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1.
Clin Lab Med ; 39(1): 171-183, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30709505

RESUMO

Immunosuppression is essential to prevent graft rejection. However, immunosuppression impairs the ability of the host immune system to control viral infection and decreases tumor immunosurveillance. Therefore, immunosuppression after organ transplantation is a major risk factor for posttransplantation cancer. Notably, recent reports suggest that immunosuppressive agents can activate tumorigenic pathways independent of the involvement of the host immune system. In this review, we focus on cell-intrinsic tumorigenic pathways directly activated by immunosuppressive agents and discuss the much-described infection- and immune-mediated mechanisms of cancer development in organ transplant recipients.


Assuntos
Imunossupressão/efeitos adversos , Neoplasias/imunologia , Transplante de Órgãos/efeitos adversos , Transdução de Sinais , Citocinas/metabolismo , Citocinas/fisiologia , Humanos , Neoplasias/metabolismo , Receptores de Quimiocinas/metabolismo , Receptores de Quimiocinas/fisiologia
2.
Arterioscler Thromb Vasc Biol ; 39(4): 583-592, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30760014

RESUMO

With the incidence and impact of atherosclerotic cardiovascular disease and its clinical manifestations still rising, therapeutic options that target the causal mechanisms of this disorder are highly desired. Since the CANTOS trial (Canakinumab Antiinflammatory Thrombosis Outcome Study) has demonstrated that lowering inflammation can be beneficial, focusing on mechanisms underlying inflammation, for example, leukocyte recruitment, is feasible. Being key orchestrators of leukocyte trafficking, chemokines have not lost their attractiveness as therapeutic targets, despite the difficult road to drug approval thus far. Still, innovative therapeutic approaches are being developed, paving the road towards the first chemokine-based therapeutic against inflammation. In this overview, recent developments for chemokines and for the chemokine-like factor MIF (macrophage migration inhibitory factor) will be discussed.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Quimiocinas/antagonistas & inibidores , Terapia de Alvo Molecular , Anticorpos Monoclonais Humanizados/uso terapêutico , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Aterosclerose/fisiopatologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Quimiocinas/fisiologia , Quimiotaxia de Leucócito , Ensaios Clínicos como Assunto , Previsões , Humanos , Inflamação/complicações , Inflamação/tratamento farmacológico , Oxirredutases Intramoleculares/antagonistas & inibidores , Oxirredutases Intramoleculares/fisiologia , Fatores Inibidores da Migração de Macrófagos/antagonistas & inibidores , Fatores Inibidores da Migração de Macrófagos/fisiologia , Estudos Multicêntricos como Assunto , Receptores de Quimiocinas/antagonistas & inibidores , Receptores de Quimiocinas/fisiologia , Terapias em Estudo/métodos , Pesquisa Médica Translacional
4.
Hypertension ; 73(2): 440-448, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30595125

RESUMO

Studies from our laboratory have revealed an important role for the maternal diet and the dietary protein source in the development of hypertension and renal injury in Dahl salt-sensitive (SS) rats. The current study sought to compare salt-induced hypertension, renal damage, and immune cell infiltration in the offspring of breeders fed either a casein- or gluten-based diet, with the hypothesis that offspring from gluten-fed breeders would fail to develop these SS phenotypes. When fed identical diets post-weaning, the F1 generation gluten offspring demonstrated lower mean arterial pressure (149.1±3.1 versus 162.5±5.8 mm Hg), albuminuria (166.2±34.6 versus 250.9±27.8 mg/day), and outer medullary protein casting (7.4±0.8% versus 13.1±1.3%) in response to high salt compared with the casein offspring (n=9-11). The gluten offspring also had fewer CD45+ leukocytes, CD11b/c+ monocytes/macrophages, CD3+ T cells, and CD45R+ B cells infiltrating the kidney. Analysis of the F2 generation gluten offspring also exhibited lower mean arterial pressure and renal damage compared with rats born from casein breeders (n=7-9), with no difference in renal immune cell infiltration. CMKLR1-receptor for the novel prohypertensive adipokine chemerin-was found via polymerase chain reaction array to be significantly upregulated (2.99-fold) in renal T cells isolated from F2 offspring of casein-fed versus gluten-fed parents. Furthermore, CMKLR1 inhibition via α-NETA (2-[α-naphthoyl] ethyltrimethylammonium iodide) treatment significantly attenuated renal immune cell infiltration, hypertension, and renal damage in SS rats fed high salt. Together, these data demonstrate the influence of the parental diet in determining the salt-induced hypertension, renal damage, and inflammatory phenotype of the offspring.


