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1.
Immunity ; 50(2): 378-389.e5, 2019 02 19.
Artículo en Inglés | MEDLINE | ID: mdl-30784579

RESUMEN

Currently, we lack an understanding of the individual and combinatorial roles for chemokine receptors in the inflammatory process. We report studies on mice with a compound deletion of Ccr1, Ccr2, Ccr3, and Ccr5, which together control monocytic and eosinophilic recruitment to resting and inflamed sites. Analysis of resting tissues from these mice, and mice deficient in each individual receptor, provides clear evidence for redundant use of these receptors in establishing tissue-resident monocytic cell populations. In contrast, analysis of cellular recruitment to inflamed sites provides evidence of specificity of receptor use for distinct leukocyte subtypes and no indication of comprehensive redundancy. We find no evidence of involvement of any of these receptors in the recruitment of neutrophils or lymphocytes to resting or acutely inflamed tissues. Our data shed important light on combinatorial inflammatory chemokine receptor function and highlight Ccr2 as the primary driver of myelomonocytic cell recruitment in acutely inflamed contexts.


Asunto(s)
Eosinófilos/inmunología , Inflamación/inmunología , Monocitos/inmunología , Receptores CCR/inmunología , Animales , Quimiocinas/inmunología , Quimiocinas/metabolismo , Eosinófilos/metabolismo , Perfilación de la Expresión Génica/métodos , Inflamación/genética , Inflamación/metabolismo , Linfocitos/inmunología , Linfocitos/metabolismo , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/metabolismo , Neutrófilos/inmunología , Neutrófilos/metabolismo , Receptores CCR/genética , Receptores CCR/metabolismo , Receptores CCR1/inmunología , Receptores CCR1/metabolismo , Receptores CCR2/inmunología , Receptores CCR2/metabolismo , Receptores CCR3/inmunología , Receptores CCR3/metabolismo , Receptores CCR5/inmunología , Receptores CCR5/metabolismo
2.
Development ; 144(1): 74-82, 2017 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-27888192

RESUMEN

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.


Asunto(s)
Glándulas Mamarias Animales/embriología , Morfogénesis/genética , Receptores CCR/fisiología , Receptores de Quimiocina/fisiología , Animales , Movimiento Celular/genética , Embrión de Mamíferos , Femenino , Linfangiogénesis/genética , Vasos Linfáticos/embriología , Vasos Linfáticos/fisiología , Macrófagos/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células del Estroma/metabolismo
3.
J Immunol ; 190(12): 6450-6456, 2013 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-23670187

RESUMEN

Chemokines, acting on their cognate receptors on infiltrating leukocytes, drive the inflammatory response. We have been interested in determining roles and potential mechanisms for the atypical chemokine-scavenging receptor D6 in the regulation of inflammation. In this study, we show that a psoriasis-like pathology that arises in inflamed skins of D6-deficient mice is characterized by a massive and aberrant localization of neutrophils to the dermal/epidermal junction, which is associated with development of the pathology. Such misplacement of neutrophils is also seen with D6-deficient mice in other inflammatory models, suggesting a role for D6 in the spatial positioning of neutrophils within inflamed sites. We further show that D6 functions cell autonomously in this context and that D6, expressed by neutrophils, limits their migrational responses to CCR1 ligands such as CCL3. Our data therefore indicate that D6 is able to play a cell-autonomous role as a migratory rheostat restricting migration of D6-expressing cells such as neutrophils toward ligands for coexpressed inflammatory chemokine receptors. These data have important implications for our understanding of the roles for D6 in regulating inflammation and for our understanding of the control of spatial positioning of leukocytes at inflamed sites.


Asunto(s)
Enfermedades del Sistema Inmune/inmunología , Trastornos Leucocíticos/inmunología , Psoriasis/inmunología , Receptores de Quimiocina/inmunología , Animales , Modelos Animales de Enfermedad , Inflamación/inmunología , Ratones , Ratones Noqueados , Microscopía Confocal , Psoriasis/patología , Piel/inmunología , Piel/patología
4.
J Biol Chem ; 288(51): 36473-83, 2013 Dec 20.
Artículo en Inglés | MEDLINE | ID: mdl-24194523

