismo , Imunoterapia Adotiva , Neoplasias Pulmonares/terapia , Receptores CCR2/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/transplante , Células A549 , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Quimiotaxia de Leucócito , Citocinas/metabolismo , Citotoxicidade Imunológica , Feminino , Proteínas Ligadas por GPI/imunologia , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Camundongos Endogâmicos NOD , Camundongos SCID , Receptores CCR2/genética , Receptores CCR4/genética , Receptores CCR4/metabolismo , Receptores de Antígenos Quiméricos/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
19.
J Cell Physiol ; 236(10): 7211-7222, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33782965

RESUMO

Monocyte chemoattractant protein-1, also called chemokine (C-C motif) ligand 2 (CCL2) or small inducible cytokine A2, is an inflammatory mediator capable of recruiting monocytes, memory T cells, and dendritic cells. CCL2 is a member of the CC chemokine superfamily, which binds to its receptor, C-C motif chemokine receptor-2 (CCR2), for the induction of chemotactic activity and an increase of calcium influx. It exerts multiple effects on a variety of cells, including monocytes, macrophages, osteoclasts, basophils, and endothelial cells, and is involved in a diverse range of diseases. This review discusses the molecular structure and role of CCL2 and CCR2 in skeletal biology and disease. Molecular structure analyses reveal that CCL2 shares a conserved C-C motif; however, it has only limited sequence homology with other CCL family members. Likewise, CCR2, as a member of the G-protein-coupled seven-transmembrane receptor superfamily, shares conserved cysteine residues, but exhibits very limited sequence homology with other CCR family members. In the skeletal system, the expression of CCL2 is regulated by a variety of factors, such as parathyroid hormone/parathyroid hormone-related peptide, interleukin 1b, tumor necrosis factor-α and transforming growth factor-beta, RANKL, and mechanical forces. The interaction of CCL2 and CCR2 activates several signaling cascades, including PI3K/Akt/ERK/NF-κB, PI3K/MAPKs, and JAK/STAT-1/STAT-3. Understanding the role of CCL2 and CCR2 will facilitate the development of novel therapies for skeletal disorders, including rheumatoid arthritis, osteolysis and other inflammatory diseases related to abnormal chemotaxis.


Assuntos
Doenças Ósseas/metabolismo , Remodelação Óssea , Osso e Ossos/metabolismo , Quimiocina CCL2/metabolismo , Osteogênese , Receptores CCR2/metabolismo , Animais , Doenças Ósseas/diagnóstico , Doenças Ósseas/tratamento farmacológico , Doenças Ósseas/fisiopatologia , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/patologia , Osso e Ossos/fisiopatologia , Quimiocina CCL2/antagonistas & inibidores , Quimiocina CCL2/química , Humanos , Osteogênese/efeitos dos fármacos , Conformação Proteica , Receptores CCR2/antagonistas & inibidores , Receptores CCR2/química , Transdução de Sinais , Relação Estrutura-Atividade
20.
J Neuroinflammation ; 18(1): 64, 2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33653377

RESUMO

BACKGROUND: Immune cell infiltration and neuroinflammation are heavily associated with spinal cord injury (SCI). C-C motif chemokine ligand 2/C-C chemokine receptor type 2 (CCL2/CCR2) axis has been identified as a critical role player during the invasion of immune cells to lesions in many diseases. γδ T cells, a subgroup of T cells, manage the course of inflammation response in various diseases; however, it remains unknown whether γδ T cells are recruited to injury site through CCL2/CCR2 signaling and exert the regulation effect on neuroinflammation after SCI. METHODS: Basso Mouse Scale (BMS), regularity index, cadence, max contact area, and motor-evoked potential testing (MEP) were measured to determine the neurological function recovery after spinal cord injury. Nissl staining was performed to identify the number of surviving motor neurons at lesion epicenter. Immunofluorescence, Western blot, enzyme-linked immunosorbent assays (ELISA), and quantitative real-time polymerase chain reaction (QRT-PCR) also were employed to evaluate the expression of associated proteins and genes. RESULTS: In this study, we demonstrated that TCRδ-/- mice present improved neurological recovery after SCI. γδ T cell recruitment to the SCI site was significantly reduced and motor functional improvement enhanced in CCL2-/- and CCR2-/- mouse strains. Furthermore, reconstitution of TCRδ-/- mice with γδ T cells extracted from CCR2-/- mice also showed similar results to CCL2 and CCR2 deficient mice. CONCLUSIONS: In conclusion, γδ T cell recruitment to SCI site promotes inflammatory response and exacerbates neurological impairment. CCL2/CCR2 signaling is a vital recruitment mechanism of γδ T cells to the SCI site, and it may be taken as a novel therapeutic target for future SCI.


Assuntos
Quimiocina CCL2/imunologia , Receptores CCR2/imunologia , Transdução de Sinais/imunologia , Traumatismos da Medula Espinal/imunologia , Linfócitos T/imunologia , Animais , Quimiocina CCL2/metabolismo , Quimiotaxia de Leucócito/imunologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Receptores CCR2/metabolismo , Traumatismos da Medula Espinal/patologia , Linfócitos T/metabolismo
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