Assuntos
Proteínas na Dieta/administração & dosagem , Hipertensão/etiologia , Fenômenos Fisiológicos da Nutrição Materna , Receptores de Quimiocinas/fisiologia , Animais , Caseínas/administração & dosagem , Feminino , Glutens/administração & dosagem , Rim/imunologia , Rim/patologia , Masculino , Ratos , Ratos Endogâmicos Dahl , Receptores de Quimiocinas/antagonistas & inibidores , Índice de Gravidade de Doença
5.
J Endod ; 44(9): 1396-1401, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30032862

RESUMO

INTRODUCTION: We recently reported that caries-associated C5a receptor (C5aR) expression and activation result in up-regulation of brain-derived neurotropic factor secretion by pulp fibroblasts inducing prominent neurite outgrowth toward the carious site. Our data further showed a negative regulation of this brain-derived neurotropic factor secretion by C5L2, another C5aR. C5L2 was considered a nonfunctional receptor and thus has received much less attention than C5aR. The aim of this study was to identify the role of C5L2 in pulp fibroblast-mediated neurite outgrowth. METHODS: In this study, lipoteichoic acid (LTA) was used to mimic dental caries-like inflammation. To evaluate the role of C5L2 in pulp neurite outgrowth, human pulp fibroblasts were C5L2 small interfering RNA silenced and cocultured with human neurons in a nerve growth assay system. RESULTS: C5L2 silencing drastically increased the neurite outgrowth toward the LTA-stimulated pulp fibroblasts. The number of neurites detected was increased in the LTA-treated pulp fibroblasts. CONCLUSIONS: Our results show that C5L2 constitutes a negative regulator of the neurite outgrowth under LTA stimulation. Of the events occurring during dentin-pulp regeneration, nerve regeneration is the key factor for maintaining tooth viability after infection or injury. Our study provides a foundation for creating therapeutic tools that target pulp fibroblasts during pulp/nerve regeneration.


Assuntos
Polpa Dentária/citologia , Fibroblastos , Inativação Gênica , Lipopolissacarídeos/farmacologia , Neuritos/efeitos dos fármacos , Neuritos/fisiologia , RNA Interferente Pequeno/genética , Receptores de Quimiocinas/genética , Ácidos Teicoicos/farmacologia , Células Cultivadas , Expressão Gênica , Humanos , Receptor da Anafilatoxina C5a , Receptores de Quimiocinas/fisiologia
6.
PLoS Comput Biol ; 14(6): e1006209, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29912865

RESUMO

Chemokines and their receptors (members of the GPCR super-family) are involved in a wide variety of physiological processes and diseases; thus, understanding the specificity of the chemokine receptor family could help develop new receptor specific drugs. Here, we explore the evolutionary mechanisms that led to the emergence of the chemokine receptors. Based on GPCR hierarchical classification, we analyzed nested GPCR sets with an eigen decomposition approach of the sequence covariation matrix and determined three key residues whose mutation was crucial for the emergence of the chemokine receptors and their subsequent divergence into homeostatic and inflammatory receptors. These residues are part of the allosteric sodium binding site. Their structural and functional roles were investigated by molecular dynamics simulations of CXCR4 and CCR5 as prototypes of homeostatic and inflammatory chemokine receptors, respectively. This study indicates that the three mutations crucial for the evolution of the chemokine receptors dramatically altered the sodium binding mode. In CXCR4, the sodium ion is tightly bound by four protein atoms and one water molecule. In CCR5, the sodium ion is mobile within the binding pocket and moves between different sites involving from one to three protein atoms and two to five water molecules. Analysis of chemokine receptor evolution reveals that a highly constrained sodium binding site characterized most ancient receptors, and that the constraints were subsequently loosened during the divergence of this receptor family. We discuss the implications of these findings for the evolution of the chemokine receptor functions and mechanisms of action.


