RESUMEN
Oropharyngeal candidiasis (OPC) is the most common human fungal infection, arising typically from T cell immune impairments. IL-17 and IL-22 contribute individually to OPC responses, but here we demonstrate that the combined actions of both cytokines are essential for resistance to OPC. Mice lacking IL-17RA and IL-22RA1 exhibited high fungal loads in esophagus- and intestinal tract, severe weight loss, and symptoms of colitis. Ultimately, mice succumbed to infection. Dual loss of IL-17RA and IL-22RA impaired expression of small proline rich proteins (SPRRs), a class of antimicrobial effectors not previously linked to fungal immunity. Sprr2a1 exhibited direct candidacidal activity in vitro, and Sprr1-3a-/- mice were susceptible to OPC. Thus, cooperative actions of Type 17 cytokines mediate oral mucosal anti-Candida defenses and reveal a role for SPRRs.
Asunto(s)
Candidiasis Bucal , Interleucina-17 , Interleucina-22 , Interleucinas , Ratones Noqueados , Animales , Ratones , Candida albicans/inmunología , Candidiasis Bucal/inmunología , Candidiasis Bucal/microbiología , Interleucina-17/inmunología , Interleucina-17/metabolismo , Interleucinas/inmunología , Interleucinas/metabolismo , Ratones Endogámicos C57BL , Receptores de Interleucina/inmunología , Receptores de Interleucina/metabolismo , Receptores de Interleucina-17/inmunología , Receptores de Interleucina-17/metabolismoRESUMEN
Group 3 innate lymphoid cells (ILC3s) regulate inflammation and tissue repair at mucosal sites, but whether these functions pertain to other tissues-like the kidneys-remains unclear. Here, we observed that renal fibrosis in humans was associated with increased ILC3s in the kidneys and blood. In mice, we showed that CXCR6+ ILC3s rapidly migrated from the intestinal mucosa and accumulated in the kidney via CXCL16 released from the injured tubules. Within the fibrotic kidney, ILC3s increased the expression of programmed cell death-1 (PD-1) and subsequent IL-17A production to directly activate myofibroblasts and fibrotic niche formation. ILC3 expression of PD-1 inhibited IL-23R endocytosis and consequently amplified the JAK2/STAT3/RORγt/IL-17A pathway that was essential for the pro-fibrogenic effect of ILC3s. Thus, we reveal a hitherto unrecognized migration pathway of ILC3s from the intestine to the kidney and the PD-1-dependent function of ILC3s in promoting renal fibrosis.
Asunto(s)
Movimiento Celular , Fibrosis , Riñón , Linfocitos , Receptor de Muerte Celular Programada 1 , Receptores CXCR6 , Receptores de Interleucina , Transducción de Señal , Animales , Fibrosis/inmunología , Ratones , Receptores CXCR6/metabolismo , Receptores CXCR6/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Transducción de Señal/inmunología , Movimiento Celular/inmunología , Humanos , Riñón/patología , Riñón/inmunología , Riñón/metabolismo , Linfocitos/inmunología , Linfocitos/metabolismo , Receptores de Interleucina/metabolismo , Receptores de Interleucina/inmunología , Ratones Endogámicos C57BL , Enfermedades Renales/inmunología , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Inmunidad Innata/inmunología , Ratones Noqueados , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Intestinos/inmunología , Intestinos/patologíaRESUMEN
Sjögren's disease (SjD) is a chronic autoimmune disease characterized by focal lymphocytic inflammation in lacrimal and salivary glands. We recently identified IL-27 as a requisite signal for the spontaneous SjD-like manifestations in nonobese diabetic (NOD) mice. Here, we define T cell-intrinsic effects of IL-27 in lacrimal gland disease in NOD mice. IL-27 receptor was required by both CD4 T effector (Te) cells and CD8 T cells to mediate focal inflammation. Intrinsic IL-27 signaling was associated with PD-1 and ICOS expressing T follicular helper (Tfh)-like CD4 Te cells within lacrimal glands, including subsets defined by CD73 or CD39 expression. CD8 T cells capable of IL-27 signaling also expressed PD-1 with subsets expressing ICOS and CD73 demonstrating a T follicular cytotoxic (Tfc)-like cell phenotype and others expressing a CD39hi exhausted-like phenotype. These findings suggest IL-27 is a key early signal driving a follicular-type response in lacrimal gland inflammation in NOD mice.
