RESUMEN
Damage to the heart can start the repair process and cause cardiac remodeling. B cells play an important role in this process. B cells are recruited to the injured place and activate cardiac remodeling through secreting antibodies and cytokines. Different types of B cells showed specific functions in the heart. Among all types of B cells, heart-associated B cells play a vital role in the heart by secreting TGFß1. B cells participate in the activation of fibroblasts and promote cardiac fibrosis. Four subtypes of B cells in the heart revealed the relationship between the B cells' heterogeneity and cardiac remodeling. Many cardiovascular diseases like atherosclerosis, heart failure (HF), hypertension, myocardial infarction (MI), and dilated cardiomyopathy (DCM) are related to B cells. The primary mechanisms of these B cell-related activities will be discussed in this review, which may also suggest potential novel therapeutic targets.
Asunto(s)
Linfocitos B , Enfermedades Cardiovasculares , Humanos , Enfermedades Cardiovasculares/inmunología , Animales , Linfocitos B/inmunología , Fibrosis/inmunologíaRESUMEN
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
Long-term inhalation of silica nanoparticles (SiNPs) can induce pulmonary fibrosis (PF), nevertheless, the potential mechanisms remain elusive. Herein, we constructed a three-dimensional (3D) co-culture model by using Matrigel to investigate the interaction among different cells and potential regulatory mechanisms after SiNPs exposure. Methodologically, we dynamically observed the changes in cell morphology and migration after exposure to SiNPs by co-culturing mouse monocytic macrophages (RAW264.7), human non-small cell lung cancer cells (A549), and medical research council cell strain-5 (MRC-5) in Matrigel for 24 h. Subsequently, we detected the expression of nuclear factor kappa B (NF-κB), inflammatory factor and epithelial-mesenchymal transition (EMT) markers. The results showed that SiNPs produced toxic effects on cells. In the 3D co-culture state, the cell's movement velocity and displacement increased, and the cell migration ability was enhanced. Meanwhile, the expression of inflammatory factor tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) were upregulated, the epithelial marker E-cadherin (E-cad) was downregulated, the mesenchymal marker N-cadherin (N-cad) and myofibroblast marker alpha-smooth muscle actin (α-SMA) expression were upregulated, while NF-κB expression was also upregulated after SiNPs exposure. We further found that cells were more prone to transdifferentiate into myofibroblasts in the 3D co-culture state. Conversely, utilizing the NF-κB-specific inhibitor BAY 11-7082 effectively downregulated the expression of TNF-α, IL-6, interleukin-1ß (IL-1ß), N-cad, α-SMA, collagen-I (COL I), and fibronectin (FN), the expression of E-cad was upregulated. These findings suggest that NF-κB is involved in regulating SiNPs-induced inflammatory, EMT, and fibrosis in the 3D co-culture state.
Asunto(s)
Transición Epitelial-Mesenquimal , Fibrosis , Enfermedades Pulmonares , Nanopartículas , Dióxido de Silicio , Animales , Humanos , Ratones , Carcinoma de Pulmón de Células no Pequeñas , Técnicas de Cocultivo , Transición Epitelial-Mesenquimal/inmunología , Fibrosis/etiología , Fibrosis/inmunología , Interleucina-6 , Neoplasias Pulmonares , Nanopartículas/toxicidad , FN-kappa B/metabolismo , Dióxido de Silicio/toxicidad , Factor de Necrosis Tumoral alfa/metabolismo , Enfermedades Pulmonares/etiología , Enfermedades Pulmonares/inmunologíaRESUMEN
Most chronic inflammatory illnesses include fibrosis as a pathogenic characteristic. Extracellular matrix (ECM) components build up in excess to cause fibrosis or scarring. The fibrotic process finally results in organ malfunction and death if it is severely progressive. Fibrosis affects nearly all tissues of the body. The fibrosis process is associated with chronic inflammation, metabolic homeostasis, and transforming growth factor-ß1 (TGF-ß1) signaling, where the balance between the oxidant and antioxidant systems appears to be a key modulator in managing these processes. Virtually every organ system, including the lungs, heart, kidney, and liver, can be affected by fibrosis, which is characterized as an excessive accumulation of connective tissue components. Organ malfunction is frequently caused by fibrotic tissue remodeling, which is also frequently linked to high morbidity and mortality. Up to 45% of all fatalities in the industrialized world are caused by fibrosis, which can damage any organ. Long believed to be persistently progressing and irreversible, fibrosis has now been revealed to be a very dynamic process by preclinical models and clinical studies in a variety of organ systems. The pathways from tissue damage to inflammation, fibrosis, and/or malfunction are the main topics of this review. Furthermore, the fibrosis of different organs with their effects was discussed. Finally, we highlight many of the principal mechanisms of fibrosis. These pathways could be considered as promising targets for the development of potential therapies for a variety of important human diseases.