Assuntos
Receptores CCR5/genética , Receptores CXCR4/genética , Sódio/metabolismo , Sítio Alostérico , Sequência de Aminoácidos/genética , Sítios de Ligação/genética , Sítios de Ligação/fisiologia , Evolução Biológica , Quimiocinas/genética , Quimiocinas/metabolismo , Simulação por Computador , Evolução Molecular , Humanos , Simulação de Dinâmica Molecular , Mutação/genética , Filogenia , Análise de Componente Principal/métodos , Ligação Proteica/genética , Conformação Proteica , Receptores CCR5/fisiologia , Receptores CXCR4/fisiologia , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/fisiologia , Transdução de Sinais
7.
Brain Behav Immun ; 70: 280-292, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29545116

RESUMO

Stroke is the second cause of mortality worldwide and occurs following the interruption of cerebral blood circulation by cerebral vessel burst or subsequent to a local thrombus formation. Ischemic lesion triggers an important inflammatory response, characterized by massive infiltration of leukocytes, activation of glial cells and neurovascular reorganization. Chemokines and their receptors, such as CCR2 and CX3CR1, play an important role in leukocyte recruitment in the damaged area. Mice genetically depleted for the two receptors CCR2 and CX3CR1 underwent focal cerebral ischemia, based on the topical application of ferric chloride to truncate the distal middle cerebral artery. The infarct, limited only to the cortical area, remained stable in WT mice, while it is reduced overtime in the transgenic mice. Moreover, we did not observe any significant changes in the level of the inflammatory response in the infarcted areas while immune cell infiltration and neurovascularization are modulated according to genotype. Our results show that the genetic deletion of both CCR2 and CX3CR1 receptors has neuroprotective effects in response to a cerebral permanent ischemia. This study underlines a key role of CCR2- and CX3CR1-expressing immune cells in the neuropathology associated with ischemic injuries.


Assuntos
Receptor 1 de Quimiocina CX3C/fisiologia , Receptores CCR2/fisiologia , Acidente Vascular Cerebral/fisiopatologia , Animais , Encéfalo , Quimiocinas/fisiologia , Modelos Animais de Doenças , Trombose Intracraniana/fisiopatologia , Macrófagos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Monócitos , Receptores de Quimiocinas/fisiologia
8.
Vet Immunol Immunopathol ; 191: 14-21, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28895861

RESUMO

Mastitis is a highly prevalent and one of the costliest diseases of dairy cows affecting the mammary gland. Milk neutrophils present in the mammary gland serve as an integral part of the mammary immunity, and their performance is influenced by different environmental conditions and lactation stages. To investigate the combined effects of seasons and lactation stages on the mammary immunity, milk and blood samples were collected from three groups of high producing indigenous Sahiwal cows. Function and receptor expression of milk neutrophils together with cortisol and inflammatory interleukins concentration in blood were studied. The first group of cows started their lactation in winter and completed their lactation in hot-humid season; the second group started their lactation in hot-dry season and completed it in winter. The third group started their lactation in hot-humid and completed by the hot-dry season. Plasma cortisol levels were very high during early lactation in all seasons. An inverse relationship was observed between cortisol levels and glucocorticoid receptor. Elevated phagocytic activity and plasma interleukin-2 levels were seen in winter and during mid lactation of all seasons. A positive correlation was noticed between plasma IL-8, the percentage of milk neutrophils and expression of chemokine receptors (CXCR1 and CXCR2). The highest expression of toll-like receptors (TLR2 and TLR4) and chemokine receptors was in hot-humid season. Reduction in the phagocytic activity of neutrophils, pro-inflammatory cytokines and elevated levels of cortisol in cows which started their lactation and attained peak lactation during hot-humid season indicated more stress in them. Integrated influence of both seasons and lactation stages on the activity of milk neutrophils along with plasma interleukins and cortisol levels may be used to develop suitable managemental strategies to improve mammary health and increase milk production in indigenous dairy breeds experiencing harsh environmental conditions.


Assuntos
Bovinos/imunologia , Citocinas/fisiologia , Lactação/imunologia , Leite/citologia , Neutrófilos/fisiologia , Receptores de Citocinas/imunologia , Animais , Bovinos/fisiologia , Citocinas/sangue , Feminino , Hidrocortisona/sangue , Hidrocortisona/fisiologia , Interleucina-8/sangue , Interleucina-8/fisiologia , Lactação/fisiologia , Receptores de Quimiocinas/sangue , Receptores de Quimiocinas/fisiologia , Receptores de Citocinas/sangue , Receptores de Citocinas/fisiologia , Estações do Ano
9.
Oncogene ; 36(21): 3025-3036, 2017 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-27941884