Asunto(s)
Linfocitos T CD8-positivos , Modelos Animales de Enfermedad , Aparato Lagrimal , Ratones Endogámicos NOD , Síndrome de Sjögren , Animales , Síndrome de Sjögren/inmunología , Ratones , Linfocitos T CD8-positivos/inmunología , Aparato Lagrimal/inmunología , Aparato Lagrimal/patología , Interleucinas/inmunología , Interleucinas/metabolismo , Linfocitos T CD4-Positivos/inmunología , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Femenino , Transducción de Señal/inmunología , Receptores de Interleucina/inmunología , Interleucina-27/metabolismo , Interleucina-27/inmunología , Proteína Coestimuladora de Linfocitos T Inducibles/inmunología , Proteína Coestimuladora de Linfocitos T Inducibles/metabolismo , Apirasa/inmunología , Apirasa/metabolismoRESUMEN
Although inflammatory mechanisms driving hepatocellular carcinoma (HCC) have been proposed, the regulators of anticancer immunity in HCC remain poorly understood. We found that IL27 receptor (IL27R) signaling promotes HCC development in vivo. High IL27EBI3 cytokine or IL27RA expression correlated with poor prognosis for patients with HCC. Loss of IL27R suppressed HCC in vivo in two different models of hepatocarcinogenesis. Mechanistically, IL27R sig-naling within the tumor microenvironment restrains the cytotoxicity of innate cytotoxic lymphocytes. IL27R ablation enhanced their accumulation and activation, whereas depletion or functional impairment of innate cytotoxic cells abrogated the effect of IL27R disruption. Pharmacologic neutralization of IL27 signaling increased infiltration of innate cytotoxic lymphocytes with upregulated cytotoxic molecules and reduced HCC development. Our data reveal an unexpected role of IL27R signaling as an immunologic checkpoint regulating innate cytotoxic lymphocytes and promoting HCC of different etiologies, thus indicating a therapeutic potential for IL27 pathway blockade in HCC. SIGNIFICANCE: HCC, the most common form of liver cancer, is characterized by a poor survival rate and limited treatment options. The discovery of a novel IL27-dependent mechanism controlling anticancer cytotoxic immune response will pave the road for new treatment options for this devastating disease. This article is highlighted in the In This Issue feature, p. 1825.
Asunto(s)
Antineoplásicos , Carcinoma Hepatocelular , Interleucina-27 , Neoplasias Hepáticas , Linfocitos T Citotóxicos , Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/inmunología , Humanos , Inmunidad Innata/genética , Inmunidad Innata/inmunología , Interleucina-27/inmunología , Interleucinas/inmunología , Neoplasias Hepáticas/inmunología , Pronóstico , Receptores de Interleucina/inmunología , Transducción de Señal , Linfocitos T Citotóxicos/inmunología , Microambiente Tumoral/inmunologíaRESUMEN
Due to the plasticity of IL-17-producing CD4 T cells (Th17 cells), a long-standing challenge in studying Th17-driven autoimmune is the lack of specific surface marker to identify the pathogenic Th17 cells in vivo. Recently, we discovered that pathogenic CD4 T cells were CXCR6 positive in experimental autoimmune encephalomyelitis (EAE), a commonly used Th17-driven autoimmune model. Herein, we further revealed that peripheral CXCR6+CD4 T cells contain a functionally distinct subpopulation, which is CCR6 positive and enriched for conventional Th17 molecules (IL-23R and RORγt) and cytotoxic signatures. Additionally, spinal cord-infiltrating CD4 T cells were highly cytotoxic by expressing Granzyme(s) along with IFNγ and GM-CSF. Collectively, this study suggested that peripheral CCR6+CXCR6+CD4 T cells were Th17 cells with cytotoxic property in EAE model, and highlighted the cytotoxic granzymes for EAE pathology.
Asunto(s)
Encefalomielitis Autoinmune Experimental/inmunología , Receptores CCR6/inmunología , Receptores CXCR6/inmunología , Células Th17/inmunología , Animales , Encefalomielitis Autoinmune Experimental/patología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Interferón gamma/inmunología , Ratones , Ratones Endogámicos C57BL , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/inmunología , Receptores de Interleucina/inmunología , Células Th17/patologíaRESUMEN
Pruritus is a common dermatological condition and negatively impacts QOL. Persistent pruritus and excessive scratching behavior can lead to the itch-scratch cycle that exacerbates inflammatory skin diseases. Conventional antipruritic drugs, such as antihistamines, corticosteroids, or anticonvulsants, are sometimes insufficient. Recently, however, molecularly targeted drugs, such as IL-31 or IL-4 receptor-targeting antibodies, have become available or are under clinical trials, dramatically changing the clinical situation. In fact, some of these drugs can improve pruritus without the need for topical steroids. Taken together, these observations point to the importance of cytokine-mediated pruritus, further understanding of which may guide improved therapies.
