RESUMEN
The lung is constantly exposed to airborne pathogens and particles that can cause alveolar damage. Hence, appropriate repair responses are essential for gas exchange and life. Here, we deciphered the spatiotemporal trajectory and function of an atypical population of macrophages after lung injury. Post-influenza A virus (IAV) infection, short-lived monocyte-derived Ly6G-expressing macrophages (Ly6G+ Macs) were recruited to the alveoli of lung perilesional areas. Ly6G+ Macs engulfed immune cells, exhibited a high metabolic potential, and clustered with alveolar type 2 epithelial cells (AT2s) in zones of active epithelial regeneration. Ly6G+ Macs were partially dependent on granulocyte-macrophage colony-stimulating factor and interleukin-4 receptor signaling and were essential for AT2-dependent alveolar regeneration. Similar macrophages were recruited in other models of injury and in the airspaces of lungs from patients with suspected pneumonia. This study identifies perilesional alveolar Ly6G+ Macs as a spatially restricted, short-lived macrophage subset promoting epithelial regeneration postinjury, thus representing an attractive therapeutic target for treating lung damage.
Asunto(s)
Antígenos Ly , Lesión Pulmonar , Macrófagos Alveolares , Ratones Endogámicos C57BL , Regeneración , Animales , Antígenos Ly/metabolismo , Antígenos Ly/inmunología , Ratones , Regeneración/inmunología , Lesión Pulmonar/inmunología , Macrófagos Alveolares/inmunología , Masculino , Humanos , Femenino , Infecciones por Orthomyxoviridae/inmunología , Alveolos Pulmonares/inmunología , Virus de la Influenza A/inmunología , Virus de la Influenza A/fisiologíaRESUMEN
Short-lived repair-promoting macrophages are recruited to foci of lung damage during influenza infection-and they are Ly6G positive (see related Research Article by Ruscitti et al.).
Asunto(s)
Antígenos Ly , Macrófagos Alveolares , Animales , Antígenos Ly/metabolismo , Antígenos Ly/inmunología , Ratones , Macrófagos Alveolares/inmunología , Pulmón/inmunología , Pulmón/citología , Biomarcadores , Macrófagos/inmunología , Infecciones por Orthomyxoviridae/inmunología , HumanosRESUMEN
Liver-resident macrophages Kupffer cells (KCs) and infiltrating Ly6Chi monocytes both contribute to liver tissue regeneration in various pathologies but also to disease progression upon disruption of orderly consecutive regeneration cascades. Little is known about molecular pathways that regulate their differentiation, maintenance, or inflammatory behavior during injury. Here, we show that copper metabolism MURR1 domain (COMMD)10-deficient KCs adopt liver-specific identity. Strikingly, COMMD10 deficiency in KCs and in other tissue-resident macrophages impedes their homeostatic survival, leading to their continuous replacement by Ly6Chi monocytes. While COMMD10 deficiency in KCs mildly worsens acetaminophen-induced liver injury (AILI), its deficiency in Ly6Chi monocytes results in exacerbated and sustained hepatic damage. Monocytes display unleashed inflammasome activation and a reduced type I interferon response and acquire "neutrophil-like" and lipid-associated macrophage differentiation fates. Collectively, COMMD10 appears indispensable for KC and other tissue-resident macrophage survival and is an important regulator of Ly6Chi monocyte fate decisions and reparative behavior in the diseased liver.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/metabolismo , Macrófagos del Hígado/metabolismo , Animales , Antígenos Ly/inmunología , Antígenos Ly/metabolismo , Diferenciación Celular/genética , Supervivencia Celular , Hematopoyesis , Inflamasomas/metabolismo , Inflamación/patología , Péptidos y Proteínas de Señalización Intracelular/genética , Macrófagos del Hígado/fisiología , Hígado/citología , Hígado/lesiones , Masculino , Ratones , Ratones Endogámicos C57BL , Monocitos/metabolismoRESUMEN
We recently discovered a novel form of trained innate immunity (TII) induced by low-virulence Candida species (i.e., Candida dubliniensis) that protects against lethal fungal/bacterial infection. Mice vaccinated by intraperitoneal (i.p.) inoculation are protected against lethal sepsis following Candida albicans/Staphylococcus aureus (Ca/Sa) intra-abdominal infection (IAI) or Ca bloodstream infection (BSI). The protection against IAI is mediated by long-lived Gr-1+ leukocytes as putative myeloid-derived suppressor cells (MDSCs) and not by prototypical trained macrophages. This study aimed to determine if a similar TII mechanism (Gr-1+ cell-mediated suppression of sepsis) is protective against BSI and whether this TII can also be induced following intravenous (i.v.) vaccination. For this, mice were vaccinated with low-virulence Candida strains (i.p. or i.v.), followed by lethal challenge (Ca/Sa i.p. or Ca i.v.) 14 days later, and observed for sepsis (hypothermia, sepsis scoring, and serum cytokines), organ fungal burden, and mortality. Similar parameters were monitored following depletion of macrophages or Gr-1+ leukocytes during lethal challenge. The results showed that mice vaccinated i.p. or i.v. were protected against lethal Ca/Sa