RESUMO

Epithelial ovarian carcinoma is the most common cause of death from gynecologic cancers largely due to advanced, relapsed and chemotherapy-resistant peritoneal metastasis, which is refractory to the currently used treatment approaches. Mechanisms supporting advanced and relapsed peritoneal metastasis are largely unknown, precluding development of more effective targeted therapies. In this study, we investigated the function of a potentially targetable fractalkine axis in the formation and the development of advanced and relapsed peritoneal metastasis and its impact on patients' outcomes. Our mouse model studies support a role for the fractalkine receptor (CX3CR1) in the initiation of peritoneal adhesion important for recolonization of relapsed peritoneal metastasis. We show that downregulation of CX3CR1 results in reduction of metastatic burden at several peritoneal sites commonly colonized by advanced and relapsed metastatic ovarian carcinoma. We show that the chemokine fractalkine (CX3CL1), an activating ligand of CX3CR1, regulates organ-specific peritoneal colonization. High expression of CX3CR1 correlates with significantly shorter survival, specifically in post-menopausal patients with advanced and terminal stages of the disease. Taken together, our studies support a key regulatory role for the fractalkine axis in advanced and relapsed peritoneal metastasis in epithelial ovarian carcinoma.


Assuntos
Quimiocina CX3CL1/fisiologia , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/secundário , Receptores de Quimiocinas/fisiologia , Animais , Receptor 1 de Quimiocina CX3C , Carcinoma Epitelial do Ovário , Linhagem Celular Tumoral , Quimiocina CX3CL1/genética , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Invasividade Neoplásica , Metástase Neoplásica , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Epiteliais e Glandulares/mortalidade , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/mortalidade , Neoplasias Peritoneais/patologia , Receptores de Quimiocinas/genética , Transdução de Sinais/genética , Análise de Sobrevida
10.
Biomed Tech (Berl) ; 62(1): 89-95, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-27107829

RESUMO

Low-intensity pulsed ultrasound (LIPUS) is an established therapy for fracture healing where bone marrow stromal cells (BMSCs) migration is crucial to bone regeneration. This work focused on different performances of C-X-C-receptor 4 (CXCR4), integrin-1ß and chemokine-chemokine receptor2 (CCR-2) in BMSCs migration by LIPUS stimulation. Single 20-min LIPUS treatment was applied to BMSCs during wound healing assay with or without the inhibitor AMD3100. The migration rate of BMSCs with LIPUS stimulation exhibited a higher closure rate than that of BMSCs without LIPUS stimulation, which was 1.89 µm/h and 1.38 µm/h, respectively. After LIPUS stimulation, significant elevation of the expression of CXCR4, integrin-1ß and CCR-2 was observed. When AMD3100 was added, the migration rate of the BMSCs was obviously declined with or without LIPUS treatment. Furthermore, the expression of CXCR4 was significantly down-regulated by AMD3100, while integrin-1ß and CCR-2 were less affected. It suggested that the enhancement of the migration of the BMSCs by LIPUS was inhibited by AMD3100. The results confirmed that LIPUS stimulation was able to activate and improve migration of BMSCs. Nevertheless, CXCR4 and both integrin-1ß and CCR-2 had different roles in BMSCs migration after LIPUS treatment.


Assuntos
Compostos Heterocíclicos/farmacologia , Integrinas/metabolismo , Células-Tronco Mesenquimais/citologia , Receptores CXCR4/metabolismo , Receptores de Quimiocinas/metabolismo , Cicatrização/efeitos dos fármacos , Compostos Heterocíclicos/química , Humanos , Integrinas/fisiologia , Células-Tronco Mesenquimais/fisiologia , Receptores CXCR4/química , Receptores de Quimiocinas/química , Receptores de Quimiocinas/fisiologia , Ondas Ultrassônicas , Cicatrização/fisiologia
11.
J Dent Res ; 96(1): 92-99, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28033061