Asunto(s)
Anticuerpos Bloqueadores/uso terapéutico , Antipruriginosos/uso terapéutico , Citocinas/metabolismo , Inmunoterapia/tendencias , Inflamación/terapia , Prurito/terapia , Piel/patología , Animales , Humanos , Inflamación/inmunología , Terapia Molecular Dirigida , Prurito/inmunología , Receptores de Interleucina/inmunología , Receptores de Interleucina-4/inmunologíaRESUMEN
Interleukin-23 (IL-23) is a pro-inflammatory cytokine involved in the host defense against pathogens but is also implicated in the development of several autoimmune disorders. The IL-23 receptor has become a key target for drug discovery, but the exact mechanism of the receptor ligand interaction remains poorly understood. In this study the affinities of IL-23 for its individual receptor components (IL23R and IL12Rß1) and the heteromeric complex formed between them have been measured in living cells using NanoLuciferase-tagged full-length proteins. Here, we demonstrate that TAMRA-tagged IL-23 has a greater than 7-fold higher affinity for IL12Rß1 than IL23R. However, in the presence of both receptor subunits, IL-23 affinity is increased more than three orders of magnitude to 27 pM. Furthermore, we show that IL-23 induces a potent change in the position of the N-terminal domains of the two receptor subunits, consistent with a conformational change in the heteromeric receptor structure.
Asunto(s)
Transferencia de Energía por Resonancia de Bioluminiscencia , Interleucina-23/inmunología , Luciferasas/inmunología , Receptores de Interleucina/inmunología , Células Cultivadas , Femenino , Células HEK293 , Humanos , Interleucina-23/química , Luciferasas/metabolismo , Unión Proteica , Receptores de Interleucina/químicaRESUMEN
Systemic sclerosis (SSc) is a chronic multisystem disorder characterized by fibrosis and autoimmunity. Interleukin (IL)-31 has been implicated in fibrosis and T helper (Th) 2 immune responses, both of which are characteristics of SSc. The exact role of IL-31 in SSc pathogenesis is unclear. Here we show the overexpression of IL-31 and IL-31 receptor A (IL-31RA) in dermal fibroblasts (DFs) from SSc patients. We elucidate the dual role of IL-31 in SSc, where IL-31 directly promotes collagen production in DFs and indirectly enhances Th2 immune responses by increasing pro-Th2 cytokine expression in DFs. Furthermore, blockade of IL-31 with anti-IL-31RA antibody significantly ameliorates fibrosis and Th2 polarization in a mouse model of SSc. Therefore, in addition to defining IL-31 as a mediator of fibrosis and Th2 immune responses in SSc, our study provides a rationale for targeting the IL-31/IL-31RA axis in the treatment of SSc.
Asunto(s)
Fibroblastos/inmunología , Interleucinas/genética , Receptores de Interleucina/genética , Esclerodermia Sistémica/inmunología , Células Th2/inmunología , Adulto , Anciano , Animales , Anticuerpos Monoclonales/farmacología , Colágeno Tipo I/genética , Colágeno Tipo I/inmunología , Cadena alfa 1 del Colágeno Tipo I , Modelos Animales de Enfermedad , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/patología , Fibrosis , Regulación de la Expresión Génica , Humanos , Interleucina-13/genética , Interleucina-13/inmunología , Interleucina-4/genética , Interleucina-4/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Interleucinas/inmunología , Masculino , Ratones , Persona de Mediana Edad , Isoformas de Proteínas/genética , Isoformas de Proteínas/inmunología , Receptores de Interleucina/antagonistas & inhibidores , Receptores de Interleucina/inmunología , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT1/inmunología , Esclerodermia Sistémica/tratamiento farmacológico , Esclerodermia Sistémica/genética , Esclerodermia Sistémica/patología , Piel/efectos de los fármacos , Piel/inmunología , Piel/patología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patología , Células Th2/efectos de los fármacos , Células Th2/patologíaRESUMEN
