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1.
Nat Immunol ; 16(5): 495-504, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25848864

RESUMO

The molecules and pathways that fine-tune innate inflammatory responses mediated by Toll-like receptor 7 (TLR7) remain to be fully elucidated. Using an unbiased genome-scale screen with short hairpin RNA (shRNA), we identified the receptor TREML4 as an essential positive regulator of TLR7 signaling. Macrophages from Treml4(-/-) mice were hyporesponsive to TLR7 agonists and failed to produce type I interferons due to impaired phosphorylation of the transcription factor STAT1 by the mitogen-activated protein kinase p38 and decreased recruitment of the adaptor MyD88 to TLR7. TREML4 deficiency reduced the production of inflammatory cytokines and autoantibodies in MRL/lpr mice, which are prone to systemic lupus erythematosus (SLE), and inhibited the antiviral immune response to influenza virus. Our data identify TREML4 as a positive regulator of TLR7 signaling and provide insight into the molecular mechanisms that control antiviral immunity and the development of autoimmunity.


Assuntos
Lúpus Eritematoso Sistêmico/imunologia , Macrófagos/fisiologia , Glicoproteínas de Membrana/metabolismo , Infecções por Orthomyxoviridae/imunologia , Orthomyxoviridae/imunologia , Receptores Imunológicos/metabolismo , Receptor 7 Toll-Like/metabolismo , Animais , Autoanticorpos/metabolismo , Autoimunidade/genética , Células Cultivadas , Citocinas/metabolismo , Humanos , Imunidade Inata/genética , Mediadores da Inflamação/metabolismo , Interferon Tipo I/metabolismo , Macrófagos/virologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos MRL lpr , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/metabolismo , RNA Interferente Pequeno/genética , Receptores Imunológicos/genética , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
2.
Nat Immunol ; 14(9): 917-26, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23892722

RESUMO

The clearance of apoptotic cells is critical for the control of tissue homeostasis; however, the full range of receptors on phagocytes responsible for the recognition of apoptotic cells remains to be identified. Here we found that dendritic cells (DCs), macrophages and endothelial cells used the scavenger receptor SCARF1 to recognize and engulf apoptotic cells via the complement component C1q. Loss of SCARF1 impaired the uptake of apoptotic cells. Consequently, in SCARF1-deficient mice, dying cells accumulated in tissues, which led to a lupus-like disease, with the spontaneous generation of autoantibodies to DNA-containing antigens, activation of cells of the immune system, dermatitis and nephritis. The discovery of such interactions of SCARF1 with C1q and apoptotic cells provides insight into the molecular mechanisms involved in the maintenance of tolerance and prevention of autoimmune disease.


Assuntos
Apoptose/genética , Apoptose/imunologia , Autoimunidade/genética , Receptores Depuradores Classe F/genética , Receptores Depuradores Classe F/imunologia , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Complemento C1q/química , Complemento C1q/imunologia , Complemento C1q/metabolismo , Feminino , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Knockout , Nefrite/genética , Nefrite/imunologia , Nefrite/patologia , Fagocitose/genética , Fagocitose/imunologia , Fosforilação , Ligação Proteica , Receptores Depuradores Classe F/metabolismo , Serina/metabolismo
3.
Immunity ; 43(4): 715-26, 2015 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-26488816

