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1.
bioRxiv ; 2024 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-39071425

RESUMEN

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.

2.
J Immunol ; 208(4): 955-967, 2022 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-35082161

RESUMEN

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.


Asunto(s)
Autoanticuerpos/inmunología , Inmunomodulación , Lupus Eritematoso Sistémico/etiología , Lupus Eritematoso Sistémico/metabolismo , Fagocitosis/inmunología , Receptores Depuradores de Clase F/genética , Animales , Autoanticuerpos/sangre , Biomarcadores , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Perfilación de la Expresión Génica , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Inmunomodulación/genética , Inmunofenotipificación , Lupus Eritematoso Sistémico/diagnóstico , Ratones , Ratones Transgénicos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Fagocitos/inmunología , Fagocitos/metabolismo , Fosforilación , Factores de Transcripción STAT/metabolismo , Receptores Depuradores de Clase F/inmunología , Receptores Depuradores de Clase F/metabolismo
3.
Sci Adv ; 6(17): eaax9856, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32494628

RESUMEN

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.

4.
JCI Insight ; 3(5)2018 03 08.
Artículo en Inglés | MEDLINE | ID: mdl-29515032

RESUMEN

Graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic stem cell transplantation induced by the influx of donor-derived effector T cells (TE) into peripheral tissues. Current treatment strategies rely on targeting systemic T cells; however, the precise location and nature of instructions that program TE to become pathogenic and trigger injury are unknown. We therefore used weighted gene coexpression network analysis to construct an unbiased spatial map of TE differentiation during the evolution of GVHD and identified wide variation in effector programs in mice and humans according to location. Idiosyncrasy of effector programming in affected organs did not result from variation in T cell receptor repertoire or the selection of optimally activated TE. Instead, TE were reprogrammed by tissue-autonomous mechanisms in target organs for site-specific proinflammatory functions that were highly divergent from those primed in lymph nodes. In the skin, we combined the correlation-based network with a module-based differential expression analysis and showed that Langerhans cells provided in situ instructions for a Notch-dependent T cell gene cluster critical for triggering local injury. Thus, the principal determinant of TE pathogenicity in GVHD is the final destination, highlighting the need for target organ-specific approaches to block immunopathology while avoiding global immune suppression.


Asunto(s)
Reprogramación Celular/inmunología , Enfermedad Injerto contra Huésped/inmunología , Células de Langerhans/inmunología , Piel/inmunología , Linfocitos T Citotóxicos/inmunología , Animales , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Superficie/genética , Antígenos de Superficie/metabolismo , Trasplante de Médula Ósea/efectos adversos , Células Cultivadas , Reprogramación Celular/genética , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica/inmunología , Enfermedad Injerto contra Huésped/patología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Células de Langerhans/metabolismo , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Masculino , Lectinas de Unión a Manosa/genética , Lectinas de Unión a Manosa/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Familia de Multigenes/genética , Familia de Multigenes/inmunología , Cultivo Primario de Células , Receptores Notch/metabolismo , Piel/citología , Piel/patología , Linfocitos T Citotóxicos/metabolismo , Quimera por Trasplante , Trasplante Homólogo/efectos adversos
5.
J Clin Invest ; 128(5): 2010-2024, 2018 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-29485974

RESUMEN

A key predictor for the success of gene-modified T cell therapies for cancer is the persistence of transferred cells in the patient. The propensity of less differentiated memory T cells to expand and survive efficiently has therefore made them attractive candidates for clinical application. We hypothesized that redirecting T cells to specialized niches in the BM that support memory differentiation would confer increased therapeutic efficacy. We show that overexpression of chemokine receptor CXCR4 in CD8+ T cells (TCXCR4) enhanced their migration toward vascular-associated CXCL12+ cells in the BM and increased their local engraftment. Increased access of TCXCR4 to the BM microenvironment induced IL-15-dependent homeostatic expansion and promoted the differentiation of memory precursor-like cells with low expression of programmed death-1, resistance to apoptosis, and a heightened capacity to generate polyfunctional cytokine-producing effector cells. Following transfer to lymphoma-bearing mice, TCXCR4 showed a greater capacity for effector expansion and better tumor protection, the latter being independent of changes in trafficking to the tumor bed or local out-competition of regulatory T cells. Thus, redirected homing of T cells to the BM confers increased memory differentiation and antitumor immunity, suggesting an innovative solution to increase the persistence and functions of therapeutic T cells.