Asunto(s)
Fibrosis , Inflamación , Estrés Oxidativo , Humanos , Progresión de la Enfermedad , Fibrosis/inmunología , Fibrosis/metabolismo , Fibrosis/patología , Inflamación/metabolismo , Hígado/metabolismo , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Cartilage oligomeric matrix protein (COMP) is an emerging regulator of tumor progression. The aim of this study was to evaluate the expression of COMP in periampullary adenocarcinoma with respect to prognostic value for survival and relapse, levels of fibrosis and infiltrating immune cells. COMP expression was evaluated using immunohistochemistry in primary tumors and subsets of paired lymph node metastases in tissue microarrays including 175 patients with periampullary adenocarcinoma. Collagen content was assessed with Sirius Red-Fast Green staining. High COMP levels were detected in cancer cells and in stroma, in 46% and 57% of the patients, respectively. High COMP expression was strongly associated with more aggressive pancreatobiliary-type (PB-type) compared to intestinal-type tumors (p < .0001). Importantly, high expression of COMP correlated with the exclusion of cytotoxic T-cells from the cancer cell compartment of the tumors, particularly in PB-type tumors. Higher levels of fibrosis measured by the density of collagen fibers correlated with high COMP levels in both cancer cells and stroma. This in turn could lead to exclusion of cytotoxic T-cells from accessing the cancer cells, a recognized immunotherapy resistance mechanism. Targeting COMP could therefore be considered as a novel therapeutic strategy in PB-type periampullary adenocarcinoma.
Asunto(s)
Adenocarcinoma , Ampolla Hepatopancreática , Proteína de la Matriz Oligomérica del Cartílago , Neoplasias del Conducto Colédoco , Adenocarcinoma/genética , Adenocarcinoma/inmunología , Adenocarcinoma/patología , Ampolla Hepatopancreática/inmunología , Ampolla Hepatopancreática/patología , Proteína de la Matriz Oligomérica del Cartílago/genética , Proteína de la Matriz Oligomérica del Cartílago/inmunología , Neoplasias del Conducto Colédoco/genética , Neoplasias del Conducto Colédoco/inmunología , Neoplasias del Conducto Colédoco/patología , Neoplasias Duodenales , Fibrosis/genética , Fibrosis/inmunología , Fibrosis/patología , Expresión Génica , Humanos , Neoplasias PancreáticasRESUMEN
The exact immunological mechanisms of post infectious bronchiolitis obliterans (PIBO) in childhood are not fully known. It has been shown that the inflammasome and IL-18 pathway play important roles in the pathogenesis of lung fibrosis. We aimed to investigate the role of caspase-1, IL-18, and IL-18 components in PIBO. From January to May 2020, children with PIBO, children with history of influenza infection without PIBO, and healthy children were asked to participate in the study in three pediatric pulmonology centers. Serum caspase-1, IL-18, IL-18BP, IL-18R, and INF-γ levels were measured by ELISA and compared between the 3 groups. There were 21 children in the PIBO group, 16 children in the influenza group, and 39 children in the healthy control group. No differences in terms of age and gender between the 3 groups were found. IL-18 and IL-18BP levels were higher in the healthy control group (p = 0.018, p = 0.005, respectively). IL-18R was higher in the PIBO group (p = 0.001) and caspase-1 was higher in the PIBO and influenza group than the healthy control group (p = 0.002). IFN-γ levels did not differ between the 3 groups. IL-18BP/IL-18 was higher in the influenza group than the PIBO group and the healthy control group (p = 0.003). CONCLUSIONS: Caspase-1 level was increased in patients with PIBO which suggests that inflammasome activation may have a role in fibrosis; however, IL-18 level was found to be low. Mediators other than IL-18 may be involved in the inflammatory pathway in PIBO. Further immunological studies investigating inflammasome pathway are needed for PIBO with chronic inflammation. WHAT IS KNOWN: ⢠Post infectious bronchiolitis obliterans (PIBO) is a rare, severe chronic lung disease during childhood which is associated with inflammation and fibrosis which lead to partial or complete luminal obstruction especially in small airways. ⢠The exact immunological mechanisms of PIBO in childhood are not fully known. WHAT IS NEW: ⢠Inflammasome activation persists even years after acute infection and may play a role in fibrosis in PIBO. ⢠Mediators other than IL-18 may be involved in these inflammatory pathway.