RESUMO

CARD9 is a central component of anti-fungal innate immune signaling via C-type lectin receptors, and several immune-related disorders are associated with CARD9 alterations. Here, we used a rare CARD9 variant that confers protection against inflammatory bowel disease as an entry point to investigating CARD9 regulation. We showed that the protective variant of CARD9, which is C-terminally truncated, acted in a dominant-negative manner for CARD9-mediated cytokine production, indicating an important role for the C terminus in CARD9 signaling. We identified TRIM62 as a CARD9 binding partner and showed that TRIM62 facilitated K27-linked poly-ubiquitination of CARD9. We identified K125 as the ubiquitinated residue on CARD9 and demonstrated that this ubiquitination was essential for CARD9 activity. Furthermore, we showed that similar to Card9-deficient mice, Trim62-deficient mice had increased susceptibility to fungal infection. In this study, we utilized a rare protective allele to uncover a TRIM62-mediated mechanism for regulation of CARD9 activation.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/fisiologia , Candidíase Invasiva/imunologia , Receptores de Angiotensina/fisiologia , Receptores de Endotelina/fisiologia , Ubiquitina-Proteína Ligases/fisiologia , Adjuvantes Imunológicos/farmacologia , Animais , Proteínas Adaptadoras de Sinalização CARD/química , Proteínas Adaptadoras de Sinalização CARD/deficiência , Proteínas Adaptadoras de Sinalização CARD/genética , Candidíase Invasiva/genética , Colite/induzido quimicamente , Colite/genética , Colite/prevenção & controle , Citocinas/biossíntese , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Genes Dominantes , Predisposição Genética para Doença , Células HEK293 , Células HeLa , Humanos , Doenças Inflamatórias Intestinais/genética , Camundongos , Camundongos da Linhagem 129 , Camundongos Knockout , Mapeamento de Interação de Proteínas , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/fisiologia , Processamento de Proteína Pós-Traducional , Estrutura Terciária de Proteína , Receptores de Angiotensina/química , Receptores de Angiotensina/deficiência , Receptores de Endotelina/química , Receptores de Endotelina/deficiência , Proteínas Recombinantes de Fusão/metabolismo , Transdução de Sinais , Organismos Livres de Patógenos Específicos , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases/química , Ubiquitinação
4.
J Immunol ; 208(4): 955-967, 2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-35082161

RESUMO

Deficiency in the clearance of cellular debris is a major pathogenic factor in the emergence of autoimmune diseases. We previously demonstrated that mice deficient for scavenger receptor class F member 1 (SCARF1) develop a lupus-like autoimmune disease with symptoms similar to human systemic lupus erythematosus (SLE), including a pronounced accumulation of apoptotic cells (ACs). Therefore, we hypothesized that SCARF1 will be important for clearance of ACs and maintenance of self-tolerance in humans, and that dysregulation of this process could contribute to SLE. In this article, we show that SCARF1 is highly expressed on phagocytic cells, where it functions as an efferocytosis receptor. In healthy individuals, we discovered that engagement of SCARF1 by ACs on BDCA1+ dendritic cells initiates an IL-10 anti-inflammatory response mediated by the phosphorylation of STAT1 and STAT3. Unexpectedly, there was no significant difference in SCARF1 expression in samples of patients with SLE compared with healthy donor samples. However, we detected anti-SCARF1 autoantibodies in 26% of patients with SLE, which was associated with dsDNA Ab positivity. Furthermore, our data show a direct correlation of the levels of anti-SCARF1 in the serum and defects in the removal of ACs. Depletion of Ig restores efferocytosis in SLE serum, suggesting that defects in the removal of ACs are partially mediated by SCARF1 pathogenic autoantibodies. Our data demonstrate that human SCARF1 is an AC receptor in dendritic cells and plays a role in maintaining tolerance and homeostasis.


Assuntos
Autoanticorpos/imunologia , Imunomodulação , Lúpus Eritematoso Sistêmico/etiologia , Lúpus Eritematoso Sistêmico/metabolismo , Fagocitose/imunologia , Receptores Depuradores Classe F/genética , Animais , Autoanticorpos/sangue , Biomarcadores , Modelos Animais de Doenças , Suscetibilidade a Doenças , Perfilação da Expressão Gênica , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunomodulação/genética , Imunofenotipagem , Lúpus Eritematoso Sistêmico/diagnóstico , Camundongos , Camundongos Transgênicos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fagócitos/imunologia , Fagócitos/metabolismo , Fosforilação , Fatores de Transcrição STAT/metabolismo , Receptores Depuradores Classe F/imunologia , Receptores Depuradores Classe F/metabolismo
5.
Nat Immunol ; 11(6): 495-502, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20473299