Asunto(s)
Médula Ósea/inmunología , Linfocitos T CD8-positivos/inmunología , Diferenciación Celular/inmunología , Movimiento Celular/inmunología , Memoria Inmunológica , Neoplasias/inmunología , Linfocitos T Reguladores/inmunología , Animales , Médula Ósea/patología , Linfocitos T CD8-positivos/patología , Línea Celular Tumoral , Quimiocina CXCL12/genética , Quimiocina CXCL12/inmunología , Humanos , Interleucina-15/genética , Interleucina-15/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Neoplasias/genética , Neoplasias/patología , Neoplasias/terapia , Receptores CXCR4/genética , Receptores CXCR4/inmunología , Linfocitos T Reguladores/patología
6.
Sci Immunol ; 2(9)2017 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-28783698

RESUMEN

Epigenetic "readers" that recognize defined posttranslational modifications on histones have become desirable therapeutic targets for cancer and inflammation. SP140 is one such bromodomain- and plant homeodomain (PHD)-containing reader with immune-restricted expression, and single-nucleotide polymorphisms (SNPs) within SP140 associate with Crohn's disease (CD). However, the function of SP140 and the consequences of disease-associated SP140 SNPs have remained unclear. We show that SP140 is critical for transcriptional programs that uphold the macrophage state. SP140 preferentially occupies promoters of silenced, lineage-inappropriate genes bearing the histone modification H3K27me3, such as the HOXA cluster in human macrophages, and ensures their repression. Depletion of SP140 in mouse or human macrophages resulted in severely compromised microbe-induced activation. We reveal that peripheral blood mononuclear cells (PBMCs) or B cells from individuals carrying CD-associated SNPs within SP140 have defective SP140 messenger RNA splicing and diminished SP140 protein levels. Moreover, CD patients carrying SP140 SNPs displayed suppressed innate immune gene signatures in a mixed population of PBMCs that stratified them from other CD patients. Hematopoietic-specific knockdown of Sp140 in mice resulted in exacerbated dextran sulfate sodium (DSS)-induced colitis, and low SP140 levels in human CD intestinal biopsies correlated with relatively lower intestinal innate cytokine levels and improved response to anti-tumor necrosis factor (TNF) therapy. Thus, the epigenetic reader SP140 is a key regulator of macrophage transcriptional programs for cellular state, and a loss of SP140 due to genetic variation contributes to a molecularly defined subset of CD characterized by ineffective innate immunity, normally critical for intestinal homeostasis.

7.
J Immunol ; 198(10): 3775-3789, 2017 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-28483986

RESUMEN

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.


Asunto(s)
Receptores Depuradores/clasificación , Receptores Depuradores/fisiología , Animales , Endocitosis , Humanos , Ligandos , Ratones , National Institute of Allergy and Infectious Diseases (U.S.)/normas , Fagocitosis , Receptores Inmunológicos/fisiología , Receptores Depuradores de Clase A/fisiología , Transducción de Señal , Terminología como Asunto , Estados Unidos
8.
Nat Commun ; 8: 13899, 2017 01 10.
Artículo en Inglés | MEDLINE | ID: mdl-28071653

RESUMEN

Ischaemic acute kidney injury (AKI), an inflammatory disease process, often progresses to chronic kidney disease (CKD), with no available effective prophylaxis. This is in part due to lack of clinically relevant CKD models in non-human primates. Here we demonstrate that inhibition of the archetypal innate immune receptor CD11b/CD18 prevents progression of AKI to CKD in cynomolgus monkeys. Severe ischaemia-reperfusion injury of the right kidney, with subsequent periods of the left ureter ligation, causes irreversible right kidney failure 3, 6 or 9 months after AKI. Moreover, prophylactic inactivation of CD11b/CD18, using the orthosteric CD11b/CD18 inhibitor mAb107, improves microvascular perfusion and histopathology, reduces intrarenal pro-inflammatory mediators and salvages kidney function long term. These studies reveal an important early role of CD11b+ leukocytes in post-ischaemic kidney fibrosis and failure, and suggest a potential early therapeutic intervention to mitigate progression of ischaemic AKI to CKD in humans.