RESUMO

The anaphylatoxin C5a constitutes a powerful fragment generated by complement system activation. Interestingly, this complement active fragment is also an important mediator of tissue regeneration. Recent findings suggest that C5a could be an initial signal orchestrating pulp nerve sprouting beneath carious injury, a critical step in dentin-pulp regeneration. Indeed, the expression and activation of the C5a active receptor (C5aR/CD88) by injured pulp fibroblasts controls the direction of neurite outgrowth toward carious injuries by modulating the secretion of brain-derived neurotrophic factor (BDNF) by pulp fibroblasts. A second C5a receptor, C5L2, has also been cloned but has received much less attention because its interaction with the ligand induces no signaling. This work aims to investigate the role of C5L2 in pulp nerve regeneration in the secretion of BDNF by pulp fibroblasts under sites of carious injury. Using fluorescence immunostaining on human tooth sections in vivo and on primary human pulp fibroblasts in vitro, the authors reveal that C5L2 and C5aR are co-expressed by pulp fibroblasts under lipoteichoic acid (LTA) stimulation. Moreover, silencing C5L2 significantly increases BDNF secretion by LTA-stimulated pulp fibroblasts. Finally, an analysis of the subcellular distribution of C5aR and C5L2 indicates that the negative regulation of BDNF secretion by C5L2 correlates with C5aR activation and its subsequent intracellular co-localization with C5L2. Overall, the current study sheds light on the mechanism of pulp nerve regeneration by identifying C5L2 as a negative regulator of BDNF secretion by pulp fibroblasts under carious teeth. This knowledge significantly increases the understanding of the functional mechanism linking C5aR and C5L2 in pulp nerve regeneration, which may be useful in future dentin-pulp engineering strategies that target fibroblast C5L2 to induce pulp innervation.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Polpa Dentária/citologia , Fibroblastos/fisiologia , Lipopolissacarídeos/farmacologia , Receptores de Quimiocinas/fisiologia , Ácidos Teicoicos/farmacologia , Células Cultivadas , Cárie Dentária/metabolismo , Cárie Dentária/fisiopatologia , Polpa Dentária/efeitos dos fármacos , Polpa Dentária/inervação , Polpa Dentária/metabolismo , Fibroblastos/efeitos dos fármacos , Humanos , Técnicas In Vitro , Regeneração Nervosa/efeitos dos fármacos , Regeneração Nervosa/fisiologia , Receptor da Anafilatoxina C5a/fisiologia
12.
J Gen Virol ; 98(3): 447-460, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27902351

RESUMO

CX3CR1 is an important chemokine receptor expressed on the surface of microglia and blood leukocytes, including monocytes. Signalling through this receptor influences the immune activity of microglia and monocyte trafficking into the central nervous system (CNS) in several neurological diseases. During experimental herpes simplex virus 1 (HSV-1) encephalitis (HSE), CX3CR1 deficiency has been reported to exacerbate the outcome of the disease. However, the precise contribution of CX3CR1 expressed in resident cells of the CNS or peripheral monocytes in protection against HSE remains unclear. To dissect the role of CX3CR1 during HSE, we reconstituted irradiated C57BL/6 WT and CX3CR1-/- mice with CX3CR1-/- (CX3CR1-/-→WT) and WT (WT→CX3CR1-/-) bone marrow cells, respectively. Our results showed that following intranasal infection with 1.2×106 p.f.u. of HSV-1, mortality rates were significantly higher in CX3CR1-/- (61.7 %) and WT→CX3CR1-/- (66.2 %) compared to WT (16.6 %; P=0.012 and P=0.016, respectively) and CX3CR1-/-→WT animals (20 %; P=0.013 and P=0.011, respectively). Higher mortality rates in CX3CR1-/- and WT→CX3CR1-/- mice were associated with increased infectious viral titres and wider HSV dissemination in brains, as well as an overproduction of inflammatory cytokines and chemokines including IL-1ß, IL-6, IFN-γ, C-C motif ligand 2 and C-C motif ligand 5. Furthermore, CX3CR1 deficiency in resident cells of the CNS resulted in excessive and sustained Ly6Chi inflammatory monocyte and neutrophil infiltration into the brain. These data suggest that CX3CR1 deficiency in resident cells of the CNS affects mouse survival, HSV-1 replication control and cerebral inflammatory response whereas its deficiency in the haematopoietic system does not appear to influence the outcome of HSE.


Assuntos
Encéfalo/imunologia , Encefalite por Herpes Simples/imunologia , Herpesvirus Humano 1 , Receptores de Quimiocinas/fisiologia , Animais , Barreira Hematoencefálica/imunologia , Barreira Hematoencefálica/virologia , Encéfalo/virologia , Receptor 1 de Quimiocina CX3C , Movimento Celular , Quimiocinas/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Microglia/imunologia , Microglia/virologia , Receptores de Quimiocinas/genética , Transdução de Sinais
13.
Development ; 144(1): 74-82, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-27888192

RESUMO

Macrophages are important regulators of branching morphogenesis during development and postnatally in the mammary gland. Regulation of macrophage dynamics during these processes can therefore have a profound impact on development. We demonstrate here that the developing mammary gland expresses high levels of inflammatory CC-chemokines, which are essential in vivo regulators of macrophage migration. We further demonstrate that the atypical chemokine receptor ACKR2, which scavenges inflammatory CC-chemokines, is differentially expressed during mammary gland development. We have previously shown that ACKR2 regulates macrophage dynamics during lymphatic vessel development. Here, we extend these observations to reveal a novel role for ACKR2 in regulating the postnatal development of the mammary gland. Specifically, we show that Ackr2-/- mice display precocious mammary gland development. This is associated with increased macrophage recruitment to the developing gland and increased density of the ductal epithelial network. These data demonstrate that ACKR2 is an important regulator of branching morphogenesis in diverse biological contexts and provide the first evidence of a role for chemokines and their receptors in postnatal development processes.