RESUMO

Chemokines and other chemoattractants direct leukocyte migration and are essential for the development and delivery of immune and inflammatory responses. To probe the molecular mechanisms that underlie chemoattractant-guided migration, we did an RNA-mediated interference screen that identified several members of the synaptotagmin family of calcium-sensing vesicle-fusion proteins as mediators of cell migration: SYT7 and SYTL5 were positive regulators of chemotaxis, whereas SYT2 was a negative regulator of chemotaxis. SYT7-deficient leukocytes showed less migration in vitro and in a gout model in vivo. Chemoattractant-induced calcium-dependent lysosomal fusion was impaired in SYT7-deficient neutrophils. In a chemokine gradient, SYT7-deficient lymphocytes accumulated lysosomes in their uropods and had impaired uropod release. Our data identify a molecular pathway required for chemotaxis that links chemoattractant-induced calcium flux to exocytosis and uropod release.


Assuntos
Movimento Celular/fisiologia , Sinaptotagminas/metabolismo , Animais , Quimiocina CXCL12/metabolismo , Quimiotaxia , Immunoblotting , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase , Receptores CXCR4/metabolismo , Sinaptotagmina II/metabolismo , Sinaptotagminas/genética , Linfócitos T/imunologia
6.
J Immunol ; 198(10): 3775-3789, 2017 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-28483986

RESUMO

Scavenger receptors constitute a large family of proteins that are structurally diverse and participate in a wide range of biological functions. These receptors are expressed predominantly by myeloid cells and recognize a diverse variety of ligands including endogenous and modified host-derived molecules and microbial pathogens. There are currently eight classes of scavenger receptors, many of which have multiple names, leading to inconsistencies and confusion in the literature. To address this problem, a workshop was organized by the United States National Institute of Allergy and Infectious Diseases, National Institutes of Health, to help develop a clear definition of scavenger receptors and a standardized nomenclature based on that definition. Fifteen experts in the scavenger receptor field attended the workshop and, after extensive discussion, reached a consensus regarding the definition of scavenger receptors and a proposed scavenger receptor nomenclature. Scavenger receptors were defined as cell surface receptors that typically bind multiple ligands and promote the removal of nonself or altered-self targets. They often function by mechanisms that include endocytosis, phagocytosis, adhesion, and signaling that ultimately lead to the elimination of degraded or harmful substances. Based on this definition, nomenclature and classification of these receptors into 10 classes were proposed. This classification was discussed at three national meetings and input from participants at these meetings was requested. The following manuscript is a consensus statement that combines the recommendations of the initial workshop and incorporates the input received from the participants at the three national meetings.


Assuntos
Receptores Depuradores/classificação , Receptores Depuradores/fisiologia , Animais , Endocitose , Humanos , Ligantes , Camundongos , National Institute of Allergy and Infectious Diseases (U.S.)/normas , Fagocitose , Receptores Imunológicos/fisiologia , Receptores Depuradores Classe A/fisiologia , Transdução de Sinais , Terminologia como Assunto , Estados Unidos
7.
J Neurosci ; 36(19): 5185-92, 2016 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-27170117

RESUMO

UNLABELLED: Multiple EGF-like domains 10 (Megf10) is a class F scavenger receptor (SR-F3) expressed on astrocytes and myosatellite cells, and recessive mutations in humans result in early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD). Here we report that Megf10-deficient mice have increased apoptotic cells in the developing cerebellum and have impaired phagocytosis of apoptotic cells by astrocytes ex vivo We also report that cells transfected with Megf10 gain the ability to phagocytose apoptotic neurons and that Megf10 binds with high affinity to C1q, an eat-me signal for apoptotic cells. In contrast, cells expressing Megf10 with EMARDD mutations have impaired apoptotic cell clearance and impaired binding to C1q. Our studies reveal that Megf10 is a receptor for C1q and identify a novel role for Megf10 in clearance of apoptotic cells in the mammalian developing brain with potential relevance to EMARDD patients and other CNS disorders. SIGNIFICANCE STATEMENT: Apoptosis is a universal homeostatic process and occurs in many disease conditions. Multiple EGF-like domains 10 (Megf10) is emerging as an essential receptor for synaptic pruning, clearance of neuronal debris, and for muscle differentiation. Here we define a novel Megf10-dependent pathway for apoptotic cell clearance and show that Megf10 is a receptor for C1q, an eat-me signal, that binds phosphatidylserine expressed on the surface of apoptotic cells. Understanding the pathways by which apoptotic cells are cleared in the CNS is relevant to many physiological and pathological conditions of the CNS.