IAI or Ca BSI. In all cases, protection was mediated by Ly6G+ Gr-1+ putative granulocytic MDSCs (G-MDSCs), with no role for macrophages, and correlated with reduced sepsis parameters. Protection also correlated with reduced fungal burden in spleen and brain but not liver or kidney. These results suggest that Ly6G+ G-MDSC-mediated TII is induced by either the i.p. and i.v. route of inoculation and protects against IAI or BSI forms of systemic candidiasis, with survival correlating with amelioration of sepsis and reduced organ-specific fungal burden. IMPORTANCE Trained innate immunity (TII) is induced following immunization with live attenuated microbes and represents a clinically important strategy to enhance innate defenses. TII was initially demonstrated following intravenous inoculation with low-virulence Candida albicans, with protection against a subsequent lethal C. albicans intravenous bloodstream infection (BSI) mediated by monocytes with enhanced cytokine responses. We expanded this by describing a novel form of TII induced by intraperitoneal inoculation with low-virulence Candida that protects against lethal sepsis induced by polymicrobial intra-abdominal infection (IAI) via Gr-1+ leukocytes as putative myeloid-derived suppressor cells (MDSCs). In this study, we addressed these two scenarios and confirmed an exclusive role for Ly6G+ Gr-1+ leukocytes in mediating TII against either IAI or BSI via either route of inoculation, with protection associated with suppression of sepsis. These studies highlight the previously unrecognized importance of Ly6G+ MDSCs as central mediators of a novel form of TII termed trained tolerogenic immunity.
Asunto(s)
Antígenos Ly/inmunología , Candida/inmunología , Candidiasis/inmunología , Candidiasis/prevención & control , Inmunidad Innata , Leucocitos/inmunología , Receptores de Quimiocina/inmunología , Vacunación/métodos , Animales , Candida/patogenicidad , Modelos Animales de Enfermedad , Femenino , Ratones , Infecciones Estafilocócicas/inmunología , Infecciones Estafilocócicas/prevención & control , VirulenciaRESUMEN
Neutrophils are essential to control several fungal infections. These cells are commonly known for their pro-inflammatory activities. However, some studies have demonstrated the anti-inflammatory properties of neutrophils during certain infectious diseases, culminating in the inhibition of T cell proliferation. Chromoblastomycosis (CBM) is a deep and progressive mycosis that affects thousands of people worldwide. Although neutrophil infiltrates are observed in the lesion histopathology, the fungus can overtake the immune system response and destroy the host-infected tissue. The present study demonstrated that neutropenic animals had an increase in the IL-6 production in the spleen and liver, followed by a lower fungal burden in these organs up to 14 days of infection. Neutropenic animals also showed a lower F. pedrosoi-specific antibody production 14-days post infection and higher T-cell proliferation in the in vitro experiments after stimulation with F. pedrosoi-purified proteins. Taken together, our results suggest that the presence of regulatory neutrophils in the mouse model of F. pedrosoi infection could act favoring the spread of the fungus and the chronicity of the infection. These findings shed light on the CBM treatment, which might target neutrophil polarization as a new therapy approach to treat CBM lesions.
Asunto(s)
Anticuerpos/efectos adversos , Antígenos Ly/inmunología , Cromoblastomicosis/inmunología , Fonsecaea/patogenicidad , Neutropenia/inmunología , Neutrófilos/metabolismo , Linfocitos T/metabolismo , Animales , Polaridad Celular , Proliferación Celular , Cromoblastomicosis/complicaciones , Modelos Animales de Enfermedad , Fonsecaea/inmunología , Humanos , Interleucina-6/metabolismo , Hígado/inmunología , Activación de Linfocitos , Ratones , Neutropenia/inducido químicamente , Bazo/inmunologíaRESUMEN
Naïve T (Tn) cells require two homeostatic signals for long-term survival: tonic T cell receptor:self-peptide-MHC contact and IL-7 stimulation. However, how microbial exposure impacts Tn homeostasis is still unclear. Here we show that infections can lead to the expansion of a subpopulation of long-lived, Ly6C+ CD8+ Tn cells with accelerated effector function. Mechanistically, mono-infection with West Nile virus transiently, and polymicrobial exposure persistently, enhances Ly6C expression selectively on CD5hiCD8+ cells, which in the case of polyinfection translates into a numerical CD8+ Tn cell increase in the lymph nodes. This conversion and expansion of Ly6C+ Tn cells depends on IFN-I, which upregulates MHC class I expression and enhances tonic TCR signaling in differentiating Tn cells. Moreover, for Ly6C+CD8+ Tn cells, IFN-I-mediated signals optimize their homing to secondary sites, extend their lifespan, and enhance their effector differentiation and antibacterial function, particularly for low-affinity clones. Our results thus uncover significant regulation of Tn homeostasis and function via infection-driven IFN-I, with potential implications for immunotherapy.