The IL-23/IL-17 axis plays causative roles in the development and progression of systemic lupus erythematosus (SLE). However, it remains unclear if the IL-17RA+ and IL-23R+ T helper (Th) cells populations are associated with the serum IL-17 and IL-23 levels, or with the immunological parameters and disease activities in SLE patients. Herein, we examined the proportion of IL-17RA+ and IL-23R+ Th cells and serum levels of IL-17 and IL-23 in established SLE patients (n = 50) compared with healthy controls (n = 50). The associations of these interleukins and their receptors with immunological parameters [anti-nuclear antibody (ANA), anti-dsDNA antibody, and C-reactive protein (CRP)] and SLE disease activity (SLEDAI-2K scores) in SLE patients were assessed. CD3+CD4+ Th cells of SLE patients demonstrated significantly elevated IL-17RA+ (p = 1.12 x 10-4) or IL-23R+ (p = 1.98 x 10-29) populations compared with the healthy controls. Serum IL-17 levels were significantly lower in SLE patients compared with the healthy controls (p = 8.32 x 10-5), while no significant difference was observed for the IL-23 serum levels between both groups. IL-23R+ Th cells population was significantly associated with higher SLEDAI-2K scores (p = 0.017). In multivariate analysis, the proportion of IL-23R+ Th cells remained significantly associated with higher SLEDAI-2K scores independent of prednisolone intake (p = 0.027). No associations were observed between the interleukin parameters (i.e., IL-17, IL-23, IL-17RA+ Th cells, and IL-23R+ Th cells) with ANA, anti-dsDNA, and CRP status, suggesting that the IL-17/IL-23 axis acts independently of these immunological parameters. In conclusion, our results support that therapeutic inhibition of the IL-23/IL-17 axis receptors on Th cells, particularly IL-23R, is potentially relevant in SLE patients.
Asunto(s)
Interleucina-17/inmunología , Interleucina-23/inmunología , Lupus Eritematoso Sistémico/inmunología , Receptores de Interleucina-17/inmunología , Receptores de Interleucina/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Adulto , Anticuerpos Antinucleares/sangre , Proteína C-Reactiva/análisis , Femenino , Humanos , Interleucina-17/sangre , Interleucina-23/sangre , Lupus Eritematoso Sistémico/sangre , Masculino , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
Interleukins (ILs) and interleukin receptors (ILRs) play important role in the antitumor immune response. However, the expression signature and clinical characteristics of the IL(R) family in lung adenocarcinoma (LUAD) remains unclear. The main purpose of this study was to explore the expression profile of IL(R) family genes and construct an IL(R)-based prognostic signature in LUAD. Five public datasets of 1,312 patients with LUAD were enrolled in this study. Samples from The Cancer Genome Atlas (TCGA) were used as the training set, and samples from the other four cohorts extracted from Gene Expression Omnibus (GEO) database were used as the validation set. Additionally, the profile of IL(R) family signature was explored, and the association between this signature and immunotherapy response was also analyzed. Meanwhile, the prognostic value was compared between this IL(R)-based signature and different immunotherapy markers. A signature based on five identified IL(R)s (IL7R, IL5RA, IL20RB, IL11, IL22RA1) was constructed using the TCGA dataset through univariate/multivariable Cox proportional hazards regression and least absolute shrinkage and selection operator (LASSO) Cox analysis. These cases with LUAD were stratified into high- and low-risk group according to the risk score. This signature showed a strong prognostic ability, which was verified by the five independent cohorts and clinical subtypes. The IL(R)-based models presented unique characteristics in terms of immune cell infiltration and immune inflammation profile in tumor microenvironment (TME). Biological pathway analysis confirmed that high-risk patients showed significant T- and B-cell immunosuppression and rapid tumor cell proliferation. More importantly, we researched the relationship between this IL(R)-based signature and immune checkpoints, tumor mutation burden (TMB), tumor purity and ploidy, and tumor immune dysfunction and exclusion (TIDE) score, which confirmed that this signature gave the best prognostic value. We first provided a robust prognostic IL(R)-based signature, which had the potential as a predictor for immunotherapy response to realize individualized treatment of LUAD.