Assuntos
Apoptose , Astrócitos/metabolismo , Complemento C1q/metabolismo , Proteínas de Membrana/metabolismo , Animais , Células Cultivadas , Cerebelo/citologia , Cerebelo/crescimento & desenvolvimento , Cerebelo/metabolismo , Miopatias Distais/genética , Células HEK293 , Humanos , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Fagocitose , Ligação Proteica
8.
Eur J Immunol ; 46(1): 192-203, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26464217

RESUMO

Dendritic cells (DCs) play a vital role in innate and adaptive immunities. Inducible depletion of CD11c(+) DCs engineered to express a high-affinity diphtheria toxin receptor has been a powerful tool to dissect DC function in vivo. However, despite reports showing that loss of DCs induces transient monocytosis, the monocyte population that emerges and the potential impact of monocytes on studies of DC function have not been investigated. We found that depletion of CD11c(+) cells from CD11c.DTR mice induced the expansion of a variant CD64(+) Ly6C(+) monocyte population in the spleen and blood that was distinct from conventional monocytes. Expansion of CD64(+) Ly6C(+) monocytes was independent of mobilization from the BM via CCR2 but required the cytokine, G-CSF. Indeed, this population was also expanded upon exposure to exogenous G-CSF in the absence of DC depletion. CD64(+) Ly6C(+) monocytes were characterized by upregulation of innate signaling apparatus despite the absence of inflammation, and an increased capacity to produce TNF-α following LPS stimulation. Thus, depletion of CD11c(+) cells induces expansion of a unique CD64(+) Ly6C(+) monocyte population poised to synthesize TNF-α. This finding will require consideration in experiments using depletion strategies to test the role of CD11c(+) DCs in immunity.


Assuntos
Células Dendríticas/imunologia , Monócitos/citologia , Monócitos/imunologia , Fator de Necrose Tumoral alfa/biossíntese , Animais , Antígenos Ly/imunologia , Antígeno CD11c/imunologia , Citometria de Fluxo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Análise de Sequência com Séries de Oligonucleotídeos , Receptores de IgG/imunologia , Fator de Necrose Tumoral alfa/imunologia
10.
J Immunol ; 192(5): 1997-2006, 2014 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-24563502

RESUMO

Scavenger receptors constitute a large family of proteins that are structurally diverse and participate in a wide range of biological functions. These receptors are expressed predominantly by myeloid cells and recognize a variety of ligands, including endogenous and modified host-derived molecules and microbial pathogens. There are currently eight classes of scavenger receptors, many of which have multiple names, leading to inconsistencies and confusion in the literature. To address this problem, a workshop was organized by the U.S. National Institute of Allergy and Infectious Diseases, National Institutes of Health to help develop a clear definition of scavenger receptors and a standardized nomenclature based on that definition. Fifteen experts in the scavenger receptor field attended the workshop and, after extensive discussion, reached a consensus regarding the definition of scavenger receptors and a proposed scavenger receptor nomenclature. Scavenger receptors were defined as cell surface receptors that typically bind multiple ligands and promote the removal of non-self or altered-self targets. They often function by mechanisms that include endocytosis, phagocytosis, adhesion, and signaling that ultimately lead to the elimination of degraded or harmful substances. Based on this definition, nomenclature and classification of these receptors into 10 classes were proposed. The discussion and nomenclature recommendations described in this report only refer to mammalian scavenger receptors. The purpose of this article is to describe the proposed mammalian nomenclature and classification developed at the workshop and to solicit additional feedback from the broader research community.