Asunto(s)
Bronquiolitis Obliterante , Caspasa 1 , Interleucina-18 , Bronquiolitis Obliterante/sangre , Bronquiolitis Obliterante/etiología , Bronquiolitis Obliterante/genética , Bronquiolitis Obliterante/inmunología , Estudios de Casos y Controles , Caspasa 1/sangre , Caspasa 1/genética , Caspasa 1/inmunología , Niño , Fibrosis/sangre , Fibrosis/genética , Fibrosis/inmunología , Humanos , Inflamasomas/inmunología , Inflamación/sangre , Inflamación/genética , Inflamación/inmunología , Gripe Humana/sangre , Gripe Humana/complicaciones , Gripe Humana/genética , Gripe Humana/inmunología , Péptidos y Proteínas de Señalización Intercelular/sangre , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/inmunología , Interleucina-18/sangre , Interleucina-18/genética , Interleucina-18/inmunologíaRESUMEN
The aim of this study was to further elucidate the molecular mechanisms that mediate pathologic foreign body response (FBR) to biomedical implants. The longevity of biomedical implants is limited by the FBR, which leads to implant failure and patient morbidity. Since the specific molecular mechanisms underlying fibrotic responses to biomedical implants have yet to be fully described, there are currently no targeted approaches to reduce pathologic FBR. We utilized proteomics analysis of human FBR samples to identify potential molecular targets for therapeutic inhibition of FBR. We then employed a murine model of FBR to further evaluate the role of this potential target. We performed histological and immunohistochemical analysis on the murine FBR capsule tissue, as well as single-cell RNA sequencing (scRNA-seq) on cells isolated from the capsules. We identified IQ motif containing GTPase activating protein 1 (IQGAP1) as the most promising of several targets, serving as a central molecular mediator in human and murine FBR compared to control subcutaneous tissue. IQGAP1-deficient mice displayed a significantly reduced FBR compared to wild-type mice as evidenced by lower levels of collagen deposition and maturity. Our scRNA-seq analysis revealed that decreasing IQGAP1 resulted in diminished transcription of mechanotransduction, inflammation, and fibrosis-related genes, which was confirmed on the protein level with immunofluorescent staining. The deficiency of IQGAP1 significantly attenuates FBR by deactivating downstream mechanotransduction signaling, inflammation, and fibrotic pathways. IQGAP1 may be a promising target for rational therapeutic design to mitigate pathologic FBR around biomedical implants.
Asunto(s)
Materiales Biocompatibles/efectos adversos , Cuerpos Extraños/inmunología , Prótesis e Implantes/efectos adversos , Transducción de Señal/inmunología , Proteínas Activadoras de ras GTPasa/inmunología , Animales , Colágeno/inmunología , Fibrosis/inmunología , Humanos , Inflamación/inmunología , Masculino , Mecanotransducción Celular/inmunología , Ratones , Ratones Endogámicos C57BL , Transcripción Genética/inmunologíaRESUMEN
Immune checkpoint inhibitors have become the mainstay of treatment for hepatocellular carcinoma (HCC). However, they are ineffective in some cases. Previous studies have reported that genetic alterations in oncogenic pathways such as Wnt/ß-catenin are the important triggers in HCC for primary refractoriness. T-cell exhaustion has been reported in various tumors and is likely to play a prominent role in the emergence of HCC due to chronic inflammation and cirrhosis-associated immune dysfunction. Immunosuppressive cells including regulatory T-cells and tumor-associated macrophages infiltrating the tumor are associated with hyperprogressive disease in the early stages of immune checkpoint inhibitor treatment. In addition, stellate cells and tumor-associated fibroblasts create an abundant desmoplastic environment by producing extracellular matrix. This strongly contributes to epithelial to mesenchymal transition via signaling activities including transforming growth factor beta, Wnt/ß-catenin, and Hippo pathway. The abundant desmoplastic environment has been demonstrated in pancreatic ductal adenocarcinoma and cholangiocarcinoma to suppress cytotoxic T-cell infiltration, PD-L1 expression, and neoantigen expression, resulting in a highly immunosuppressive niche. It is possible that a similar immunosuppressive environment is created in HCC with advanced fibrosis in the background liver. Although sufficient understanding is required for the establishment of immune therapies of HCC, further investigations are still required in this field.
