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OBJECTIVES: T helper 9 (Th9) cells are recognised for their characteristic expression of the transcription factor PU.1 and production of interleukin-9 (IL-9), which has been implicated in various autoimmune diseases. However, its precise relationship with rheumatoid arthritis (RA) pathogenesis needs to be further clarified. METHODS: The expression levels of PU.1 and IL-9 in patients with RA were determined by ELISA, western blotting (WB) and immunohistochemical staining. PU.1-T cell-conditional knockout (KO) mice, IL-9 KO and IL-9R KO mice were used to establish collagen antibody-induced arthritis (CAIA), respectively. The inhibitor of PU.1 and IL-9 blocking antibody was used in collagen-induced arthritis (CIA). In an in vitro study, the effects of IL-9 were investigated using siRNAs and IL-9 recombinant proteins. Finally, the underlying mechanisms were further investigated by luciferase reporter analysis, WB and Chip-qPCR. RESULTS: The upregulation of IL-9 expression in patients with RA exhibited a positive correlation with clinical markers. Using CAIA and CIA model, we demonstrated that interventions targeting PU.1 and IL-9 substantially mitigated the inflammatory phenotype. Furthermore, in vitro assays provided the proinflammatory role of IL-9, particularly in the hyperactivation of macrophages and fibroblast-like synoviocytes. Mechanistically, we uncovered that PU.1 and IL-9 form a positive feedback loop in RA: (1) PU.1 directly binds to the IL-9 promoter, activating its transcription and (2) Th9-derived IL-9 induces PU.1 via the IL-9R-JAK1/STAT3 pathway. CONCLUSIONS: These results support that the PU.1-IL-9 axis forms a positive loop in Th9 dysregulation of RA. Targeting this signalling axis presents a potential target approach for treating RA.
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Multi-layer complex structures are widely used in large-scale engineering structures because of their diverse combinations of properties and excellent overall performance. However, multi-layer complex structures are prone to interlaminar debonding damage during use. Therefore, it is necessary to monitor debonding damage in engineering applications to determine structural integrity. In this paper, a damage information extraction method with ladder feature mining for Lamb waves is proposed. The method is able to optimize and screen effective damage information through ladder-type damage extraction. It is suitable for evaluating the severity of debonding damage in aluminum-foamed silicone rubber, a novel multi-layer complex structure. The proposed method contains ladder feature mining stages of damage information selection and damage feature fusion, realizing a multi-level damage information extraction process from coarse to fine. The results show that the accuracy of damage severity assessment by the damage information extraction method with ladder feature mining is improved by more than 5% compared to other methods. The effectiveness and accuracy of the method in assessing the damage severity of multi-layer complex structures are demonstrated, providing a new perspective and solution for damage monitoring of multi-layer complex structures.
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OBJECTIVES: To uncover the function and underlying mechanism of an essential transcriptional factor, PU.1, in the development of rheumatoid arthritis (RA). METHODS: The expression and localisation of PU.1 and its potential target, FMS-like tyrosine kinase 3 (FLT3), in the synovium of patients with RA were determined by western blot and immunohistochemical (IHC) staining. UREΔ (with PU.1 knockdown) and FLT3-ITD (with FLT3 activation) mice were used to establish collagen antibody-induced arthritis (CAIA). For the in vitro study, the effects of PU.1 and FLT3 on primary macrophages and fibroblast-like synoviocytes (FLS) were investigated using siRNAs. Mechanistically, luciferase reporter assays, western blotting, FACS and IHC were conducted to show the direct regulation of PU.1 on the transcription of FLT3 in macrophages and FLS. Finally, a small molecular inhibitor of PU.1, DB2313, was used to further illustrate the therapeutic effects of DB2313 on arthritis using two in vivo models, CAIA and collagen-induced arthritis (CIA). RESULTS: The expression of PU.1 was induced in the synovium of patients with RA when compared with that in osteoarthritis patients and normal controls. FLT3 and p-FLT3 showed opposite expression patterns compared with PU.1 in RA. The CAIA model showed that PU.1 was an activator, whereas FLT3 was a repressor, of the development of arthritis in vivo. Moreover, results from in vitro assays were consistent with the in vivo results: PU.1 promoted hyperactivation and inflammatory status of macrophages and FLS, whereas FLT3 had the opposite effects. In addition, PU.1 inhibited the transcription of FLT3 by directly binding to its promoter region. The PU.1 inhibitor DB2313 clearly alleviated the effects on arthritis development in the CAIA and CIA models. CONCLUSIONS: These results support the role of PU.1 in RA and may have therapeutic implications by directly repressing FLT3. Therefore, targeting PU.1 might be a potential therapeutic approach for RA.