Assuntos
Receptores Depuradores/classificação , Animais , Humanos , Receptores Depuradores/imunologia , Terminologia como Assunto
11.
Nat Med ; 13(4): 432-8, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17351623

RESUMO

Microglia are the principal immune cells of the brain. In Alzheimer disease, these brain mononuclear phagocytes are recruited from the blood and accumulate in senile plaques. However, the role of microglia in Alzheimer disease has not been resolved. Microglia may be neuroprotective by phagocytosing amyloid-beta (Abeta), but their activation and the secretion of neurotoxins may also cause neurodegeneration. Ccr2 is a chemokine receptor expressed on microglia, which mediates the accumulation of mononuclear phagocytes at sites of inflammation. Here we show that Ccr2 deficiency accelerates early disease progression and markedly impairs microglial accumulation in a transgenic mouse model of Alzheimer disease (Tg2576). Alzheimer disease mice deficient in Ccr2 accumulated Abeta earlier and died prematurely, in a manner that correlated with Ccr2 gene dosage, indicating that absence of early microglial accumulation leads to decreased Abeta clearance and increased mortality. Thus, Ccr2-dependent microglial accumulation plays a protective role in the early stages of Alzheimer disease by promoting Abeta clearance.


Assuntos
Doença de Alzheimer/imunologia , Doença de Alzheimer/prevenção & controle , Encéfalo/imunologia , Quimiocinas/metabolismo , Microglia/imunologia , Modelos Imunológicos , Receptores CCR2/deficiência , Peptídeos beta-Amiloides/metabolismo , Análise de Variância , Animais , Cruzamentos Genéticos , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Monócitos/imunologia , Receptores CCR2/imunologia
12.
bioRxiv ; 2024 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-39071425

RESUMO

Immune-mediated diseases are characterized by aberrant immune responses, posing significant challenges to global health. In both inflammatory and autoimmune diseases, dysregulated immune reactions mediated by tissue-residing immune and non-immune cells precipitate chronic inflammation and tissue damage that is amplified by peripheral immune cell extravasation into the tissue. Chemokine receptors are pivotal in orchestrating immune cell migration, yet deciphering the signaling code across cell types, diseases and tissues remains an open challenge. To delineate disease-specific cell-cell communications involved in immune cell migration, we conducted a meta-analysis of publicly available single-cell RNA sequencing (scRNA-seq) data across diverse immune diseases and tissues. Our comprehensive analysis spanned multiple immune disorders affecting major organs: atopic dermatitis and psoriasis (skin), chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis (lung), ulcerative colitis (colon), IgA nephropathy and lupus nephritis (kidney). By interrogating ligand-receptor (L-R) interactions, alterations in cell proportions, and differential gene expression, we unveiled intricate disease-specific and common immune cell chemoattraction and extravasation patterns. Our findings delineate disease-specific L-R networks and shed light on shared immune responses across tissues and diseases. Insights gleaned from this analysis hold promise for the development of targeted therapeutics aimed at modulating immune cell migration to mitigate inflammation and tissue damage. This nuanced understanding of immune cell dynamics at the single-cell resolution opens avenues for precision medicine in immune disease management.