Asunto(s)
Antígenos Ly/genética , Linfocitos T CD8-positivos/inmunología , Homeostasis/genética , Memoria Inmunológica/genética , Interferón-alfa/genética , Interferón gamma/genética , Fiebre del Nilo Occidental/genética , Animales , Antígenos Ly/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virología , Antígenos CD5/genética , Antígenos CD5/inmunología , Antígenos CD8/genética , Antígenos CD8/inmunología , Linfocitos T CD8-positivos/virología , Diferenciación Celular , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Homeostasis/inmunología , Interferón-alfa/inmunología , Interferón gamma/inmunología , Interleucina-7/genética , Interleucina-7/inmunología , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , Transducción de Señal , Fiebre del Nilo Occidental/inmunología , Fiebre del Nilo Occidental/patología , Fiebre del Nilo Occidental/virología , Virus del Nilo Occidental/inmunología , Virus del Nilo Occidental/patogenicidadRESUMEN
Simultaneous triggering of NK1.1 and MHC class I on NK cells gives a higher Ca2+ flux response compared to triggering the NK1.1 receptor alone. The data suggest a novel costimulatory role for MHC class I molecules on NK cell responses.
Asunto(s)
Antígenos Ly/inmunología , Calcio/metabolismo , Antígenos de Histocompatibilidad Clase I/inmunología , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Subfamilia B de Receptores Similares a Lectina de Células NK/inmunología , Transducción de Señal , Animales , Antígenos H-2/genética , Antígenos H-2/inmunología , RatonesRESUMEN
Neuroinflammation has been put forward as a mechanism triggering axonal regrowth in the mammalian central nervous system (CNS), yet little is known about the underlying cellular and molecular players connecting these two processes. In this study, we provide evidence that MMP2 is an essential factor linking inflammation to axonal regeneration by using an in vivo mouse model of inflammation-induced axonal regeneration in the optic nerve. We show that infiltrating myeloid cells abundantly express MMP2 and that MMP2 deficiency results in reduced long-distance axonal regeneration. However, this phenotype can be rescued by restoring MMP2 expression in myeloid cells via a heterologous bone marrow transplantation. Furthermore, while MMP2 deficiency does not affect the number of infiltrating myeloid cells, it does determine the coordinated expression of pro- and anti-inflammatory molecules. Altogether, in addition to its role in axonal regeneration via resolution of the glial scar, here, we reveal a new mechanism via which MMP2 facilitates axonal regeneration, namely orchestrating the expression of pro- and anti-inflammatory molecules by infiltrating innate immune cells.
Asunto(s)
Axones/inmunología , Trasplante de Médula Ósea , Metaloproteinasa 2 de la Matriz/genética , Regeneración Nerviosa/inmunología , Traumatismos del Nervio Óptico/inmunología , Nervio Óptico/inmunología , Animales , Antígenos Ly/genética , Antígenos Ly/inmunología , Axones/ultraestructura , Receptor 1 de Quimiocinas CX3C/genética , Receptor 1 de Quimiocinas CX3C/inmunología , Movimiento Celular , Proteína GAP-43/genética , Proteína GAP-43/inmunología , Regulación de la Expresión Génica , Inmunidad Innata , Inflamación , Antígenos Comunes de Leucocito/genética , Antígenos Comunes de Leucocito/inmunología , Metaloproteinasa 2 de la Matriz/deficiencia , Metaloproteinasa 2 de la Matriz/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células Mieloides/citología , Células Mieloides/inmunología , Regeneración Nerviosa/genética , Nervio Óptico/metabolismo , Traumatismos del Nervio Óptico/genética , Traumatismos del Nervio Óptico/patología , Retina/inmunología , Retina/lesiones , Retina/metabolismo , Trasplante Heterólogo , Irradiación Corporal TotalRESUMEN
Understanding the rationale of combining immunotherapy and other anticancer treatment modalities is of great interest because of interpatient variability in single-agent immunotherapy. Here, we demonstrated that topoisomerase I inhibitors, a class of chemotherapeutic drugs, can alter the tumor immune landscape, corroborating their antitumor effects combined with immunotherapy. We observed that topotecan-conditioned TC-1 tumors were occupied by a vast number of monocytic cells that highly express CD11c, CD64, and costimulatory molecules responsible for the favorable changes in the tumor microenvironment. Ly6C+MHC-II+CD11chiCD64hi cells, referred to as topotecan-induced monocyte-derived dendritic cells (moDCs), proliferate and activate antigen-specific CD8+ T cells to levels equivalent to those of conventional DCs. Phenotypic changes in Ly6C+ cells towards moDCs were similarly induced by exposure to topotecan in vitro, which was more profoundly facilitated in the presence of tumor cells. Notably, anti-M-CSFR reversed the acquisition of DC-like properties of topotecan-induced moDCs, leading to the abolition of the antitumor effect of topotecan combined with a cancer vaccine. In short, topoisomerase I inhibitors generate monocyte-derived antigen-presenting cells in tumors, which could be mediated by M-CSF-M-CSFR signaling.