Asunto(s)
Carcinoma Hepatocelular/terapia , Fibrosis/terapia , Inhibidores de Puntos de Control Inmunológico/farmacología , Inmunoterapia , Neoplasias Hepáticas/terapia , Nicho de Células Madre/efectos de los fármacos , Animales , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Fibrosis/inmunología , Fibrosis/patología , Humanos , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , Nicho de Células Madre/inmunologíaRESUMEN
BACKGROUND: IgG4-related disease (IgG4-RD) is a fibroinflammatory condition involving loss of B-cell tolerance and production of autoantibodies. However, the relevant targets and role of these aberrant humoral immune responses are not defined. OBJECTIVE: Our aim was to identify novel autoantibodies and autoantigen targets that promote pathogenic responses in IgG4-RD. METHODS: We sequenced plasmablast antibody repertoires in patients with IgG4-RD. Representative mAbs were expressed and their specificities characterized by using cytokine microarrays. The role of anti-IL-1 receptor antagonist (IL-1RA) autoantibodies was investigated by using in vitro assays. RESULTS: We identified strong reactivity against human IL-1RA by using a clonally expanded plasmablast-derived mAb from a patient with IgG4-RD. Plasma from patients with IgG4-RD exhibited elevated levels of reactivity against IL-1RA compared with plasma from the controls and neutralized IL-1RA activity, resulting in inflammatory and fibrotic mediator production in vitro. IL-1RA was detected in lesional tissues from patients with IgG4-RD. Patients with anti-IL-1RA autoantibodies of the IgG4 subclass had greater numbers of organs affected than did those without anti-IL-1RA autoantibodies. Peptide analyses identified IL-1RA epitopes targeted by anti-IL-1RA antibodies at sites near the IL-1RA/IL-1R interface. Serum from patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) also had elevated levels of anti-IL-1RA autoantibodies compared with those of the controls. CONCLUSION: A subset of patients with IgG4-RD have anti-IL-1RA autoantibodies, which promote proinflammatory and profibrotic meditator production via IL-1RA neutralization. These findings support a novel immunologic mechanism underlying the pathogenesis of IgG4-RD. Anti-IL-1RA autoantibodies are also present in a subset of patients with SLE and RA, suggesting a potential common pathway in multiple autoimmune diseases.
Asunto(s)
Anticuerpos Neutralizantes/sangre , Autoanticuerpos/sangre , Fibrosis/inmunología , Inmunoglobulina G/inmunología , Receptores de Interleucina-1/antagonistas & inhibidores , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Artritis Reumatoide/sangre , Artritis Reumatoide/inmunología , Autoantígenos , Niño , Preescolar , Femenino , Fibrosis/sangre , Humanos , Inmunoglobulina G/sangre , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/inmunología , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/sangre , Esclerosis Múltiple/inmunología , Receptores de Interleucina-1/inmunología , Adulto JovenRESUMEN
The severity of chronic schistosomiasis has been mainly associated with the intensity and extension of the inflammatory response induced by egg-secreted antigens in the host tissue, especially in the liver and intestine. During acute schistosomiasis, eosinophils account for approximately 50% of the cells that compose the liver granulomas; however, the role of this cell-type in the pathology of schistosomiasis remains controversial. In the current study, we compared the parasite burden and liver immunopathological changes during experimental schistosomiasis in wild-type (WT) BALB/c mice and BALB/c mice selectively deficient for the differentiation of eosinophils (ΔdblGATA). Our data demonstrated that the absence of eosinophil differentiation did not alter the S. mansoni load or the liver retention of parasite eggs; however, there were significant changes in the liver immune response profile and tissue damage. S. mansoni infection in ΔdblGATA mice resulted in significantly lower liver concentrations of IL-5, IL-13, IL-33, IL-17, IL-10, and TGF-ß and higher concentrations of IFN-γ and TNF-α, as compared to WT mice. The changes in liver immune response observed in infected ΔdblGATA mice were accompanied by lower collagen deposition, but higher liver damage and larger granulomas. Moreover, the absence of eosinophils resulted in a higher mortality rate in mice infected with a high parasite load. Therefore, the data indicated that eosinophils participate in the establishment and/or amplification of liver Th-2 and regulatory response induced by S. mansoni, which is necessary for the balance between liver damage and fibrosis, which in turn is essential for modulating disease severity.
Asunto(s)
Eosinófilos/inmunología , Inmunidad/inmunología , Hepatopatías/inmunología , Hígado/inmunología , Enfermedades Desatendidas/inmunología , Esquistosomiasis mansoni/inmunología , Animales , Citocinas/inmunología , Modelos Animales de Enfermedad , Eosinófilos/parasitología , Femenino , Fibrosis/inmunología , Fibrosis/parasitología , Granuloma/inmunología , Granuloma/parasitología , Intestinos/inmunología , Intestinos/parasitología , Hígado/parasitología , Hepatopatías/parasitología , Ratones , Ratones Endogámicos BALB C , Enfermedades Desatendidas/parasitologíaRESUMEN
Despite antigen affinity of B cells varying from cell to cell, functional analyses of antigen-reactive B cells on individual B cells are missing due to technical difficulties. Especially in the field of autoimmune diseases, promising pathogenic B cells have not been adequately studied to date because of its rarity. In this study, functions of autoantigen-reactive B cells in autoimmune disease were analyzed at the single-cell level. Since topoisomerase I is a distinct autoantigen, we targeted systemic sclerosis as autoimmune disease. Decreased and increased affinities for topoisomerase I of topoisomerase I-reactive B cells led to anti-inflammatory and pro-inflammatory cytokine production associated with the inhibition and development of fibrosis, which is the major symptom of systemic sclerosis. Furthermore, inhibition of pro-inflammatory cytokine production and increased affinity of topoisomerase I-reactive B cells suppressed fibrosis. These results indicate that autoantigen-reactive B cells contribute to the disease manifestations in autoimmune disease through their antigen affinity.