RESUMEN

The inflammatory response is normally limited by mechanisms regulating its resolution. In the absence of resolution, inflammatory pathologies can emerge, resulting in substantial morbidity and mortality. We have been studying the D6 chemokine scavenging receptor, which played an indispensable role in the resolution phase of inflammatory responses and does so by facilitating removal of inflammatory CC chemokines. In D6-deficient mice, otherwise innocuous cutaneous inflammatory stimuli induce a grossly exaggerated inflammatory response that bears many similarities to human psoriasis. In the present study, we have used transcriptomic approaches to define the molecular make up of this response. The data presented highlight potential roles for a number of cytokines in initiating and maintaining the psoriasis-like pathology. Most compellingly, we provide data indicating a key role for the type I interferon pathway in the emergence of this pathology. Neutralizing antibodies to type I interferons are able to ameliorate the psoriasis-like pathology, confirming a role in its development. Comparison of transcriptional data generated from this mouse model with equivalent data obtained from human psoriasis further demonstrates the strong similarities between the experimental and clinical systems. As such, the transcriptional data obtained in this preclinical model provide insights into the cytokine network active in exaggerated inflammatory responses and offer an excellent tool to evaluate the efficacy of compounds designed to therapeutically interfere with inflammatory processes.


Asunto(s)
Interferón Tipo I/metabolismo , Psoriasis/inmunología , Receptores CCR10/genética , Animales , Femenino , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Interferón Tipo I/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Análisis de Secuencia por Matrices de Oligonucleótidos , Ésteres del Forbol/toxicidad , Psoriasis/inducido químicamente , Psoriasis/genética , Psoriasis/patología , Transcripción Genética , Receptor de Quimiocina D6
5.
Am J Pathol ; 181(4): 1158-64, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22867710

RESUMEN

D6 is a scavenging-receptor for inflammatory CC chemokines that are essential for resolution of inflammatory responses in mice. Here, we demonstrate that D6 plays a central role in controlling cutaneous inflammation, and that D6 deficiency is associated with development of a psoriasis-like pathology in response to varied inflammatory stimuli in mice. Examination of D6 expression in human psoriatic skin revealed markedly elevated expression in both the epidermis and lymphatic endothelium in "uninvolved" psoriatic skin (ie, skin that was more than 8 cm distant from psoriatic plaques). Notably, this increased D6 expression is associated with elevated inflammatory chemokine expression, but an absence of plaque development, in uninvolved skin. Along with our previous observations of the ability of epidermally expressed transgenic D6 to impair cutaneous inflammatory responses, our data support a role for elevated D6 levels in suppressing inflammatory chemokine action and lesion development in uninvolved psoriatic skin. D6 expression consistently dropped in perilesional and lesional skin, coincident with development of psoriatic plaques. D6 expression in uninvolved skin also was reduced after trauma, indicative of a role for trauma-mediated reduction in D6 expression in triggering lesion development. Importantly, D6 is also elevated in peripheral blood leukocytes in psoriatic patients, indicating that upregulation may be a general protective response to inflammation. Together our data demonstrate a novel role for D6 as a regulator of the transition from uninvolved to lesional skin in psoriasis.


Asunto(s)
Psoriasis/metabolismo , Psoriasis/patología , Receptores CCR10/metabolismo , Animales , Epidermis/metabolismo , Epidermis/patología , Regulación de la Expresión Génica , Humanos , Inflamación/metabolismo , Inflamación/patología , Ratones , Psoriasis/complicaciones , Psoriasis/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores CCR10/genética , Heridas y Lesiones/complicaciones , Heridas y Lesiones/patología , Receptor de Quimiocina D6
6.
Blood ; 118(23): 6220-9, 2011 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-21979941

RESUMEN

Lymphatic endothelial cells are important for efficient flow of antigen-bearing fluid and antigen-presenting cells (APCs) from peripheral sites to lymph nodes (LNs). APC movement to LNs is dependent on the constitutive chemokine receptor CCR7, although how conflicting inflammatory and constitutive chemokine cues are integrated at lymphatic surfaces during this process is not understood. Here we reveal a previously unrecognized aspect of the regulation of this process. The D6 chemokine-scavenging receptor, which is expressed on lymphatic endothelial cells (LECs), maintains lymphatic surfaces free of inflammatory CC-chemokines and minimizes interaction of inflammatory leukocytes with these surfaces. D6 does not alter the level of CCR7 ligands on LECs, thus ensuring selective presentation of homeostatic chemokines for interaction with CCR7(+) APCs. Accordingly, in D6-deficient mice, inflammatory CC-chemokine adherence to LECs results in inappropriate perilymphatic accumulation of inflammatory leukocytes at peripheral inflamed sites and draining LNs. This results in lymphatic congestion and impaired movement of APCs, and fluid, from inflamed sites to LNs. We propose that D6, by suppressing inflammatory chemokine binding to lymphatic surfaces, and thereby preventing inappropriate inflammatory leukocyte adherence, is a key regulator of lymphatic function and a novel, and indispensable, contributor to the integration of innate and adaptive immune responses.