Asunto(s)
Lesión Renal Aguda/prevención & control , Anticuerpos Monoclonales/farmacología , Antígeno CD11b/antagonistas & inhibidores , Antígenos CD18/antagonistas & inhibidores , Lesión Renal Aguda/metabolismo , Animales , Modelos Animales de Enfermedad , Fibrosis/prevención & control , Mediadores de Inflamación/metabolismo , Isquemia/tratamiento farmacológico , Isquemia/fisiopatología , Riñón/irrigación sanguínea , Riñón/efectos de los fármacos , Riñón/patología , Pruebas de Función Renal , Macaca fascicularis , Masculino , Terapia Molecular Dirigida/métodos , Daño por Reperfusión/patología
9.
J Neurosci ; 36(19): 5185-92, 2016 05 11.
Artículo en Inglés | MEDLINE | ID: mdl-27170117

RESUMEN

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.


Asunto(s)
Apoptosis , Astrocitos/metabolismo , Complemento C1q/metabolismo , Proteínas de la Membrana/metabolismo , Animales , Células Cultivadas , Cerebelo/citología , Cerebelo/crecimiento & desarrollo , Cerebelo/metabolismo , Miopatías Distales/genética , Células HEK293 , Humanos , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Mutación , Fagocitosis , Unión Proteica
10.
Eur J Immunol ; 46(1): 192-203, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26464217

RESUMEN

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.


Asunto(s)
Células Dendríticas/inmunología , Monocitos/citología , Monocitos/inmunología , Factor de Necrosis Tumoral alfa/biosíntesis , Animales , Antígenos Ly/inmunología , Antígeno CD11c/inmunología , Citometría de Flujo , Ratones , Ratones Noqueados , Ratones Transgénicos , Análisis de Secuencia por Matrices de Oligonucleótidos , Receptores de IgG/inmunología , Factor de Necrosis Tumoral alfa/inmunología
11.
Immunity ; 43(4): 715-26, 2015 Oct 20.
Artículo en Inglés | MEDLINE | ID: mdl-26488816

RESUMEN

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.


Asunto(s)
Proteínas Adaptadoras de Señalización CARD/fisiología , Candidiasis Invasiva/inmunología , Receptores de Angiotensina/fisiología , Receptores de Endotelina/fisiología , Ubiquitina-Proteína Ligasas/fisiología , Adyuvantes Inmunológicos/farmacología , Animales , Proteínas Adaptadoras de Señalización CARD/química , Proteínas Adaptadoras de Señalización CARD/deficiencia , Proteínas Adaptadoras de Señalización CARD/genética , Candidiasis Invasiva/genética , Colitis/inducido químicamente , Colitis/genética , Colitis/prevención & control , Citocinas/biosíntesis , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Genes Dominantes , Predisposición Genética a la Enfermedad , Células HEK293 , Células HeLa , Humanos , Enfermedades Inflamatorias del Intestino/genética , Ratones , Ratones de la Cepa 129 , Ratones Noqueados , Mapeo de Interacción de Proteínas , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/fisiología , Procesamiento Proteico-Postraduccional , Estructura Terciaria de Proteína , Receptores de Angiotensina/química , Receptores de Angiotensina/deficiencia , Receptores de Endotelina/química , Receptores de Endotelina/deficiencia , Proteínas Recombinantes de Fusión/metabolismo , Transducción de Señal , Organismos Libres de Patógenos Específicos , Proteínas de Motivos Tripartitos , Ubiquitina-Proteína Ligasas/química , Ubiquitinación
12.
Nat Immunol ; 16(5): 495-504, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25848864

RESUMEN

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.


Asunto(s)
Lupus Eritematoso Sistémico/inmunología , Macrófagos/fisiología , Glicoproteínas de Membrana/metabolismo , Infecciones por Orthomyxoviridae/inmunología , Orthomyxoviridae/inmunología , Receptores Inmunológicos/metabolismo , Receptor Toll-Like 7/metabolismo , Animales , Autoanticuerpos/metabolismo , Autoinmunidad/genética , Células Cultivadas , Citocinas/metabolismo , Humanos , Inmunidad Innata/genética , Mediadores de Inflamación/metabolismo , Interferón Tipo I/metabolismo , Macrófagos/virología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos MRL lpr , Ratones Noqueados , Factor 88 de Diferenciación Mieloide/metabolismo , ARN Interferente Pequeño/genética , Receptores Inmunológicos/genética , Factor de Transcripción STAT1/metabolismo , Transducción de Señal/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
13.
J Clin Invest ; 125(1): 102-4, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25500879

RESUMEN

Systemic lupus erythematosus (SLE) is a severe autoimmune disease characterized by the presence of nucleic acid- and protein-targeting autoantibodies and an aberrant type I IFN expression signature. Aicardi-Goutières syndrome (AGS) is an autosomal-recessive encephalopathy in children that is characterized by mutations in numerous nucleic acid repair enzymes and elevated IFN levels. Phenotypically, patients with AGS and SLE share many similarities. Ribonuclease H2 (RNase H2) is a nucleic acid repair enzyme that removes unwanted ribonucleotides from DNA. In this issue of the JCI, Günther and colleagues provide an in-depth investigation of the mechanisms underlying the link between defective removal of ribonucleotides in AGS and SLE, and these findings will likely serve as a strong springboard to provide novel therapeutic inroads.