Assuntos
Glândulas Mamárias Animais/embriologia , Morfogênese/genética , Receptores CCR/fisiologia , Receptores de Quimiocinas/fisiologia , Animais , Movimento Celular/genética , Embrião de Mamíferos , Feminino , Linfangiogênese/genética , Vasos Linfáticos/embriologia , Vasos Linfáticos/fisiologia , Macrófagos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Estromais/metabolismo
14.
J Am Soc Nephrol ; 28(5): 1450-1461, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-27927779

RESUMO

An accumulating body of evidence shows that gut microbiota fulfill an important role in health and disease by modulating local and systemic immunity. The importance of the microbiome in the development of kidney disease, however, is largely unknown. To study this concept, we depleted gut microbiota with broad-spectrum antibiotics and performed renal ischemia-reperfusion (I/R) injury in mice. Depletion of the microbiota significantly attenuated renal damage, dysfunction, and remote organ injury and maintained tubular integrity after renal I/R injury. Gut flora-depleted mice expressed lower levels of F4/80 and chemokine receptors CX3CR1 and CCR2 in the F4/80+ renal resident macrophage population and bone marrow (BM) monocytes than did control mice. Additionally, compared with control BM monocytes, BM monocytes from gut flora-depleted mice had decreased migratory capacity toward CX3CL1 and CCL2 ligands. To study whether these effects were driven by depletion of the microbiota, we performed fecal transplants in antibiotic-treated mice and found that transplant of fecal material from an untreated mouse abolished the protective effect of microbiota depletion upon renal I/R injury. In conclusion, we show that depletion of gut microbiota profoundly protects against renal I/R injury by reducing maturation status of F4/80+ renal resident macrophages and BM monocytes. Therefore, dampening the inflammatory response by targeting microbiota-derived mediators might be a promising therapy against I/R injury.


Assuntos
Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Microbioma Gastrointestinal/efeitos dos fármacos , Rim/irrigação sanguínea , Traumatismo por Reperfusão/microbiologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Receptor 1 de Quimiocina CX3C , Fator de Crescimento Epidérmico/fisiologia , Macrófagos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Quimiocinas/fisiologia
15.
Eur J Neurosci ; 44(12): 3046-3055, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27717112

RESUMO

Complex regional pain syndrome type 1 (CRPS-I) remains one of the most clinically challenging neuropathic pain syndromes and its mechanism has not been fully characterized. Cannabinoid receptor 2 (CB2) has emerged as a promising target for treating different neuropathic pain syndromes. In neuropathic pain models, activated microglia expressing CB2 receptors are seen in the spinal cord. Chemokine fractalkine receptor (CX3CR1) plays a substantial role in microglial activation and neuroinflammation. We hypothesized that a CB2 agonist could modulate neuroinflammation and neuropathic pain in an ischemia model of CRPS by regulating CB2 and CX3CR1 signaling. We used chronic post-ischemia pain (CPIP) as a model of CRPS-I. Rats in the CPIP group exhibited significant hyperemia and edema of the ischemic hindpaw and spontaneous pain behaviors (hindpaw shaking and licking). Intraperitoneal administration of MDA7 (a selective CB2 agonist) attenuated mechanical allodynia induced by CPIP. MDA7 treatment was found to interfere with early events in the CRPS-I neuroinflammatory response by suppressing peripheral edema, spinal microglial activation and expression of CX3CR1 and CB2 receptors on the microglia in the spinal cord. MDA7 also mitigated the loss of intraepidermal nerve fibers induced by CPIP. Neuroprotective effects of MDA7 were blocked by a CB2 antagonist, AM630. Our findings suggest that MDA7, a novel CB2 agonist, may offer an innovative therapeutic approach for treating neuropathic symptoms and neuroinflammatory responses induced by CRPS-I in the setting of ischemia and reperfusion injury.