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Artritis Experimental , Artritis Reumatoide , Proteínas Proto-Oncogénicas , Sinoviocitos , Transactivadores , Animales , Ratones , Artritis Experimental/metabolismo , Artritis Reumatoide/tratamiento farmacológico , Proliferación Celular , Células Cultivadas , Fibroblastos/metabolismo , Tirosina Quinasa 3 Similar a fms/metabolismo , Tirosina Quinasa 3 Similar a fms/farmacología , Tirosina Quinasa 3 Similar a fms/uso terapéutico , Membrana Sinovial/metabolismo , Sinoviocitos/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Transactivadores/metabolismoRESUMEN
BACKGROUND: The chimeric antigen receptor (CAR)-T therapy has a limited therapeutic effect on solid tumors owing to the limited CAR-T cell infiltration into solid tumors and the inactivation of CAR-T cells by the immunosuppressive tumor microenvironment. Macrophage is an important component of the innate and adaptive immunity, and its unique phagocytic function has been explored to construct CAR macrophages (CAR-Ms) against solid tumors. This study aimed to investigate the therapeutic application of CAR-Ms in ovarian cancer. METHODS: In this study, we constructed novel CAR structures, which consisted of humanized anti-HER2 or CD47 scFv, CD8 hinge region and transmembrane domains, as well as the 4-1BB and CD3ζ intracellular domains. We examined the phagocytosis of HER2 CAR-M and CD47 CAR-M on ovarian cancer cells and the promotion of adaptive immunity. Two syngeneic tumor models were used to estimate the in vivo antitumor activity of HER2 CAR-M and CD47 CAR-M. RESULTS: We constructed CAR-Ms targeting HER2 and CD47 and verified their phagocytic ability to ovarian cancer cells in vivo and in vitro. The constructed CAR-Ms showed antigen-specific phagocytosis of ovarian cancer cells in vitro and could activate CD8+ cytotoxic T lymphocyte (CTL) to secrete various anti-tumor factors. For the in vivo model, mice with human-like immune systems were used. We found that CAR-Ms enhanced CD8+ T cell activation, affected tumor-associated macrophage (TAM) phenotype, and led to tumor regression. CONCLUSIONS: We demonstrated the inhibition effect of our constructed novel HER2 CAR-M and CD47 CAR-M on target antigen-positive ovarian cancer in vitro and in vivo, and preliminarily verified that this inhibitory effect is due to phagocytosis, promotion of adaptive immunity and effect on tumor microenvironment.
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Antígeno CD47 , Neoplasias Ováricas , Humanos , Femenino , Animales , Ratones , Neoplasias Ováricas/terapia , Macrófagos , Fagocitosis , Microambiente TumoralRESUMEN
The tumor-suppressor role of long noncoding RNA (lncRNA) growth arrest-specific transcript 5 (GAS5) has been proven in various types of cancer. However, the specific function of GAS5 in tumor-associated macrophages (TAMs) of endometrial cancer (EC) is elusive. Quantitative PCR results showed that GAS5 expression decreased in EC tissues and primary TAMs from EC tumors. Tumor-associated macrophage infiltration was significantly positively associated with the developmental stage of EC. Direct coculture of GAS5-overexpressing TAMs and EC cells showed that GAS5 enhanced phagocytosis, antigen presentation, and activation of cytotoxic T cells, and repressed "Don't eat me" signals between TAMs and EC cells. Tumor formation in immunodeficient mice showed that GAS5-overexpressing macrophages could repress EC formation in vivo. GAS5 promoted M1 polarization by activating the microRNA-21- phosphatase and tensin homolog (PTEN)-AKT signaling pathway and directly repressing the nuclear accumulation and phosphorylation of oncogenic yes-associated protein 1 (YAP1) in TAMs. GAS5 inhibited the development of EC from both innate and adaptive immunity by transforming TAMs from a protumor to an antitumor phenotype. These antitumor effects of GAS5 on TAMs were mediated by the activation of the miR-21-PTEN-AKT pathway and inhibition of YAP1.