Asunto(s)
Líquidos Corporales/inmunología , Movimiento Celular/inmunología , Células Endoteliales/inmunología , Ganglios Linfáticos/inmunología , Receptores de Quimiocina/inmunología , Inmunidad Adaptativa/inmunología , Animales , Células Presentadoras de Antígenos/citología , Células Presentadoras de Antígenos/inmunología , Quimiocina CCL2/inmunología , Quimiocina CCL2/metabolismo , Quimiocina CCL5/inmunología , Quimiocina CCL5/metabolismo , Células Endoteliales/citología , Células Endoteliales/metabolismo , Inmunidad Innata/inmunología , Leucocitos/citología , Leucocitos/inmunología , Linfa/inmunología , Linfa/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Receptores CCR2/inmunología , Receptores CCR2/metabolismo , Receptores CCR7/inmunología , Receptores CCR7/metabolismo , Receptores de Quimiocina/genética
7.
Shock ; 49(6): 682-689, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29589840

RESUMEN

Sepsis is a systemic inflammatory response as a result of uncontrolled infections. Neutrophils are the first cells to reach the primary sites of infection, and chemokines play a key role in recruiting neutrophils. However, in sepsis chemokines could also contribute to neutrophil infiltration to vital organs leading to multiple organ failure. ACKR2 is an atypical chemokine receptor, which can remove and degrade inflammatory CC chemokines. The role of ACK2 in sepsis is unknown. Using a model of cecal ligation and puncture (CLP), we demonstrate here that ACKR2 deficient () mice exhibited a significant reduction in the survival rate compared with similarly treated wild-type (WT) mice. However, neutrophil migration to the peritoneal cavity and bacterial load were similar between WT and ACKR2 mice during CLP. In contrast, ACKR2 mice showed increased neutrophil infiltration and elevated CC chemokine levels in the lung, kidney, and heart compared with the WT mice. In addition, ACKR2 mice also showed more severe lesions in the lung and kidney than those in the WT mice. Consistent with these results, WT mice under nonsevere sepsis (90% survival) had higher expression of ACKR2 in these organs than mice under severe sepsis (no survival). Finally, the lungs from septic patients showed increased number of ACKR2 cells compared with those of nonseptic patients. Our data indicate that ACKR2 may have a protective role during sepsis, and the absence of ACKR2 leads to exacerbated chemokine accumulation, neutrophil infiltration, and damage to vital organs.


Asunto(s)
Insuficiencia Multiorgánica/metabolismo , Infiltración Neutrófila , Neutrófilos/metabolismo , Receptores de Quimiocina/metabolismo , Sepsis/metabolismo , Animales , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Insuficiencia Multiorgánica/patología , Neutrófilos/patología , Sepsis/patología
8.
Sci Rep ; 7: 42681, 2017 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-28205614

RESUMEN

CXCR2 is an essential regulator of neutrophil recruitment to inflamed and damaged sites and plays prominent roles in inflammatory pathologies and cancer. It has therefore been highlighted as an important therapeutic target. However the success of the therapeutic targeting of CXCR2 is threatened by our relative lack of knowledge of its precise in vivo mode of action. Here we demonstrate that CXCR2-deficient mice display a counterintuitive transient exaggerated inflammatory response to cutaneous and peritoneal inflammatory stimuli. In both situations, this is associated with reduced expression of cytokines associated with the resolution of the inflammatory response and an increase in macrophage accumulation at inflamed sites. Analysis using neutrophil depletion strategies indicates that this is a consequence of impaired recruitment of a non-neutrophilic CXCR2 positive leukocyte population. We suggest that these cells may be myeloid derived suppressor cells. Our data therefore reveal novel and previously unanticipated roles for CXCR2 in the orchestration of the inflammatory response.

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