Assuntos
Encefalite/fisiopatologia , Hiperalgesia/fisiopatologia , Microglia/fisiologia , Receptor CB2 de Canabinoide/fisiologia , Receptores de Quimiocinas/fisiologia , Distrofia Simpática Reflexa/fisiopatologia , Animais , Benzofuranos/administração & dosagem , Receptor 1 de Quimiocina CX3C , Modelos Animais de Doenças , Encefalite/complicações , Encefalite/prevenção & controle , Epiderme/inervação , Hiperalgesia/complicações , Hiperalgesia/prevenção & controle , Isquemia/fisiopatologia , Masculino , Microglia/efeitos dos fármacos , Dor/prevenção & controle , Piperidinas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Receptor CB2 de Canabinoide/agonistas , Distrofia Simpática Reflexa/complicações , Corno Dorsal da Medula Espinal/efeitos dos fármacos , Corno Dorsal da Medula Espinal/fisiologia
16.
Am J Physiol Heart Circ Physiol ; 311(2): H498-507, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27371688

RESUMO

The adipokine chemerin causes arterial contraction and is implicated in blood pressure regulation, especially in obese subjects with elevated levels of circulating chemerin. Because chemerin is expressed in the perivascular adipose tissue (PVAT) that surrounds the sympathetic innervation of the blood vessel, we tested the hypothesis that chemerin (endogenous and exogenous) amplifies the sympathetic nervous system in mediating electrical field-stimulated (EFS) contraction. The superior mesenteric artery, with or without PVAT and with endothelium and sympathetic nerve intact, was mounted into isolated tissue baths and used for isometric contraction and stimulation. Immunohistochemistry validated a robust expression of chemerin in the PVAT surrounding the superior mesenteric artery. EFS (0.3-20 Hz) caused a frequency-dependent contraction in isolated arteries that was reduced by the chemerin receptor ChemR23 antagonist CCX832 alone (100 nM; with, but not without, PVAT), but not by the inactive congener CCX826 (100 nM). Exogenous chemerin-9 (1 µM)-amplified EFS-induced contraction in arteries (with and without PVAT) was blocked by CCX832 and the α-adrenergic receptor antagonist prazosin. CCX832 did not directly inhibit, nor did chemerin directly amplify, norepinephrine-induced contraction. Whole mount immunohistochemical experiments support colocalization of ChemR23 with the sympathetic nerve marker tyrosine hydroxylase in superior mesenteric PVAT and, to a lesser extent, in arteries and veins. These studies support the idea that exogenous chemerin modifies sympathetic nerve-mediated contraction through ChemR23 and that ChemR23 may be endogenously activated. This is significant because of the well-appreciated role of the sympathetic nervous system in blood pressure control.


Assuntos
Tecido Adiposo/metabolismo , Quimiocinas/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Artéria Mesentérica Superior/inervação , Receptores de Quimiocinas/metabolismo , Sistema Nervoso Simpático/metabolismo , Adipocinas , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Quimiocinas/fisiologia , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Masculino , Artéria Mesentérica Superior/efeitos dos fármacos , Artéria Mesentérica Superior/fisiologia , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Norepinefrina/farmacologia , Prazosina/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Quimiocinas/antagonistas & inibidores , Receptores de Quimiocinas/fisiologia , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiologia , Simpatomiméticos/farmacologia , Tirosina 3-Mono-Oxigenase/metabolismo
17.
PLoS One ; 11(4): e0153835, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27089041

RESUMO

Ischemic stroke is a devastating complication of bone fracture. Bone fracture shortly after stroke enhances stroke injury by augmenting inflammation. We hypothesize that bone fracture shortly before ischemic stroke also exacerbates ischemic cerebral injury. Tibia fracture was performed 6 or 24 hours before permanent middle cerebral artery occlusion (pMCAO) on C57BL/6J mice or Ccr2RFP/+Cx3cr1GFP/+ mice that have the RFP gene knocked into one allele of Ccr2 gene and GFP gene knocked into one allele of Cx3cr1 gene. Behavior was tested 3 days after pMCAO. Infarct volume, the number of CD68+ cells, apoptotic neurons, bone marrow-derived macrophages (RFP+), and microgila (GFP+) in the peri-infarct region were quantified. Compared to mice subjected to pMCAO only, bone fracture 6 or 24 hours before pMCAO increased behavioral deficits, the infarct volume, and the number of CD68+ cells and apoptotic neurons in the peri-infarct area. Both bone marrow-derived macrophages (CCR2+) and microglia (CX3CR1+) increased in the peri-infarct regions of mice subjected to bone fracture before pMCAO compared to stroke-only mice. The mice subjected to bone fracture 6 hours before pMCAO had more severe injury than mice that had bone fracture 24 hours before pMCAO. Our data showed that bone fracture shortly before stroke also increases neuroinflammation and exacerbates ischemic cerebral injury. Our findings suggest that inhibition of neuroinflammation or management of stroke risk factors before major bone surgery would be beneficial for patients who are likely to suffer from stroke.