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Neoplasias Endometriales , ARN Largo no Codificante , Animales , Línea Celular Tumoral , Proliferación Celular/genética , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Femenino , Humanos , Ratones , MicroARNs/genética , Fosfohidrolasa PTEN , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Largo no Codificante/genética , Macrófagos Asociados a Tumores , Proteínas Señalizadoras YAPRESUMEN
Neonatal germ cell development provides the foundation of spermatogenesis. However, a systematic understanding of this process is still limited. To resolve cellular and molecular heterogeneity in this process, we profiled single cell transcriptomes of undifferentiated germ cells from neonatal mouse testes and employed unbiased clustering and pseudotime ordering analysis to assign cells to distinct cell states in the developmental continuum. We defined the unique transcriptional programs underlying migratory capacity, resting cellular states and apoptosis regulation in transitional gonocytes. We also identified a subpopulation of primitive spermatogonia marked by CD87 (plasminogen activator, urokinase receptor), which exhibited a higher level of self-renewal gene expression and migration potential. We further revealed a differentiation-primed state within the undifferentiated compartment, in which elevated Oct4 expression correlates with lower expression of self-renewal pathway factors, higher Rarg expression, and enhanced retinoic acid responsiveness. Lastly, a knockdown experiment revealed the role of Oct4 in the regulation of gene expression related to the MAPK pathway and cell adhesion, which may contribute to stem cell differentiation. Our study thus provides novel insights into cellular and molecular regulation during early germ cell development.
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Regulación del Desarrollo de la Expresión Génica , Análisis de Secuencia de ARN , Espermatogonias/citología , Animales , Animales Recién Nacidos , Apoptosis , Adhesión Celular , Diferenciación Celular , Perfilación de la Expresión Génica , Sistema de Señalización de MAP Quinasas , Masculino , Ratones , Microscopía Fluorescente , Factor 3 de Transcripción de Unión a Octámeros/fisiología , Receptores de Ácido Retinoico/fisiología , Receptores del Activador de Plasminógeno Tipo Uroquinasa/fisiología , Espermatogénesis/genética , Transcriptoma , Tretinoina/fisiología , Receptor de Ácido Retinoico gammaRESUMEN
The chronic inflammatory autoimmune disease rheumatoid arthritis (RA) is characterized by an infiltration of activated proinflammatory immune cells into the joint that is accompanied by an overproduction of various mediators, leading to destruction of cartilage and bone erosion. Angiotensin II type 2 receptor (AT2R) is involved in antioxidative, anti-inflammatory, and antifibrotic responses. Synovial macrophages (SMs) are a type of tissue macrophages that are derived from bone marrow cells. SMs plays a central role in synovial regional immunization, which is significantly increased in both collagen-induced mice with arthritis mice and RA patients. AT2R activation caused a reversal of the polarization of SMs in the joint from the proinflammatory M1 SM to the tolerogenic, benign M2 SM. In consequence, this switch resulted in an attenuated form of the joint pathology in a rat model of collagen-induced arthritis. These results were mechanistically linked to the observation that GRK2 was translocated into cytoplasm, and ERK1/2 and NF-κB activation were inhibited. These findings open the way to a new therapeutic approach using an activation of AT2R to subvert joint inflammation in RA.
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Artritis Experimental/inducido químicamente , Artritis Experimental/metabolismo , Colágeno/farmacología , Quinasa 2 del Receptor Acoplado a Proteína-G/metabolismo , Macrófagos/metabolismo , Receptor de Angiotensina Tipo 2/metabolismo , Membrana Sinovial/metabolismo , Animales , Artritis Reumatoide/inducido químicamente , Artritis Reumatoide/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Inflamación/inducido químicamente , Inflamación/metabolismo , Macrófagos/efectos de los fármacos , Ratones , Transporte de Proteínas/fisiología , Ratas , Ratas Sprague-Dawley , Transducción de Señal/fisiologíaRESUMEN
Osteoarthritis (OA), the most ubiquitous degenerative disease affecting the entire joint, is characterized by cartilage degradation and synovial inflammation. Although the pathogenesis of OA remains poorly understood, synovial inflammation is known to play an important role in OA development. However, studies on OA pathophysiology have focused more on cartilage degeneration and osteophytes, rather than on the inflamed and thickened synovium. Fibroblast-like synoviocytes (FLS) produce a series of pro-inflammatory regulators, such as inflammatory cytokines, nitric oxide (NO) and prostaglandin E2 (PGE2 ). These regulators are positively associated with the clinical symptoms of OA, such as inflammatory pain, joint swelling and disease development. A better understanding of the inflammatory immune response in OA-FLS could provide a novel approach to comprehensive treatment strategies for OA. Here, we have summarized recently published literatures referring to epigenetic modifications, activated signalling pathways and inflammation-associated factors that are involved in OA-FLS-mediated inflammation. In addition, the current related clinical trials and future perspectives were also summarized.