Asunto(s)
Linfocitos B/inmunología , ADN-Topoisomerasas de Tipo I , Esclerodermia Sistémica/inmunología , Esclerodermia Sistémica/patología , Adulto , Animales , Autoantígenos , Linfocitos B/patología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Fibrosis/inmunología , Fibrosis/patología , Humanos , Masculino , Ratones , Persona de Mediana EdadRESUMEN
Systemic sclerosis (SSc) is a chronic connective tissue disorder characterized by immune dysregulation, chronic inflammation, vascular endothelial cell dysfunction, and progressive tissue fibrosis of the skin and internal organs. Moreover, increased cancer incidence and accelerated aging are also found. The increased cancer incidence is believed to be a result of chromosome instability. Accelerated cellular senescence has been confirmed by the shortening of telomere length due to increased DNA breakage, abnormal DNA repair response, and telomerase deficiency mediated by enhanced oxidative/nitrative stresses. The immune dysfunctions of SSc patients are manifested by excessive production of proinflammatory cytokines IL-1, IL-6, IL-17, IFN-α, and TNF-α, which can elicit potent tissue inflammation followed by tissue fibrosis. Furthermore, a number of autoantibodies including anti-topoisomerase 1 (anti-TOPO-1), anti-centromere (ACA or anti-CENP-B), anti-RNA polymerase enzyme (anti-RNAP III), anti-ribonuclear proteins (anti-U1, U2, and U11/U12 RNP), anti-nucleolar antigens (anti-Th/T0, anti-NOR90, anti-Ku, anti-RuvBL1/2, and anti-PM/Scl), and anti-telomere-associated proteins were also found. Based on these data, inflamm-aging caused by immune dysfunction-mediated inflammation exists in patients with SSc. Hence, increased cellular senescence is elicited by the interactions among excessive oxidative stress, pro-inflammatory cytokines, and autoantibodies. In the present review, we will discuss in detail the molecular basis of chromosome instability, increased oxidative stress, and functional adaptation by deranged immunome, which are related to inflamm-aging in patients with SSc.
Asunto(s)
Envejecimiento/genética , Fibrosis/genética , Inflamación/genética , Esclerodermia Sistémica/genética , Envejecimiento/inmunología , Envejecimiento/patología , Autoanticuerpos/inmunología , Células Endoteliales/patología , Fibrosis/complicaciones , Fibrosis/inmunología , Fibrosis/patología , Humanos , Enfermedades del Sistema Inmune/complicaciones , Enfermedades del Sistema Inmune/genética , Enfermedades del Sistema Inmune/inmunología , Enfermedades del Sistema Inmune/patología , Inflamación/complicaciones , Inflamación/inmunología , Inflamación/patología , Mediadores de Inflamación , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/inmunología , Esclerodermia Sistémica/patología , Enfermedades de la Piel/complicaciones , Enfermedades de la Piel/genética , Enfermedades de la Piel/inmunología , Enfermedades de la Piel/patologíaRESUMEN
Fibroproliferative disorders such as systemic sclerosis (SSc) have no effective therapies and result in significant morbidity and mortality. We recently demonstrated that the C-terminal domain of endostatin, known as E4, prevented and reversed both dermal and pulmonary fibrosis. Our goal was to identify the mechanism by which E4 abrogates fibrosis and its cell surface binding partner(s). Our findings show that E4 activated the urokinase pathway and increased the urokinase plasminogen activator (uPA) to type 1 plasminogen activator inhibitor (PAI-1) ratio. In addition, E4 substantially increased MMP-1 and MMP-3 expression and activity. In vivo, E4 reversed bleomycin induction of PAI-1 and increased uPA activity. In patients with SSc, the uPA/PAI-1 ratio was decreased in both lung tissues and pulmonary fibroblasts compared with normal donors. Proteins bound to biotinylated-E4 were identified as enolase-1 (ENO) and uPA receptor (uPAR). The antifibrotic effects of E4 required uPAR. Further, ENO mediated the fibrotic effects of TGF-ß1 and exerted TGF-ß1-independent fibrotic effects. Our findings suggest that the antifibrotic effect of E4 is mediated, in part, by regulation of the urokinase pathway and induction of MMP-1 and MMP-3 levels and activity in a uPAR-dependent manner, thus promoting extracellular matrix degradation. Further, our findings identify a moonlighting function for the glycolytic enzyme ENO in fibrosis.