Asunto(s)
Células Presentadoras de Antígenos/inmunología , Inmunoterapia , Neoplasias/terapia , Inhibidores de Topoisomerasa I/farmacología , Animales , Antígenos Ly/inmunología , Antígeno CD11c/inmunología , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/farmacología , Proliferación Celular/genética , Técnicas de Cocultivo , Terapia Combinada , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Humanos , Inmunidad Innata/efectos de los fármacos , Inmunidad Innata/inmunología , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/inmunología , Ratones , Neoplasias/inmunología , Neoplasias/patología , Receptores de IgG/inmunología , Linfocitos T/inmunología , Inhibidores de Topoisomerasa I/inmunología , Topotecan/farmacología , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunologíaAsunto(s)
Autoanticuerpos/sangre , Dermatomiositis/diagnóstico , Adulto , Anciano , Antígenos Ly/inmunología , Autoanticuerpos/inmunología , Autoanticuerpos/aislamiento & purificación , Biomarcadores/sangre , Dermatomiositis/sangre , Dermatomiositis/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Helicasa Inducida por Interferón IFIH1/inmunología , Japón , Masculino , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/inmunología , Persona de Mediana Edad , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Factores de Transcripción/inmunología , Activador de Plasminógeno de Tipo Uroquinasa/inmunologíaRESUMEN
NK cells are innate immune cells implicated in ALS; whether NK cells impact ALS in a sex- and age-specific manner was investigated. Herein, NK cells were depleted in male and female SOD1G93A ALS mice, survival and neuroinflammation were assessed, and data were stratified by sex. NK cell depletion extended survival in female but not male ALS mice with sex-specific effects on spinal cord microglia. In humans, NK cell numbers, NK cell subpopulations, and NK cell surface markers were examined in prospectively blood collected from subjects with ALS and control subjects; longitudinal changes in these metrics were correlated to revised ALS functional rating scale (ALSFRS-R) slope and stratified by sex and age. Expression of NK cell trafficking and cytotoxicity markers was elevated in subjects with ALS, and changes in CXCR3+ NK cells and 7 trafficking and cytotoxicity markers (CD11a, CD11b, CD38, CX3CR1, NKG2D, NKp30, NKp46) correlated with disease progression. Age affected the associations between ALSFRS-R and markers NKG2D and NKp46, whereas sex impacted the NKp30 association. Collectively, these findings suggest that NK cells contribute to ALS progression in a sex- and age-specific manner and demonstrate that age and sex are critical variables when designing and assessing ALS immunotherapy.