Asunto(s)
Autoinmunidad/genética , Reparación del ADN , Lupus Eritematoso Sistémico/genética , Dímeros de Pirimidina/metabolismo , Humanos
14.
J Immunol ; 192(5): 1997-2006, 2014 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-24563502

RESUMEN

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.


Asunto(s)
Receptores Depuradores/clasificación , Animales , Humanos , Receptores Depuradores/inmunología , Terminología como Asunto
15.
Nat Neurosci ; 16(12): 1896-905, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24162652

RESUMEN

Microglia, the principal neuroimmune sentinels of the brain, continuously sense changes in their environment and respond to invading pathogens, toxins and cellular debris. Microglia exhibit plasticity and can assume neurotoxic or neuroprotective priming states that determine their responses to danger. We used direct RNA sequencing, without amplification or cDNA synthesis, to determine the quantitative transcriptomes of microglia of healthy adult and aged mice. We validated our findings using fluorescence dual in situ hybridization, unbiased proteomic analysis and quantitative PCR. We found that microglia have a distinct transcriptomic signature and express a unique cluster of transcripts encoding proteins for sensing endogenous ligands and microbes that we refer to as the sensome. With aging, sensome transcripts for endogenous ligand recognition were downregulated, whereas those involved in microbe recognition and host defense were upregulated. In addition, aging was associated with an overall increase in the expression of microglial genes involved in neuroprotection.


Asunto(s)
Microglía/metabolismo , Análisis de Secuencia de ARN/métodos , Transcriptoma/fisiología , Factores de Edad , Animales , Antígeno CD11b/metabolismo , Biología Computacional , Citometría de Flujo , Antígenos Comunes de Leucocito/metabolismo , Ligandos , Macrófagos Peritoneales , Espectrometría de Masas , Ratones , Ratones Endogámicos C57BL , Transcriptoma/genética
16.
Nat Immunol ; 14(9): 917-26, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23892722

RESUMEN

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.


Asunto(s)
Apoptosis/genética , Apoptosis/inmunología , Autoinmunidad/genética , Receptores Depuradores de Clase F/genética , Receptores Depuradores de Clase F/inmunología , Animales , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Complemento C1q/química , Complemento C1q/inmunología , Complemento C1q/metabolismo , Femenino , Inflamación/genética , Inflamación/inmunología , Inflamación/metabolismo , Masculino , Ratones , Ratones Noqueados , Nefritis/genética , Nefritis/inmunología , Nefritis/patología , Fagocitosis/genética , Fagocitosis/inmunología , Fosforilación , Unión Proteica , Receptores Depuradores de Clase F/metabolismo , Serina/metabolismo
17.
Nat Commun ; 4: 2030, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23799536

RESUMEN

In Alzheimer's disease, soluble amyloid-ß causes synaptic dysfunction and neuronal loss. Receptors involved in clearance of soluble amyloid-ß are not known. Here we use short hairpin RNA screening and identify the scavenger receptor Scara1 as a receptor for soluble amyloid-ß expressed on myeloid cells. To determine the role of Scara1 in clearance of soluble amyloid-ß in vivo, we cross Scara1 null mice with PS1-APP mice, a mouse model of Alzheimer's disease, and generate PS1-APP-Scara1-deficient mice. Scara1 deficiency markedly accelerates Aß accumulation, leading to increased mortality. In contrast, pharmacological upregulation of Scara1 expression on mononuclear phagocytes increases Aß clearance. This approach is a potential treatment strategy for Alzheimer's disease.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Progresión de la Enfermedad , Leucocitos Mononucleares/metabolismo , Fagocitos/metabolismo , Receptores Depuradores de Clase A/deficiencia , Animales , Antígenos CD36/metabolismo , Cisteína Endopeptidasas/farmacología , Combinación de Medicamentos , Células HEK293 , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Microglía/efectos de los fármacos , Microglía/metabolismo , Fagocitos/efectos de los fármacos , Presenilina-1/metabolismo , Proteolisis/efectos de los fármacos , ARN Interferente Pequeño/metabolismo , Receptores Depuradores de Clase A/metabolismo , Solubilidad , Análisis de Supervivencia , Regulación hacia Arriba/efectos de los fármacos
18.
Virulence ; 3(7): 635-46, 2012 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-23076328