Asunto(s)
Adenocarcinoma del Pulmón/genética , Biomarcadores de Tumor/genética , Perfilación de la Expresión Génica , Interleucinas/genética , Neoplasias Pulmonares/genética , Receptores de Interleucina/genética , Transcriptoma , Microambiente Tumoral/genética , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/terapia , Anciano , Biomarcadores de Tumor/inmunología , Toma de Decisiones Clínicas , Bases de Datos Genéticas , Femenino , Humanos , Inmunoterapia , Interleucinas/inmunología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/terapia , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Receptores de Interleucina/inmunología , Medición de Riesgo , Factores de Riesgo , Microambiente Tumoral/inmunologíaRESUMEN
Inflammatory monocyte-derived dendritic cells (Mo-DCs) have been described in several chronic inflammatory disorders, such as rheumatoid arthritis (RA), and are suspected to play a detrimental role by fueling inflammation and skewing adaptive immune responses. However, the characterization of their phenotype is still limited, as well as the comprehension of the factors that govern their differentiation. Here, we show that inflammatory Mo-DCs generated in vitro expressed a large and atypical panel of C-type lectin receptors, including isoforms of CD209 and CD206, CD303 and CD207, as well as intracellular proteins at their surfaces such as the lysosomal protein CD208. Combination of these markers allowed us to identify cells in the synovial fluid of RA patients with a close phenotype of inflammatory Mo-DCs generated in vitro. Finally, we found in coculture experiments that RA synoviocytes critically affected the phenotypic differentiation of monocytes into Mo-DCs, suggesting that the crosstalk between infiltrating monocytes and local mesenchymal cells is decisive for Mo-DCs generation.
Asunto(s)
Artritis Reumatoide/inmunología , Células Dendríticas/inmunología , Regulación de la Expresión Génica/inmunología , Monocitos/inmunología , Sinoviocitos/inmunología , Antígenos CD/genética , Antígenos CD/inmunología , Artritis Reumatoide/genética , Artritis Reumatoide/patología , Antígenos B7/genética , Antígenos B7/inmunología , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/inmunología , Diferenciación Celular , Técnicas de Cocultivo , Células Dendríticas/patología , Humanos , Inmunofenotipificación , Lectinas Tipo C/genética , Lectinas Tipo C/inmunología , Proteínas de Membrana de los Lisosomas/genética , Proteínas de Membrana de los Lisosomas/inmunología , Lectinas de Unión a Manosa/genética , Lectinas de Unión a Manosa/inmunología , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/inmunología , Monocitos/patología , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/inmunología , Fenotipo , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/inmunología , Receptores Inmunológicos/genética , Receptores Inmunológicos/inmunología , Receptores de Interleucina/genética , Receptores de Interleucina/inmunología , Transducción de Señal , Líquido Sinovial/citología , Líquido Sinovial/inmunología , Sinoviocitos/patología , Receptores Toll-Like/genética , Receptores Toll-Like/inmunologíaRESUMEN
PURPOSE OF THE STUDY: The involvement of the IL-23/IL23R pathway is well known in the disease pathogenesis of sarcoidosis and other inflammatory diseases. To date, the pathogenic mechanism of IL-23 is most notably described on CD4+ Th17 lymphocytes. However, the function of the IL23R on myeloid cells in sarcoidosis is poorly understood. Thus, the aim of the study is to investigate the role of the IL23R on myeloid cell in pulmonary granuloma formation. Methods: We generated IL23RLysMCre mice lacking the IL23R gene in myeloid cells. The importance of IL23R in myeloid cells for the development of sarcoidosis was studied in a mouse model of inflammatory lung granuloma formation through embolization of PPD from Mycobacterium bovis-coated Sepharose beads into previously PPD-immunized mice. In addition the function of IL23R on myeloid cells was studied in LPS or IFNγ stimulated BMDMs and BMDCs. The mRNA and protein expression levels of relevant cytokines were analyzed by RT-PCR (TaqMan) and ELISA. The composition of immune cells in BALF was quantified by flow cytometry and alteration in granuloma sizes were observed by H&E stained lung sections. Results: Mycobacterium Ag-elicted pulmonary granulomas tend to be smaller in IL23RLysMCre mice and NF-κB dependent Th1 cytokines in the murine lungs are reduced compared to wildtype mice. In line, we observed that IL23R-deficient bone marrow-derived macrophages show a reduced production of Th1 cytokines after LPS stimulation. Conclusion: We here for the first time demonstrate a role for IL23R on myeloid cells in pulmonary inflammation and granuloma formation. Our findings provide essential insights in the pathogenesis of inflammatory lung diseases like sarcoidosis, which might be useful for the development of novel therapeutics targeting distinct immunological pathways like IL-23/IL23R.