13.
J Exp Med ; 204(6): 1327-34, 2007 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-17548518

RESUMO

Inflammatory bowel disease (IBD) is an idiopathic inflammatory disease of the intestine. CD4(+) T lymphocytes play an important role in both initiating and regulating intestinal inflammatory immune responses. CD4(+)CD25(+)CD45RB(low) regulatory T (T reg) cells are capable of preventing the development of colitis in a mouse model of IBD. The precise mechanism of T reg cell-mediated prevention of colitis in this model is unclear, and the role of chemokine receptors in the trafficking and function of T reg cells in this model has not been determined. We examined the role of the chemokine receptor CCR4 in in vivo trafficking and suppressive function of T reg cells in a mouse adoptive transfer model of IBD. CCR4-deficient T reg cells failed to accumulate in the mesenteric lymph nodes (MLNs) at early time points (2-5 d) after adoptive transfer, resulting in a failure to suppress the generation of pathogenic T cells and the development of colitis. Moreover, although CCR4-deficent T cells had equivalent in vitro suppressive activity and accumulated in MLNs at later time points (42-56 d), they were unable to suppress colitis. Our study demonstrates that CCR4 plays an important role in T reg cell trafficking in LNs and that this is critical for T reg cell suppressive function in vivo.


Assuntos
Doenças Inflamatórias Intestinais/imunologia , Receptores CCR4/imunologia , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
14.
Blood ; 117(26): 7063-9, 2011 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-21566096

RESUMO

Langerhans cells (LCs) are a distinct population of dendritic cells that form a contiguous network in the epidermis of the skin. Although LCs possess many of the properties of highly proficient dendritic cells, recent studies have indicated that they are not necessary to initiate cutaneous immunity. In this study, we used a tractable model of cutaneous GVHD, induced by topical application of a Toll-like receptor agonist, to explore the role of LCs in the development of tissue injury. By adapting this model to permit inducible and selective depletion of host LCs, we found that GVHD was significantly reduced when LCs were absent. However, LCs were not required either for CD8 T-cell activation within the draining lymph node or subsequent homing of effector cells to the epidermis. Instead, we found that LCs were necessary for inducing transcription of IFN-γ and other key effector molecules by donor CD8 cells in the epidermis, indicating that they license CD8 cells to induce epithelial injury. These data demonstrate a novel regulatory role for epidermal LCs during the effector phase of an inflammatory immune response in the skin.


Assuntos
Comunicação Celular , Citotoxicidade Imunológica , Epiderme/imunologia , Epiderme/patologia , Células de Langerhans/imunologia , Linfócitos T Citotóxicos/imunologia , Aminoquinolinas/toxicidade , Animais , Células Cultivadas , Quimera , Epiderme/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Doença Enxerto-Hospedeiro/imunologia , Granzimas/genética , Granzimas/metabolismo , Imiquimode , Interferon gama/genética , Interferon gama/metabolismo , Células de Langerhans/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , RNA Mensageiro/metabolismo , Linfócitos T Citotóxicos/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/genética , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Receptores Toll-Like/agonistas , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
15.
EMBO Rep ; 12(1): 5-7, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21164515

RESUMO

The Aegean Conferences' first International Conference on Model Hosts took place on the picturesque Greek island of Crete. This meeting was the first of its kind and gathered together international experts who are using a vast array of hosts as models of infection, including worms, insects, mice, fish, rats, humans, squids, pigs, monkeys, protozoa, amoebae and ticks.


Assuntos
Modelos Animais de Doenças , Interações Hospedeiro-Patógeno , Animais , Infecções Bacterianas/imunologia , Infecções Bacterianas/microbiologia , Experimentação Humana , Humanos , Micoses/imunologia , Micoses/microbiologia
16.
J Exp Med ; 202(1): 97-110, 2005 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-15998790

RESUMO

Leukotriene B4 is a lipid mediator that recently has been shown to have potent chemotactic activity for effector T lymphocytes mediated through its receptor, BLT1. Here, we developed a novel murine model of acute lung rejection to demonstrate that BLT1 controls effector CD8+ T cell trafficking into the lung and that disruption of BLT1 signaling in CD8+ T cells reduces lung inflammation and mortality in the model. In addition, we used BLT1-deficient mice and a BLT1 antagonist in two tracheal transplant models of lung transplantation to demonstrate the importance of BLT1 for the recruitment of T cells into tracheal allografts. We also show that BLT1-mediated CD8+ T cell recruitment plays an important role in the development of airway fibroproliferation and obliteration. Finally, in human studies of lung transplant recipients, we found that BLT1 is up-regulated on T lymphocytes isolated from the airways of patients with obliterative bronchiolitis. These data demonstrate that BLT1 contributes to the development of lung rejection and obliterative bronchiolitis by mediating effector T lymphocyte trafficking into the lung. This is the first report that describes a pathologic role for BLT1-mediated T lymphocyte recruitment in disease and identifies BLT1 as a potential therapeutic target after lung transplantation.