RESUMEN

Dendritic cells (DCs) are the bridge between the innate and adaptive immune system. DCs are responsible for sensing and patrolling the environment, initiating a host response and instructing the proper adaptive immune response against pathogens. Recent advances in medical treatments have led to increased use of immunosuppressive drugs, leading to the emergence of fungal species that cause life-threatening infections in humans. Three of these opportunistic fungal pathogens: Aspergillus fumigatus, Candida albicans and Cryptococcus neoformans pose the biggest concern for the immune-compromised host. Here we will review the interactions between DCs and these fungal pathogens, the receptors expressed on DCs that mediate these responses and the signaling mechanisms that shape the adaptive host response.


Asunto(s)
Aspergillus fumigatus/inmunología , Candida albicans/inmunología , Cryptococcus neoformans/inmunología , Células Dendríticas/inmunología , Aspergilosis/inmunología , Aspergilosis/microbiología , Candidiasis/inmunología , Candidiasis/microbiología , Criptococosis/inmunología , Criptococosis/microbiología , Humanos , Huésped Inmunocomprometido
19.
Blood ; 117(26): 7063-9, 2011 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-21566096

RESUMEN

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.


Asunto(s)
Comunicación Celular , Citotoxicidad Inmunológica , Epidermis/inmunología , Epidermis/patología , Células de Langerhans/inmunología , Linfocitos T Citotóxicos/inmunología , Aminoquinolinas/toxicidad , Animales , Células Cultivadas , Quimera , Epidermis/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Enfermedad Injerto contra Huésped/inmunología , Granzimas/genética , Granzimas/metabolismo , Imiquimod , Interferón gamma/genética , Interferón gamma/metabolismo , Células de Langerhans/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , ARN Mensajero/metabolismo , Linfocitos T Citotóxicos/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/genética , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Receptores Toll-Like/agonistas , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo
20.
J Clin Invest ; 121(4): 1574-84, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21403403

RESUMEN

Donor lymphocyte infusion (DLI), whereby donor mononuclear cells are infused into patients, is one of the few effective immunotherapeutic strategies that generate long-lasting tumor remissions. We previously demonstrated that chronic myelogenous leukemia (CML) patients treated with DLI develop high-titer plasma antibodies specific for CML-associated antigens, the majority of which have been reported to bind nucleic acids These observations led us to predict that circulating antibody-antigen complexes in DLI-responsive patients carry nucleic acids that can engage innate immune sensors. Consistent with this, we report here that post-DLI plasma from 5 CML patients that responded to DLI treatment induced massive upregulation of MIP-1α, IP-10, and IFN-α in normal blood mononuclear cells. Importantly, this was not observed with plasma obtained before DLI and from DLI nonresponders and imatinib-treated patients. This endogenous immunostimulatory activity required nucleic acid and protein for its adjuvant effect and activated antigen-presenting cells through the RNA and DNA sensors TLR8 and TLR9. Presence of the immunoglobulin Fc receptor CD32 enhanced cellular responses, suggesting that immunoglobulins associate with this activity. Finally, a TLR-induced expression signature was detectable in post-DLI but not pre-DLI blood, consistent with an active circulating TLR8/9-stimulating factor. We have therefore demonstrated that effective tumor immunity correlates with the presence of endogenous nucleic acid-immunoglobulin complexes in patient plasma, thus providing a putative mechanism for the induction of potent antigen-specific immunity against malignant cells.


Asunto(s)
Complejo Antígeno-Anticuerpo/sangre , Trasplante de Médula Ósea/inmunología , Efecto Injerto vs Leucemia/inmunología , Leucemia Mielógena Crónica BCR-ABL Positiva/inmunología , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Receptores Toll-Like/inmunología , Adulto , Anciano , Quimiocina CCL3/sangre , Quimiocina CXCL10/sangre , Femenino , Humanos , Inmunidad Innata , Interferón-alfa/sangre , Leucemia Mielógena Crónica BCR-ABL Positiva/sangre , Transfusión de Linfocitos , Masculino , Persona de Mediana Edad , Ácidos Nucleicos/inmunología , Donantes de Tejidos , Trasplante Homólogo , Regulación hacia Arriba , Adulto Joven
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