Asunto(s)
Granuloma , Neumonía , Receptores de Interleucina/inmunología , Sarcoidosis/inmunología , Animales , Citocinas , Granuloma/inmunología , Pulmón , Macrófagos , Ratones , Neumonía/inmunologíaRESUMEN
Enhancer RNAs (eRNAs) are a subclass of non-coding RNAs that are generated during the transcription of enhancer regions and play an important role in tumourigenesis. In this study, we focused on the crucial eRNAs that participate in immune responses in invasive breast cancer (IBC). We first used The Cancer Genome Atlas and Human enhancer RNA Atlas to screen for tissue-specific eRNAs and their target genes. Through Pearson correlation analysis with immune genes, the eRNA WAKMAR2 was identified as a key candidate involved in IBC. Our further research suggested that WAKMAR2 is crucial in regulating the tumour microenvironment and may function by regulating immune-related genes, including IL27RA, RAC2, FABP7, IGLV1-51, IGHA1, and IGHD. Quantitative reverse transcription-polymerase chain reaction was used to detect the expression of WAKMAR2 in IBC and normal tissues, and the effect of WAKMAR2 on the regulation of downstream genes in MB-231 and MCF7 cells was studied in vitro. WAKMAR2 was found to be highly involved in tumour immunity and was downregulated in IBC tissues. Furthermore, the expression of WAKMAR2 and its target genes was observed at the pan-cancer level. This study provides evidence to suggest new potential targets for the treatment of breast cancer.
Asunto(s)
Neoplasias de la Mama/genética , Carcinogénesis/genética , Elementos de Facilitación Genéticos , ARN no Traducido/genética , Atlas como Asunto , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Carcinogénesis/inmunología , Carcinogénesis/patología , Línea Celular Tumoral , Enanismo Hipofisario/genética , Enanismo Hipofisario/inmunología , Proteína de Unión a los Ácidos Grasos 7/genética , Proteína de Unión a los Ácidos Grasos 7/inmunología , Femenino , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Inmunoglobulinas/genética , Inmunoglobulinas/inmunología , Células MCF-7 , Modelos Moleculares , Invasividad Neoplásica , Conformación de Ácido Nucleico , Unión Proteica , Conformación Proteica , ARN no Traducido/inmunología , Receptores de Interleucina/genética , Receptores de Interleucina/inmunología , Análisis de Supervivencia , Transcripción Genética , Microambiente Tumoral , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/inmunologíaRESUMEN
Necrotizing enterocolitis (NEC) is a deadly intestinal inflammatory disorder that primarily affects premature infants and lacks adequate therapeutics. Interleukin (IL)-22 plays a critical role in gut barrier maintenance, promoting epithelial regeneration, and controlling intestinal inflammation in adult animal models. However, the importance of IL-22 signaling in neonates during NEC remains unknown. We investigated the role of IL-22 in the neonatal intestine under homeostatic and inflammatory conditions by using a mouse model of NEC. Our data reveal that Il22 expression in neonatal murine intestine is negligible until weaning, and both human and murine neonates lack IL-22 production during NEC. Mice deficient in IL-22 or lacking the IL-22 receptor in the intestine display a similar susceptibility to NEC, consistent with the lack of endogenous IL-22 during development. Strikingly, treatment with recombinant IL-22 during NEC substantially reduces inflammation and enhances epithelial regeneration. These findings may provide a new therapeutic strategy to attenuate NEC.
Asunto(s)
Enterocolitis Necrotizante/inmunología , Interleucinas/genética , Mucosa Intestinal/inmunología , Proteínas Recombinantes/farmacología , Regeneración/inmunología , Animales , Animales Recién Nacidos , Quimiocina CXCL1/genética , Quimiocina CXCL1/inmunología , Quimiocina CXCL2/genética , Quimiocina CXCL2/inmunología , Modelos Animales de Enfermedad , Enterocolitis Necrotizante/tratamiento farmacológico , Enterocolitis Necrotizante/microbiología , Enterocolitis Necrotizante/patología , Microbioma Gastrointestinal/inmunología , Regulación del Desarrollo de la Expresión Génica , Humanos , Recién Nacido , Enfermedades del Recién Nacido/inmunología , Enfermedades del Recién Nacido/microbiología , Enfermedades del Recién Nacido/patología , Recien Nacido Prematuro , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Interleucinas/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Ratones , Ratones Noqueados , Isoformas de Proteínas/genética , Isoformas de Proteínas/inmunología , Receptores de Interleucina/genética , Receptores de Interleucina/inmunología , Regeneración/genética , Transducción de Señal , Destete , Interleucina-22RESUMEN
WSX1, a receptor subunit for IL-27, is widely expressed in immune cells and closely involved in immune response, but its function in nonimmune cells remains unknown. Here we report that WSX1 is highly expressed in human hepatocytes but downregulated in hepatocellular carcinoma (HCC) cells. Using NRAS/AKT-derived spontaneous HCC mouse models, we reveal an IL-27-independent tumor-suppressive effect of WSX1 that largely relies on CD8+ T-cell immune surveillance via reducing neoplastic PD-L1 expression and the associated CD8+ T-cell exhaustion. Mechanistically, WSX1 transcriptionally downregulates an isoform of PI3K-PI3Kδ and thereby inactivates AKT, reducing AKT-induced GSK3ß inhibition. Activated GSK3ß then boosts PD-L1 degradation, resulting in PD-L1 reduction. Overall, we demonstrate that WSX1 is a tumor suppressor that reinforces hepatic immune surveillance by blocking the PI3Kδ/AKT/GSK3ß/PD-L1 pathway. Our results may yield insights into the host homeostatic control of immune response and benefit the development of cancer immunotherapies.