Asunto(s)
Esclerosis Amiotrófica Lateral/inmunología , Células Asesinas Naturales/inmunología , Enfermedades Neuroinflamatorias/inmunología , Médula Espinal/inmunología , Factores de Edad , Anciano , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , Animales , Antígenos Ly/inmunología , Antígenos Ly/metabolismo , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Eosinófilos/citología , Eosinófilos/inmunología , Femenino , Humanos , Células Asesinas Naturales/citología , Células Asesinas Naturales/metabolismo , Leucocitos/citología , Leucocitos/inmunología , Masculino , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Monocitos/citología , Monocitos/inmunología , Subfamilia B de Receptores Similares a Lectina de Células NK/inmunología , Subfamilia B de Receptores Similares a Lectina de Células NK/metabolismo , Neutrófilos/citología , Neutrófilos/inmunología , Factores Sexuales , Médula Espinal/citología , Superóxido Dismutasa/genética , Tasa de SupervivenciaRESUMEN
To develop a machine learning (ML) model that predicts disease groups or autoantibodies in patients with idiopathic inflammatory myopathies (IIMs) using muscle MRI radiomics features. Twenty-two patients with dermatomyositis (DM), 14 with amyopathic dermatomyositis (ADM), 19 with polymyositis (PM) and 19 with non-IIM were enrolled. Using 2D manual segmentation, 93 original features as well as 93 local binary pattern (LBP) features were extracted from MRI (short-tau inversion recovery [STIR] imaging) of proximal limb muscles. To construct and compare ML models that predict disease groups using each set of features, dimensional reductions were performed using a reproducibility analysis by inter-reader and intra-reader correlation coefficients, collinearity analysis, and the sequential feature selection (SFS) algorithm. Models were created using the linear discriminant analysis (LDA), quadratic discriminant analysis (QDA), support vector machine (SVM), k-nearest neighbors (k-NN), random forest (RF) and multi-layer perceptron (MLP) classifiers, and validated using tenfold cross-validation repeated 100 times. We also investigated whether it was possible to construct models predicting autoantibody status. Our ML-based MRI radiomics models showed the potential to distinguish between PM, DM, and ADM. Models using LBP features provided better results, with macro-average AUC values of 0.767 and 0.714, accuracy of 61.2 and 61.4%, and macro-average recall of 61.9 and 59.8%, in the LDA and k-NN classifiers, respectively. In contrast, the accuracies of radiomics models distinguishing between non-IIM and IIM disease groups were low. A subgroup analysis showed that classification models for anti-Jo-1 and anti-ARS antibodies provided AUC values of 0.646-0.853 and 0.692-0.792, with accuracy of 71.5-81.0 and 65.8-78.3%, respectively. ML-based TA of muscle MRI may be used to predict disease groups or the autoantibody status in patients with IIM and is useful in non-invasive assessments of disease mechanisms.
Asunto(s)
Dermatomiositis/diagnóstico , Interpretación de Imagen Asistida por Computador/métodos , Aprendizaje Automático , Músculos/diagnóstico por imagen , Polimiositis/diagnóstico , Adulto , Anciano , Anticuerpos Antinucleares/análisis , Anticuerpos Antinucleares/inmunología , Antígenos Ly/inmunología , Biopsia , Dermatomiositis/inmunología , Dermatomiositis/patología , Diagnóstico Diferencial , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Músculos/inmunología , Músculos/patología , Polimiositis/inmunología , Polimiositis/patología , Curva ROC , Reproducibilidad de los Resultados , Estudios Retrospectivos , Activador de Plasminógeno de Tipo Uroquinasa/inmunologíaRESUMEN
Echinococcus granulosus is a cestode parasite which causes cystic echinococcosis disease. Previously we observed that vaccination with E. granulosus antigens from human hydatid cyst fluid (HCF) significantly inhibits colon cancer growth. In the present work, we evaluate the anti-tumor immune response induced by human HCF against LL/2 lung cancer in mice. HCF vaccination protected from tumor growth, both in prophylactic and therapeutic settings, and significantly increased mouse survival compared to control mice. Considering that tumor-associated carbohydrate antigens are expressed in E. granulosus, we oxidized terminal carbohydrates in HCF with sodium periodate. This treatment abrogates the anti-tumor activity induced by HCF vaccination. We found that HCF vaccination-induced IgG antibodies that recognize LL/2 tumor cells by flow cytometry. An antigen-specific immune response is induced with HCF vaccination in the tumor-draining lymph nodes and spleen characterized by the production of IL-5 and, in less extent, IFNÉ£. In the tumor microenvironment, we found that NK1.1 positive cells from HCF-treated mice showed higher expression of CD69 than control mice ones, indicating a higher level of activation. When we depleted these cells by administrating the NK-specific antibody NK1.1, a significantly decreased survival was observed in HCF-induced mice, suggesting that NK1.1+ cells mediate the anti-tumor protection induced by HCF. These results suggest that HCF can evoke an integrated anti-tumor immune response involving both, the innate and adaptive components, and provide novel insights into the understanding of the intricate relationship between HCF vaccination and tumor growth.