Assuntos
Bronquiolite Obliterante/etiologia , Linfócitos T CD8-Positivos/fisiologia , Rejeição de Enxerto/etiologia , Transplante de Pulmão/efeitos adversos , Receptores do Leucotrieno B4/fisiologia , Animais , Sequência de Bases , Bronquiolite Obliterante/imunologia , Bronquiolite Obliterante/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Colágeno/metabolismo , Modelos Animais de Doenças , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/patologia , Humanos , Transplante de Pulmão/imunologia , Transplante de Pulmão/patologia , Transplante de Pulmão/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Ovalbumina/imunologia , Receptores do Leucotrieno B4/deficiência , Receptores do Leucotrieno B4/genética , Traqueia/transplante
17.
Nature ; 435(7044): 969-73, 2005 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-15959517

RESUMO

The organization of cellular niches is known to have a key role in regulating normal stem cell differentiation and regeneration, but relatively little is known about the architecture of microenvironments that support malignant metastasis. Using dynamic in vivo confocal imaging, here we show that murine bone marrow contains unique anatomic regions defined by specialized endothelium. This vasculature expresses the adhesion molecule E-selectin and the chemoattractant stromal-cell-derived factor 1 (SDF-1) in discrete, discontinuous areas that influence the homing of a variety of tumour cell lines. Disruption of the interactions between SDF-1 and its receptor CXCR4 inhibits the homing of Nalm-6 cells (an acute lymphoblastic leukaemia cell line) to these vessels. Further studies revealed that circulating leukaemic cells can engraft around these vessels, suggesting that this molecularly distinct vasculature demarcates a microenvironment for early metastatic tumour spread in bone marrow. Finally, purified haematopoietic stem/progenitor cells and lymphocytes also localize to the same microdomains, indicating that this vasculature might also function in benign states to demarcate specific portals for the entry of cells into the marrow space. Specialized vascular structures therefore appear to delineate a microenvironment with unique physiology that can be exploited by circulating malignant cells.


Assuntos
Células da Medula Óssea/citologia , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Microscopia Confocal/métodos , Neoplasias/patologia , Animais , Células da Medula Óssea/metabolismo , Adesão Celular , Linhagem Celular Tumoral , Movimento Celular , Citocinas/metabolismo , Selectina E/metabolismo , Leucemia/metabolismo , Leucemia/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Receptores CXCR4/metabolismo , Crânio/citologia
18.
J Exp Med ; 197(12): 1657-66, 2003 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-12796468

RESUMO

Accumulation of inflammatory microglia in Alzheimer's senile plaques is a hallmark of the innate response to beta-amyloid fibrils and can initiate and propagate neurodegeneration characteristic of Alzheimer's disease (AD). The molecular mechanism whereby fibrillar beta-amyloid activates the inflammatory response has not been elucidated. CD36, a class B scavenger receptor, is expressed on microglia in normal and AD brains and binds to beta-amyloid fibrils in vitro. We report here that microglia and macrophages, isolated from CD36 null mice, had marked reductions in fibrillar beta-amyloid-induced secretion of cytokines, chemokines, and reactive oxygen species. Intraperitoneal and stereotaxic intracerebral injection of fibrillar beta-amyloid in CD36 null mice induced significantly less macrophage and microglial recruitment into the peritoneum and brain, respectively, than in wild-type mice. Our data reveal that CD36, a major pattern recognition receptor, mediates microglial and macrophage response to beta-amyloid, and imply that CD36 plays a key role in the proinflammatory events associated with AD.