Asunto(s)
Proteínas E4 de Adenovirus/inmunología , Biomarcadores de Tumor/inmunología , Proteínas de Unión al ADN/inmunología , Fibrosis/inmunología , Fosfopiruvato Hidratasa/inmunología , Proteínas Supresoras de Tumor/inmunología , Activador de Plasminógeno de Tipo Uroquinasa/inmunología , Humanos , Transducción de Señal , TransfecciónRESUMEN
The SARS-CoV-2 virus's ability to induce hypercytokinemia and cause multiple organ failure makes it imperative to find effective treatments. To understand the mechanism of viral infection and its effects on organ tissues, we analyzed multiple single-cell and bulk RNAseq data from COVID-19 patients' organ samples. Various levels of severity of infection were accounted for, with comparative analyses between mild, moderate, and severely infected patients. Our analysis uncovered an upregulation of the innate immune response via several inflammatory genes, IL-2, IL-6, IL-8, IL-17A, and NF-κB. Consequently, we found that the upregulation of these downstream effects can lead to organ injury. The downregulated pathways such as eukaryotic initiation factor 2 (eIF2) and eIF4-mediated host translation, were found to lead to an increased viral translation. We also found that the loss of inhibitory peptides can suppress an overactive innate immune response via NF-κB and interleukin-mediated pathways. Investigation of viral-host protein mapping showed that the interaction of viral proteins with host proteins correlated with the down- and upregulation of host pathways such as decreased eIF2-mediated host translation and increased hypertrophy and fibrosis. Inflammation was increased via the stimulation of pro-inflammatory cytokines and suppression of host translation pathways that led to reduced inflammatory inhibitors. Cardiac hypertrophy and organ fibrosis were the results of increased inflammation in organs of severe and critical patients. Finally, we identified potential therapeutic targets for the treatment of COVID-19 and its deleterious effects on organs. Further experimental investigation would conclusively determine the effects of COVID-19 infection on organs other than the lungs and the effectiveness of the proposed therapeutic targets.
Asunto(s)
COVID-19/inmunología , Citocinas/inmunología , Inmunidad Innata , Inflamación/inmunología , Análisis de Secuencia de ARN , Análisis de la Célula Individual , COVID-19/genética , Síndrome de Liberación de Citoquinas , Citocinas/genética , Fibrosis/inmunología , Expresión Génica , Humanos , Pulmón/inmunología , SARS-CoV-2 , Índice de Severidad de la EnfermedadRESUMEN
Fibroblasts in the synovial membrane secrete molecules essential to forming the extracellular matrix (ECM) and supporting joint homeostasis. While evidence suggests that fibroblasts contribute to the response to joint injury, the outcomes appear to be patient-specific and dependent on interactions between resident immune cells, particularly macrophages (Mφs). On the other hand, the response of Mφs to injury depends on their functional phenotype. The goal of these studies was to further explore these issues in an in vitro 3D microtissue model that simulates a pathophysiological disease-specific microenvironment. Two sources of fibroblasts were used to assess patient-specific influences: mesenchymal stem cell (MSC)- and induced pluripotent stem cell (iPSC)-derived fibroblasts. These were co-cultured with either M1 or M2 Mφs, and the cultures were challenged with polyethylene particles coated with lipopolysaccharide (cPE) to model wear debris generated from total joint arthroplasties. Our results indicated that the fibroblast response to cPE was dependent on the source of the fibroblasts and the presence of M1 or M2 Mφs: the fibroblast response as measured by gene expression changes was amplified by the presence of M2 Mφs. These results demonstrate that the immune system modulates the function of fibroblasts; furthermore, different sources of differentiated fibroblasts may lead to divergent results. Overall, our research suggests that M2 Mφs may be a critical target for the clinical treatment of cPE induced fibrosis.
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Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Macrófagos/citología , Macrófagos/efectos de los fármacos , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/efectos de los fármacos , Polietileno/farmacología , Artroplastia/métodos , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Técnicas de Cocultivo , Matriz Extracelular , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Fibroblastos/inmunología , Fibroblastos/metabolismo , Fibrosis/tratamiento farmacológico , Fibrosis/inmunología , Fibrosis/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Células Madre Mesenquimatosas/inmunologíaRESUMEN
Expansion of biliary epithelial cells (BECs) during ductular reaction (DR) is observed in liver diseases including cystic fibrosis (CF), and associated with inflammation and fibrosis, albeit without complete understanding of underlying mechanism. Using two different genetic mouse knockouts of ß-catenin, one with ß-catenin loss is hepatocytes and BECs (KO1), and another with loss in only hepatocytes (KO2), we demonstrate disparate long-term repair after an initial injury by 2-week choline-deficient ethionine-supplemented diet. KO2 show gradual liver repopulation with BEC-derived ß-catenin-positive hepatocytes and resolution of injury. KO1 showed persistent loss of ß-catenin, NF-κB activation in BECs, progressive DR and fibrosis, reminiscent of CF histology. We identify interactions of ß-catenin, NFκB, and CF transmembranous conductance regulator (CFTR) in BECs. Loss of CFTR or ß-catenin led to NF-κB activation, DR, and inflammation. Thus, we report a novel ß-catenin-NFκB-CFTR interactome in BECs, and its disruption may contribute to hepatic pathology of CF.