Asunto(s)
Antígenos Ly/inmunología , Equinococosis/inmunología , Echinococcus granulosus/inmunología , Subfamilia B de Receptores Similares a Lectina de Células NK/inmunología , Animales , Línea Celular Tumoral , Neoplasias del Colon/inmunología , Humanos , Inmunidad/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Bazo/inmunología , Microambiente Tumoral/inmunologíaRESUMEN
Interleukin 6 (IL-6) is a pleiotropic cytokine that is elevated in inflammatory bowel disease. However, the role of IL-6 deficiency in colitis is not well-defined. Some IL-6 and IL-6 receptor antagonists are associated with severe gastrointestinal immune adverse effects, but the mechanisms of the effects are not clear. This study aimed to investigate the effect of IL-6 in ulcerative colitis in Il6-/- mice. Results indicated that physiological deficiency of IL-6 promoted the development of colitis. Moreover, IL-6 deficiency significantly increased the mRNA levels of monocytes chemokine Ccl2 and its receptor Ccr2 in colon tissues. Similarly, the percentage of Ly6Chigh monocytes and neutrophils were increased in the colon of Il6-/- mice. Intestinal crypts more strongly increased the migration of Il6-/- macrophages than wild-type ones. Moreover, Il6-/- macrophages promoted the migration of neutrophils. Most importantly, RS102895, an antagonist of CCR2, diminished chemotaxis of macrophages and inhibited colitis in Il6-/- mice. Collectively, these results indicate that Il6-/- macrophages migrate to inflamed colon tissues and recruit neutrophils, thereby promoting the effect of Il6-/- on colitis. This study expands our understanding on the effect of IL-6 deficiency in colitis and the development of gastrointestinal immune adverse effects.
Asunto(s)
Antígenos Ly/inmunología , Quimiocina CCL2/inmunología , Colitis Ulcerosa/genética , Colon/inmunología , Interleucina-6/deficiencia , Monocitos/inmunología , Receptores CCR2/inmunología , Animales , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/patología , Colon/efectos de los fármacos , Colon/metabolismo , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Microbioma Gastrointestinal/genética , Microbioma Gastrointestinal/inmunología , Técnicas de Inactivación de Genes , Inflamación/genética , Inflamación/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Macrófagos/inmunología , Masculino , Ratones , Ratones Noqueados , Neutrófilos/inmunología , Receptores CCR2/antagonistas & inhibidoresRESUMEN
The Lymphocyte antigen-6 (Ly-6) superfamily has been considered to play an important role in the innate immunity of mammals. The functions of Ly-6 proteins are diverse since their low sequence homology. Currently, the function of Ly-6D, a member of Ly-6 family proteins, is completely unknown in teleost. In the present study, we identified and characterized a Ly-6D homologue (named PoLy-6D) from the teleost fish Paralichthys olivaceus and examined its immune function. PoLy-6D possesses a hydrophobic signal peptide, a LU domain including a conserved "LXCXXC" motif in N-terminus and a "CCXXXXCN" motif in C-terminus. Under normal physiological condition, PoLy-6D expression distributes in all the examined tissues, the highest three tissues are successively spleen, head kidney, and blood. When infected by extracellular and intracellular bacterial pathogens and viral pathogen, PoLy-6D expression was induced and the patterns vary with different types of microbial pathogens infection and different immune tissues. In vitro experiment showed recombinant PoLy-6D (rPoLy-6D) inhibited the lysis of rabbit red blood cells by serum and selectively improved bacterial survival in serum. After serum were treated by antibody of rPoLy-6D, bacteriostatic effect of serum was obviously enhanced. These results indicate the importance of PoLy-6D as a complement regulator. rPoLy-6D possessed the binding activity to multiple bacteria but did not exhibit antimicrobial activities. The interaction between rPoLy-6D and bacteria suggests that PoLy-6D is involved in host clearance of pathogens probably by serving as a receptor for pathogens. Overexpression of PoLy-6D in vivo promoted the host defense against invading E. piscicida. These findings add new insights into the regulation mechanism of the complement system in teleost and emphasize the importance of Ly-6D products for the control of pathogen infection.
Asunto(s)
Antígenos Ly/inmunología , Activación de Complemento/inmunología , Proteínas Inactivadoras de Complemento/metabolismo , Proteínas del Sistema Complemento/inmunología , Lenguado/inmunología , Secuencia de Aminoácidos , Animales , Antígenos Ly/genética , Secuencia de Bases , Edwardsiella/inmunología , Enfermedades de los Peces/inmunología , Enfermedades de los Peces/microbiología , Proteínas de Peces/genética , Proteínas de Peces/inmunología , Inmunidad Innata/inmunología , Factores Inmunológicos/inmunología , Dominios Proteicos , Alineación de Secuencia , Análisis de Secuencia de ADN , Virus/inmunologíaRESUMEN
Natural killer (NK) cells are innate effectors armed with cytotoxic and cytokine-secreting capacities whose spontaneous antitumor activity is key to numerous immunotherapeutic strategies. However, current mouse models fail to mirror the extensive immune system variation that exists in the human population which may impact on NK cell-based therapies. We performed a comprehensive profiling of NK cells in the Collaborative Cross (CC), a collection of novel recombinant inbred mouse strains whose genetic diversity matches that of humans, thereby providing a unique and highly diverse small animal model for the study of immune variation. We demonstrate that NK cells from CC strains displayed a breadth of phenotypic and functional variation reminiscent of that reported for humans with regards to cell numbers, key marker expression, and functional capacities. We took advantage of the vast genetic diversity of the CC and identified nine genomic loci through quantitative trait locus mapping driving these phenotypic variations. SNP haplotype patterns and variant effect analyses identified candidate genes associated with lung NK cell numbers, frequencies of CD94+ NK cells, and expression levels of NKp46. Thus, we demonstrate that the CC represents an outstanding resource to study NK cell diversity and its regulation by host genetics.