Assuntos
Doença de Alzheimer/imunologia , Peptídeos beta-Amiloides/imunologia , Antígenos CD36/fisiologia , Macrófagos Peritoneais/imunologia , Microglia/imunologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Antígenos CD36/genética , Antígenos CD36/imunologia , Adesão Celular/fisiologia , Células Cultivadas , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Quimiocinas/genética , Quimiocinas/imunologia , Quimiocinas/metabolismo , Quimiotaxia/fisiologia , Humanos , Imuno-Histoquímica , Interleucina-1/genética , Interleucina-1/imunologia , Interleucina-1/metabolismo , Macrófagos Peritoneais/citologia , Macrófagos Peritoneais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/citologia , Microglia/metabolismo , Placa Amiloide/imunologia , Placa Amiloide/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo
19.
Sci Adv ; 6(17): eaax9856, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32494628

RESUMO

Cytomegalovirus (CMV) is an important cause of morbidity and mortality in the immunocompromised host. In transplant recipients, a variety of clinically important "indirect effects" are attributed to immune modulation by CMV, including increased mortality from fungal disease, allograft dysfunction and rejection in solid organ transplantation, and graft-versus-host-disease in stem cell transplantation. Monocytes, key cellular targets of CMV, are permissive to primary, latent and reactivated CMV infection. Here, pairing unbiased bulk and single cell transcriptomics with functional analyses we demonstrate that human monocytes infected with CMV do not effectively phagocytose fungal pathogens, a functional deficit which occurs with decreased expression of fungal recognition receptors. Simultaneously, CMV-infected monocytes upregulate antiviral, pro-inflammatory chemokine, and inflammasome responses associated with allograft rejection and graft-versus-host disease. Our study demonstrates that CMV modulates both immunosuppressive and immunostimulatory monocyte phenotypes, explaining in part, its paradoxical "indirect effects" in transplantation. These data could provide innate immune targets for the stratification and treatment of CMV disease.

20.
J Am Soc Nephrol ; 19(6): 1177-89, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18337479

RESUMO

Chemokines are instrumental in macrophage- and T cell-dependent diseases. The chemokine CCL2 promotes kidney disease in two models of immune-mediated nephritis (MRL-Fas(lpr) mice and the nephrotoxic serum nephritis model), but evidence suggests that multiple chemokines are involved. For identification of additional therapeutic targets for immune-mediated nephritis, chemokine ligands and receptors in CCL2-/- and wild-type (WT) MRL-Fas(lpr) kidneys were profiled. The focus was on intrarenal chemokine ligand/receptor pairs that were highly upregulated downstream of CCL2; the chemokine CXCL10 and its cognate receptor, CXCR3, stood out as potential therapeutic targets. However, renal disease was not suppressed in CXCL10-/- MRL-Fas(lpr) mice, and CXCL10-/- C57BL/6 mice were not protected from nephrotoxic serum nephritis compared with WT mice. Because CXCR3 engages with the ligand CXCL9, CXCR3-/- , CXCL9-/- , and CXCL10-/- B6 mice were compared with WT mice with nephrotoxic serum nephritis. Kidney disease, measured by loss of renal function and histopathology, was suppressed in both CXCR3-/- and CXCL9-/- mice but not in CXCL10-/- mice. With nephrotoxic serum nephritis, CXCR3-/- and CXCL9-/- mice had fewer intrarenal activated T cells and activated macrophages. Both IgG glomerular deposits and antigen-specific IgG in serum were reduced in these mice, suggesting that although CXCR3 and CXCL9 initiate nephritis through cell-mediated events, renal inflammation may be sustained by their regulation of IgG. It is concluded that specific blockade of CXCL9


Assuntos
Quimiocina CXCL10/fisiologia , Quimiocina CXCL9/fisiologia , Nefrite/imunologia , Receptores CXCR3/fisiologia , Animais , Camundongos , Nefrite/etiologia
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