Asunto(s)
Antígeno B7-H1/metabolismo , Carcinoma Hepatocelular/inmunología , Neoplasias Hepáticas/inmunología , Receptores de Interleucina/inmunología , Proteínas Supresoras de Tumor/inmunología , Animales , Linfocitos T CD8-positivos/inmunología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Fosfatidilinositol 3-Quinasa Clase I/genética , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Femenino , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Vigilancia Inmunológica , Hígado/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Masculino , Ratones , Persona de Mediana Edad , Pronóstico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores de Interleucina/metabolismo , Transducción de Señal/inmunología , Proteínas Supresoras de Tumor/metabolismoRESUMEN
In chronic Chagas disease, Trypanosoma cruzi-specific T-cell function decreases over time, and alterations in the homeostatic IL-7/IL-7R axis are evident, consistent with a process of immune exhaustion. IL-27 is an important immunoregulatory cytokine that shares T-cell signaling with IL-7 and other cytokines of the IL-12 family and might be involved in the transcriptional regulation of T-cell function. Here, we evaluated the expression and function of IL-27R in antigen-experienced T cells from subjects with chronic Chagas disease and assessed whether in vitro treatment with IL-27 and IL-7 might improve T. cruzi-specific polyfunctional T-cell responses. In vitro exposure of PBMCs to T. cruzi induced a downregulation of IL-27R in CD4+ T cells and an upregulation in CD8+ T cells in subjects without heart disease, while IL-27R expression remained unaltered in subjects with more severe clinical stages. The modulation of IL-27R was associated with functional signaling through STAT3 and STAT5 and induction of the downstream genes TBX21, EOMES and CXCL9 in response to IL-27. In vitro treatment of PBMCs with IL-27 and IL-7 improved monofunctional and polyfunctional Th1 responses, accompanied by the induction of IL-10 and Bcl-2 expression in subjects without heart disease but did not improve those in subjects with cardiomyopathy. Our findings support the process of desensitization of the IL-27/IL-27R pathway along with disease severity and that the pro-inflammatory and immunomodulatory mechanisms of IL-27 might be interconnected.
Asunto(s)
Enfermedad de Chagas/inmunología , Interleucina-27/inmunología , Adulto , Anciano , Linfocitos T CD8-positivos/inmunología , Enfermedad de Chagas/genética , Enfermedad de Chagas/parasitología , Enfermedad Crónica , Femenino , Humanos , Interleucina-27/genética , Interleucina-7/genética , Interleucina-7/inmunología , Leucocitos Mononucleares/inmunología , Masculino , Persona de Mediana Edad , Receptores de Interleucina/genética , Receptores de Interleucina/inmunología , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/inmunología , Trypanosoma cruzi/genética , Trypanosoma cruzi/fisiologíaRESUMEN
Low-grade inflammatory monocytes critically contribute to the pathogenesis of chronic inflammatory diseases such as atherosclerosis. The elevated expression of coactivating molecule CD40 as well as key adhesion molecule CD11a is a critical signature of inflammatory monocytes from both human patients with coronary artery diseases as well as in animal models of atherosclerosis. In this study, we report that subclinical superlow-dose LPS, a key risk factor for low-grade inflammation and atherosclerosis, can potently trigger the induction of CD40 and CD11a on low-grade inflammatory monocytes. Subclinical endotoxin-derived monocytes demonstrate immune-enhancing effects and suppress the generation of regulatory CD8+CD122+ T cells, which further exacerbate the inflammatory environment conducive for chronic diseases. Mechanistically, subclinical endotoxemia activates TRAM-mediated signaling processes, leading to the activation of MAPK and STAT5, which is responsible for the expression of CD40 and CD11a. We also demonstrate that TRAM-mediated monocyte polarization can be suppressed by IRAK-M. IRAK-M-deficient monocytes have increased expression of TRAM, elevated induction of CD40 and CD11a by subclinical-dose endotoxin, and are more potent in suppressing the CD8 regulatory T cells. Mice with IRAK-M deficiency generate an increased population of inflammatory monocytes and a reduced population of CD8 T regulatory cells. In contrast, mice with TRAM deficiency exhibit a significantly reduced inflammatory monocyte population and an elevated CD8 T regulatory cell population. Together, our data reveal a competing intracellular circuitry involving TRAM and IRAK-M that modulate the polarization of low-grade inflammatory monocytes with an immune-enhancing function.