Asunto(s)
Antígenos Ly , Regulación de la Expresión Génica/inmunología , Células Asesinas Naturales/inmunología , Subfamília D de Receptores Similares a Lectina de las Células NK , Receptor 1 Gatillante de la Citotoxidad Natural , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo/inmunología , Animales , Antígenos Ly/genética , Antígenos Ly/inmunología , Cruzamientos Genéticos , Ratones , Ratones Endogámicos , Subfamília D de Receptores Similares a Lectina de las Células NK/genética , Subfamília D de Receptores Similares a Lectina de las Células NK/inmunología , Receptor 1 Gatillante de la Citotoxidad Natural/genética , Receptor 1 Gatillante de la Citotoxidad Natural/inmunologíaRESUMEN
Dexmedetomidine (DEX) is a highly selective α2-adrenoceptor agonist, which can regulate inflammatory responses. However, whether DEX interferes with the inflammation resolving remains unclear. Here, we reported the effects of DEX on zymosan-induced generalized inflammation in mice during resolution. Mice were administered intraperitoneally with DEX after the initiation of sepsis. The resolution interval (Ri), a vital resolution indice, decreased from twelve hours to eight hours after the administration of DEX. The induction of peritoneal pro-inflammatory interleukin [IL] - 1ß and tumour necrosis factor-α (TNF-α) appeared to be inhibited. Of interest, the anti-inflammatory transforming growth factor-ß1 (TGF-ß1) but not IL-10 levels were up-regulated at twenty-four hours in the DEX group along with 1.0 mg/mice zymosan A (ZyA) treatment. The expression levels of multiple genes related to protective immune processes and clearance functions were detected and revealed the same trends. DEX markedly increased the F4/80+Ly6G+ macrophage population. Additionally, the adequate apoptotic neutrophil clearance from injury after DEX installation could be reverse by opsonization or co-instillation of TGF-ß1 neutralizing antibody in vivo, promoting the inflammation-resolution programs. In conclusion, DEX post-treatment, via the increase of F4/80+Ly6G+ macrophages, provokes further secretion of TGF-ß1, leading to the attenuated cytokine storm and accelerated inflammation resolving.
Asunto(s)
Antiinflamatorios/uso terapéutico , Dexmedetomidina/uso terapéutico , Macrófagos/efectos de los fármacos , Peritonitis/tratamiento farmacológico , Factor de Crecimiento Transformador beta1/inmunología , Animales , Antiinflamatorios/farmacología , Antígenos de Diferenciación/inmunología , Antígenos Ly/inmunología , Citocinas/genética , Citocinas/inmunología , Dexmedetomidina/farmacología , Macrófagos/inmunología , Masculino , Ratones Endogámicos C57BL , Peritonitis/genética , Peritonitis/inmunología , Factor de Crecimiento Transformador beta1/genéticaRESUMEN
Background: Murine monocytes (MC) are classified into Ly6Chigh and Ly6Clow MC. Ly6Chigh MC is the pro-inflammatory subset and the counterpart of human CD14++CD16+ intermediate MC which contributes to systemic and tissue inflammation in various metabolic disorders, including hyperhomocysteinemia (HHcy). This study aims to explore molecule signaling mediating MC subset differentiation in HHcy and control mice. Methods: RNA-seq was performed in blood Ly6Chigh and Ly6Clow MC sorted by flow cytometry from control and HHcy cystathionine ß-synthase gene-deficient (Cbs-/-) mice. Transcriptome data were analyzed by comparing Ly6Chigh vs. Ly6Clow in control mice, Ly6Chigh vs. Ly6Clow in Cbs-/- mice, Cbs-/- Ly6Chigh vs. control Ly6Chigh MC and Cbs-/- Ly6Clow vs. control Ly6Clow MC by using intensive bioinformatic strategies. Significantly differentially expressed (SDE) immunological genes and transcription factor (TF) were selected for functional pathways and transcriptional signaling identification. Results: A total of 7,928 SDE genes and 46 canonical pathways derived from it were identified. Ly6Chigh MC exhibited activated neutrophil degranulation, lysosome, cytokine production/receptor interaction and myeloid cell activation pathways, and Ly6Clow MC presented features of lymphocyte immunity pathways in both mice. Twenty-four potential transcriptional regulatory pathways were identified based on SDE TFs matched with their corresponding SDE immunological genes. Ly6Chigh MC presented downregulated co-stimulatory receptors (CD2, GITR, and TIM1) which direct immune cell proliferation, and upregulated co-stimulatory ligands (LIGHT and SEMA4A) which trigger antigen priming and differentiation. Ly6Chigh MC expressed higher levels of macrophage (MΦ) markers, whereas, Ly6Clow MC highly expressed lymphocyte markers in both mice. HHcy in Cbs-/- mice reinforced inflammatory features in Ly6Chigh MC by upregulating inflammatory TFs (Ets1 and Tbx21) and strengthened lymphocytes functional adaptation in Ly6Clow MC by increased expression of CD3, DR3, ICOS, and Fos. Finally, we established 3 groups of transcriptional models to describe Ly6Chigh to Ly6Clow MC subset differentiation, immune checkpoint regulation, Ly6Chigh MC to MΦ subset differentiation and Ly6Clow MC to lymphocyte functional adaptation. Conclusions: Ly6Chigh MC displayed enriched inflammatory pathways and favored to be differentiated into MΦ. Ly6Clow MC manifested activated T-cell signaling pathways and potentially can adapt the function of lymphocytes. HHcy reinforced inflammatory feature in Ly6Chigh MC and strengthened lymphocytes functional adaptation in Ly6Clow MC.