The liver has an incredible capacity to repair itself or 'regenerate' that is, it has the ability to replace damaged tissue with new tissue. In order to do this, the organ relies on hepatocytes (the cells that form the liver) and bile duct cells (the cells that form the biliary ducts) dividing and transforming into each other to repair and replace damaged tissue, in case the insult is dire. During long-lasting or chronic liver injury, bile duct cells undergo a process called 'ductular reaction', which causes the cells to multiply and produce proteins that stimulate inflammation, and can lead to liver scarring (fibrosis). Ductular reaction is a hallmark of severe liver disease, and different diseases exhibit ductular reactions with distinct features. For example, in cystic fibrosis, a unique type of ductular reaction occurs at late stages, accompanied by both inflammation and fibrosis. Despite the role that ductular reaction plays in liver disease, it is not well understood how it works at the molecular level. Hu et al. set out to investigate how a protein called ß-catenin which can cause many types of cells to proliferate is involved in ductular reaction. They used three types of mice for their experiments: wild-type mice, which were not genetically modified; and two strains of genetically modified mice. One of these mutant mice did not produce ß-catenin in biliary duct cells, while the other lacked ß-catenin both in biliary duct cells and in hepatocytes. After a short liver injury which Hu et al. caused by feeding the mice a specific diet the wild-type mice were able to regenerate and repair the liver without exhibiting any ductular reaction. The mutant mice that lacked ß-catenin in hepatocytes showed a temporary ductular reaction, and ultimately repaired their livers by turning bile duct cells into hepatocytes. On the other hand, the mutant mice lacking ß-catenin in both hepatocytes and bile duct cells displayed sustained ductular reactions, inflammation and fibrosis, which looked like that seen in patients with liver disease associated to cystic fibrosis. Further probing showed that ß-catenin interacts with a protein called CTFR, which is involved in cystic fibrosis. When bile duct cells lack either of these proteins, another protein called NF-B gets activated, which causes the ductular reaction, leading to inflammation and fibrosis. The findings of Hu et al. shed light on the role of ß-catenin in ductular reaction. Further, the results show a previously unknown interaction between ß-catenin, CTFR and NF-B, which could lead to better treatments for cystic fibrosis in the future.
Asunto(s)
Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Fibrosis/genética , Inflamación/genética , FN-kappa B/genética , beta Catenina/genética , Animales , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Células Epiteliales/metabolismo , Fibrosis/inmunología , Inflamación/inmunología , Ratones , Ratones Transgénicos , FN-kappa B/metabolismo , beta Catenina/metabolismoRESUMEN
Frozen shoulder is a common fibroproliferative disease characterized by the insidious onset of pain and restricted range of shoulder movement with a significant socioeconomic impact. The pathophysiological mechanisms responsible for chronic inflammation and matrix remodeling in this prevalent fibrotic disorder remain unclear; however, increasing evidence implicates dysregulated immunobiology. IL-17A is a key cytokine associated with inflammation and tissue remodeling in numerous musculoskeletal diseases, and thus, we sought to determine the role of IL-17A in the immunopathogenesis of frozen shoulder. We demonstrate an immune cell landscape that switches from a predominantly macrophage population in nondiseased tissue to a T cell-rich environment in disease. Furthermore, we observed a subpopulation of IL-17A-producing T cells capable of inducing profibrotic and inflammatory responses in diseased fibroblasts through enhanced expression of the signaling receptor IL-17RA, rendering diseased cells more sensitive to IL-17A. We further established that the effects of IL-17A on diseased fibroblasts was TRAF-6/NF-κB dependent and could be inhibited by treatment with an IKKß inhibitor or anti-IL-17A antibody. Accordingly, targeting of the IL-17A pathway may provide future therapeutic approaches to the management of this common, debilitating disease.
Asunto(s)
Bursitis/fisiopatología , Fibrosis/patología , Inflamación/patología , Interleucina-17/inmunología , Linfocitos T/inmunología , Estudios de Casos y Controles , Células Cultivadas , Citocinas/metabolismo , Femenino , Fibroblastos/inmunología , Fibroblastos/metabolismo , Fibroblastos/patología , Fibrosis/inmunología , Fibrosis/metabolismo , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Interleucina-17/metabolismo , Masculino , Persona de Mediana Edad , FN-kappa B/metabolismo , Transducción de SeñalRESUMEN
Transglutaminase 2 (TG2) is a ubiquitously expressed enzyme catalyzing the crosslinking between Gln and Lys residues and involved in various pathophysiological events. Besides this crosslinking activity, TG2 functions as a deamidase, GTPase, isopeptidase, adapter/scaffold, protein disulfide isomerase, and kinase. It also plays a role in the regulation of hypusination and serotonylation. Through these activities, TG2 is involved in cell growth, differentiation, cell death, inflammation, tissue repair, and fibrosis. Depending on the cell type and stimulus, TG2 changes its subcellular localization and biological activity, leading to cell death or survival. In normal unstressed cells, intracellular TG2 exhibits a GTP-bound closed conformation, exerting prosurvival functions. However, upon cell stimulation with Ca2+ or other factors, TG2 adopts a Ca2+-bound open conformation, demonstrating a transamidase activity involved in cell death or survival. These functional discrepancies of TG2 open form might be caused by its multifunctional nature, the existence of splicing variants, the cell type and stimulus, and the genetic backgrounds and variations of the mouse models used. TG2 is also involved in the phagocytosis of dead cells by macrophages and in fibrosis during tissue repair. Here, we summarize and discuss the multifunctional and controversial roles of TG2, focusing on cell death/survival and fibrosis.