Asunto(s)
Moléculas de Adhesión Celular/inmunología , Inflamación/inmunología , Quinasas Asociadas a Receptores de Interleucina-1/inmunología , Monocitos/inmunología , Receptores de Interleucina/inmunología , Receptor Toll-Like 4/inmunología , Animales , Células Cultivadas , Quinasas Asociadas a Receptores de Interleucina-1/deficiencia , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
IL-12 (p35/p40) and IL-23 (p19/p40) signal through IL-12R (IL-12Rß2/ß1) and IL-23R (IL-23Rα/IL-12Rß1), respectively, which can promote pathogenic T lymphocyte activation, differentiation, and function in graft-versus-host disease (GVHD). With the use of murine models of allogeneic hematopoietic cell transplantation (HCT), we found that IL-12Rß1 on donor T cells was dispensable to induce acute GVHD development in certain circumstances, while IL-23Rα was commonly required. This observation challenges the current paradigm regarding IL-12Rß1 as a prerequisite to transmit IL-23 signaling. We hypothesized that p19/EBI3 (IL-39) may have an important role during acute GVHD. With the use of gene transfection and immunoprecipitation approaches, we verified that p19 and EBI3 can form biological heterodimers. We found that IL-39 levels in recipient serum positively correlated with development of acute GVHD in experimental models and in clinical settings, thereby implicating IL-39 in the pathogenesis of acute GVHD. Furthermore, we observed that human T cells can signal in response to IL-39. In chronic GVHD, IL-23Rα and IL-12Rß1 were similarly required for donor T cell pathogenicity, and IL-39 levels were not significantly different from controls without GVHD. Collectively, we identify a novel cytokine, IL-39, as a pathogenic factor in acute GVHD, which represents a novel potential therapeutic target to control GVHD and other inflammatory disorders.
Asunto(s)
Enfermedad Injerto contra Huésped , Interleucinas/inmunología , Receptores de Interleucina/inmunología , Animales , Enfermedad Injerto contra Huésped/etiología , Humanos , Interleucina-12 , Interleucina-23 , Ratones , Linfocitos T , VirulenciaRESUMEN
Group 2 innate lymphoid cells (ILC2s) play an important role in the pathophysiology of asthma via the robust production of type 2 cytokines. Recent studies have demonstrated that TLR7 (Toll-like receptor 7) signaling skews toward a type 1 inflammatory response in asthma, which may lead to the development of novel treatment strategies. However, the effect of TLR7 signaling on ILC2-dependent nonallergic eosinophilic inflammation remains unclear. In this study, we investigated the effects of R848, a TLR7 agonist, in a mouse model of IL-33-induced eosinophilic airway inflammation. Intranasal administration of R848 decreased infiltration of airway eosinophils and ILC2s, mucus production in epithelial cells, and type 2 cytokine production. Flow cytometric analysis identified an increased number of interstitial macrophages (IMs) expressing a high level of TLR7 in the lung upon IL-33 stimulation. IL-33-induced IMs also expressed high levels of alternatively activated (M2)-type genes and chemokines (CCL17 and CCL24). However, R848 stimulation modified these gene expressions and elicited the production of IL-27. Coculture experiments revealed that IL-33-induced IMs directly suppressed ILC2 activation in response to R848. In addition, the inhibitory effects of R848 on ILC2-induced type 2 inflammation were defective in WSX-1-deficient mice lacking the IL-27 receptor. Taken together, these findings indicate that R848 stimulates IL-33-induced IMs to suppress ILC2-mediated type 2 airway inflammation via IL-27. These findings highlight the therapeutic potential of TLR7 agonists and/or IL-27 cascades in nonallergic asthma.