Asunto(s)
Antígenos Ly/inmunología , Hiperhomocisteinemia/inmunología , Monocitos/inmunología , Animales , Antígenos Ly/metabolismo , Diferenciación Celular/inmunología , Cistationina betasintasa/deficiencia , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Hiperhomocisteinemia/metabolismo , Proteínas de Punto de Control Inmunitario/genética , Inflamación , Linfocitos/inmunología , Lisosomas/inmunología , Macrófagos/inmunología , Ratones , Monocitos/metabolismo , Transducción de Señal , Factores de Transcripción/genéticaRESUMEN
The gut microbiome has garnered attention as an effective target to boost immunity and improve cancer immunotherapy. We found that B cell-defective (BCD) mice, such as µ-membrane targeted deletion (µMT) and activation-induced cytidine deaminase (AID) knockouts (KOs), have elevated antitumor immunity under specific pathogen-free but not germ-free conditions. Microbial dysbiosis in these BCD mice enriched the type I IFN (IFN) signature in mucosal CD8+ T cells, resulting in up-regulation of the type I IFN-inducible protein stem cell antigen-1 (Sca-1). Among CD8+ T cells, naïve cells predominantly circulate from the gut to the periphery, and those that had migrated from the mesenteric lymph nodes (mLNs) to the periphery had significantly higher expression of Sca-1. The gut-educated Sca-1+ naïve subset is endowed with enhanced mitochondrial activity and antitumor effector potential. The heterogeneity and functional versatility of the systemic naïve CD8+ T cell compartment was revealed by single-cell analysis and functional assays of CD8+ T cell subpopulations. These results indicate one of the potential mechanisms through which microbial dysbiosis regulates antitumor immunity.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Microbioma Gastrointestinal/inmunología , Interferón Tipo I/inmunología , Neoplasias Experimentales/inmunología , Animales , Antígenos Ly/inmunología , Antígenos Ly/metabolismo , Linfocitos B , Línea Celular Tumoral , Células Cultivadas , Disbiosis/inmunología , Inmunoglobulina A/inmunología , Inmunoglobulina A/metabolismo , Interferón Tipo I/metabolismo , Ganglios Linfáticos/citología , Proteínas de la Membrana/inmunología , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de Señal/inmunologíaRESUMEN
Macrophages are important innate immune cells that play crucial roles in inflammatory responses. Accumulating evidence has demonstrated macrophage heterogeneity based on biomarkers, functions, and localization. Here, we report a novel stem cell antigen-1 (Sca-1)-positive macrophage population induced in the pathological conditions caused by lipopolysaccharide (LPS). Sca-1 is only upregulated in macrophages but not in monocytes and neutrophils upon LPS injection. Sca-1+ macrophages develop from resident peritoneal macrophages. LPS-induced Sca-1+ macrophage generation was partly blocked by anti-IFN-γ antibody, suggesting a role of IFN-γ in the process. LPS-stimulated production of IL-6, TNF-α, and CCL2 is significantly lower in Sca-1+ macrophages compared to their counterpart Sca-1- macrophages. Depletion of Sca-1+ macrophages using anti-Sca-1 antibody significantly increased survival rate and reduced lung and kidney damage in an LPS-induced sepsis model. Taken together, we discovered a novel population of Sca-1+ macrophages in LPS-induced septic conditions.