Asunto(s)
Aminoaciltransferasas/genética , Liasas de Carbono-Nitrógeno/genética , Fibrosis/enzimología , Proteínas de Unión al GTP/genética , Inflamación/enzimología , Proteína Disulfuro Isomerasas/genética , Transglutaminasas/genética , Empalme Alternativo , Aminoaciltransferasas/inmunología , Animales , Calcio/inmunología , Calcio/metabolismo , Liasas de Carbono-Nitrógeno/inmunología , Muerte Celular , Supervivencia Celular , Fibrosis/genética , Fibrosis/inmunología , Fibrosis/patología , Proteínas de Unión al GTP/inmunología , Expresión Génica , Guanosina Trifosfato/inmunología , Guanosina Trifosfato/metabolismo , Humanos , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Isoenzimas/genética , Isoenzimas/inmunología , Macrófagos/enzimología , Macrófagos/inmunología , Fagocitosis/genética , Proteína Disulfuro Isomerasas/inmunología , Proteína Glutamina Gamma Glutamiltransferasa 2 , Transglutaminasas/inmunologíaRESUMEN
Tumor-associated macrophages (TAM) are heterogeneous in nature and comprise antitumor M1-like (M1-TAM) or pro-tumor M2-like (M2-TAM) TAMs. M2-TAMs are a major component of stroma in breast tumors and enhance metastasis by reducing their phagocytic ability and increasing tumor fibrosis. However, the molecular mechanisms that regulate phenotypic plasticity of TAMs are not well known. Here we report a novel tumor suppressor Slit2 in breast cancer by regulating TAMs in the tumor microenvironment. Slit2 reduced the in vivo growth and metastasis of spontaneous and syngeneic mammary tumor and xenograft breast tumor models. Slit2 increased recruitment of M1-TAMs to the tumor and enhanced the ability of M1-TAMs to phagocytose tumor cells in vitro and in vivo. This Slit2-mediated increase in M1-TAM phagocytosis occurred via suppression of IL6. Slit2 was also shown to diminish fibrosis in breast cancer mouse models by increasing the expression of matrix metalloproteinase 13 in M1-TAMs. Analysis of patient samples showed high Slit2 expression strongly associated with better patient survival and inversely correlated with the abundance of CD163+ TAMs. Overall, these studies define the role of Slit2 in inhibiting metastasis by activating M1-TAMs and depleting tumor fibrosis. Furthermore, these findings suggest that Slit2 can be a promising immunotherapeutic agent to redirect TAMs to serve as tumor killers for aggressive and metastatic breast cancers. In addition, Slit2 expression along with CD163+ TAMs could be used as an improved prognostic biomarker in patients with breast cancer. SIGNIFICANCE: This study provides evidence that the antitumor effect of Slit2 in breast cancer occurs by activating the phagocytic activity of M1-like tumor-associated macrophages against tumor cells and diminishing fibrosis.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/prevención & control , Fibrosis/prevención & control , Regulación Neoplásica de la Expresión Génica , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Fagocitosis , Macrófagos Asociados a Tumores/inmunología , Animales , Apoptosis , Biomarcadores de Tumor/genética , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular , Femenino , Fibrosis/inmunología , Fibrosis/metabolismo , Fibrosis/patología , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Metaloproteinasa 13 de la Matriz/genética , Metaloproteinasa 13 de la Matriz/metabolismo , Ratones , Ratones Endogámicos NOD , Ratones SCID , Metástasis de la Neoplasia , Proteínas del Tejido Nervioso/genética , Pronóstico , Tasa de Supervivencia , Células Tumorales Cultivadas , Microambiente Tumoral , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
In this review, we examine senescent cells and the overlap between the direct biological impact of senescence and the indirect impact senescence has via its effects on other cell types, particularly the macrophage. The canonical roles of macrophages in cell clearance and in other physiological functions are discussed with reference to their functions in diseases of the kidney and other organs. We also explore the translational potential of different approaches based around the macrophage in future interventions to target senescent cells, with the goal of preventing or reversing pathologies driven or contributed to in part by senescent cell load in vivo.