Assuntos
Lesões Encefálicas/etiologia , Isquemia Encefálica/etiologia , Modelos Animais de Doenças , Fraturas Ósseas/complicações , Acidente Vascular Cerebral/etiologia , Animais , Comportamento Animal , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Receptor 1 de Quimiocina CX3C , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Fraturas Ósseas/metabolismo , Fraturas Ósseas/patologia , Técnicas Imunoenzimáticas , Infarto da Artéria Cerebral Média/fisiopatologia , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microglia/imunologia , Microglia/patologia , Receptores CCR2/fisiologia , Receptores de Quimiocinas/fisiologia , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia
18.
Med Sci (Paris) ; 32(3): 260-6, 2016 Mar.
Artigo em Francês | MEDLINE | ID: mdl-27011244

RESUMO

Allergic asthma and atopic dermatitis are diseases mainly resulting from the activation of Th2 cells, that produce cytokines favouring IgE production and eosinophilia but also of Th1 cells, that contribute to inflammation chronicity. Lymphocyte recruitment and retention of Th cells in target organs are 2 key events for asthma and atopic dermatitis pathogenesis. While lymphocyte migration is regulated by chemokines and lipid mediators such as leukotrienes and prostaglandins, factors involved in lymphocyte retention and survival within inflammatory tissues remain poorly understood. Recent works show that, in allergic diseases, there is an increased expression of fractalkine/CX3CL1 and its unique receptor CX3CR1 and that this chemokine does not act as chemoattractant. In allergic asthma, CX3CR1 expression regulates Th2 and Th1 cell survival in the inflammatory lung, while, in atopic dermatitis, it regulate Th2 and Th1 cell retention into the inflammatory site. Use of peptides blocking fractalkine binding to its receptor is currently tested in the treatment of asthma and atopic dermatitis.


Assuntos
Quimiocina CX3CL1/fisiologia , Hipersensibilidade/genética , Receptores de Quimiocinas/fisiologia , Animais , Receptor 1 de Quimiocina CX3C , Movimento Celular/genética , Sobrevivência Celular/genética , Regulação da Expressão Gênica , Humanos , Hipersensibilidade/imunologia , Distribuição Tecidual
20.
Adv Exp Med Biol ; 904: 77-85, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26900064

RESUMO

The peripheral nervous system and the immune system perform a series of similar functionalities such as recognizing, responding, and adapting to external or internal stimuli despite significant morphological differences. The peripheral nervous system actively communicates and coordinates with the immune system to function as a unified defense system. The peripheral nervous system is highly regulated by the immune system, especially under inflammatory conditions. On the other hand, the nervous system can modulate the immune system via neurotransmitters and chemokines released by the peripheral nerve endings, particularly from nociceptors. In both physiological and pathological conditions, peripheral nociceptive (including pruriceptive) neurons may express a variety of immune-related receptors, such as chemokine receptors and immunoglobulin (Fc) receptors that are usually found on immune cells. Certain ligands such as chemokines and immune complexes may induce abnormal neuronal hyperexcitability and even ectopic action potential discharges, therefore producing the sensation of pain and/or itch in immune-related diseases. The immune-sensing mechanisms of peripheral nociceptors may play an important role in the development of chronic pain and pruritus and may indicate novel therapeutic strategies for these pathological conditions.


Assuntos
Nociceptores/fisiologia , Dor/fisiopatologia , Prurido/fisiopatologia , Animais , Complexo Antígeno-Anticorpo/imunologia , Dor Crônica/imunologia , Dor Crônica/fisiopatologia , Citocinas/fisiologia , Humanos , Inflamação , Macrófagos/fisiologia , Mastócitos/fisiologia , Neuroimunomodulação , Neurotransmissores/fisiologia , Nociceptores/imunologia , Dor/imunologia , Sistema Nervoso Periférico/imunologia , Sistema Nervoso Periférico/fisiopatologia , Prurido/imunologia , Receptores de Quimiocinas/fisiologia , Receptores Fc/imunologia , Receptores Imunológicos/imunologia
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