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Fibroblastos/patología , Osteoartritis/patología , Sinoviocitos/patología , Sinovitis/patología , Animales , Humanos , Inflamación/patología , Transducción de Señal/fisiologíaRESUMEN
RA is a chronic, autoimmune-mediated inflammatory pathology. Long non-coding RNAs (lncRNAs) are a novel group of non-coding RNAs with a length of >200 nucleotides. There are reports emerging that suggest that lncRNAs participate in establishing and sustaining autoimmune diseases, including RA. In this review article, we highlight the functions of lncRNAs in different cell types in RA. Our review indicates that lncRNAs affect various cellular components and are novel candidates that could constitute promising targets for the diagnosis and treatment of RA.
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Artritis Reumatoide/genética , Fibroblastos/metabolismo , Leucocitos Mononucleares/metabolismo , ARN Largo no Codificante/fisiología , Linfocitos T/metabolismo , Humanos , Líquido Sinovial/citologíaRESUMEN
The ontogeny of macrophages in most organs has already been established. Owing to the limited number and inaccessibility of synovial macrophages (SMs), the origin of SMs has not been fully elucidated. Previous studies suggested that SMs have two major origins, namely, tissue-resident and monocyte-derived SMs. However, no systematic analysis to identify SM ontology in either physiological or pathological conditions has been available to date. In this review, we summarize relevant studies on the two main origins of SMs in rheumatoid arthritis (RA) and forecast the future research directions for this field. Furthermore, we discuss the current state of RA therapy that is based on targeting different SM subsets.
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Artritis Reumatoide/etiología , Macrófagos/fisiología , Sinoviocitos/fisiología , Animales , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/inmunología , Humanos , Macrófagos/efectos de los fármacosRESUMEN
During spermatogenesis, a group of undifferentiated spermatogonia undergoes an essential transition to a differentiating stage, which involves gain of Kit receptor. In the current study, we showed that a small non-coding RNA, miRNA-26b could induce transition from Kit- to Kit+ and inhibit proliferation of spermatogonia. A key transcriptional factor for undifferentiated spermatogonia, Plzf, was proven as a direct target of miR-26b. When undifferentiated spermatogonia were treated with Retinoic acid (RA), miR-26b was increased, further promoting RA-induced differentiation of spermatogonia. In addition, miR-26b could repress 5-hydroxymethylcytosine (5hmC) via repression of Tet3 in spermatogonia. These findings demonstrate that miR-26b might play a role in promoting the transition from Kit- to Kit+ SSCs.
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MicroARNs/fisiología , Espermatogénesis , Espermatogonias/metabolismo , 5-Metilcitosina/análogos & derivados , 5-Metilcitosina/metabolismo , Animales , Apoptosis , Diferenciación Celular/efectos de los fármacos , Proliferación Celular , Células Cultivadas , Proteínas de Unión al ADN/metabolismo , Dioxigenasas , Masculino , Ratones , MicroARNs/metabolismo , Proteína de la Leucemia Promielocítica con Dedos de Zinc/genética , Proteína de la Leucemia Promielocítica con Dedos de Zinc/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-kit/análisis , Espermatogonias/citología , Espermatogonias/efectos de los fármacos , Tretinoina/farmacologíaRESUMEN
MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at the posttranscriptional level via direct binding to the 3'-untranslated region (UTR) of target mRNAs. Emerging evidence shows that miRNAs play crucial roles in controlling and modulating immune system-related diseases. This review focuses on the role played by miRNAs in fibroblast-like synoviocytes (FLS), which is a key cellular component within synovia, during the establishment and maintenance of rheumatoid arthritis (RA), a systemic inflammatory autoimmune disease. It also provides an overview and classification of known functional miRNAs in RA FLS and summarizes the potential uses of these small molecules in RA diagnosis and treatment.
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Artritis Reumatoide/metabolismo , MicroARNs/metabolismo , Animales , Epigénesis Genética/genética , Fibroblastos/citología , Fibroblastos/metabolismo , Humanos , MicroARNs/genética , Transducción de Señal/genética , Transducción de Señal/fisiología , Sinoviocitos/citología , Sinoviocitos/metabolismoRESUMEN
Ten eleven translocation (Tet) family-mediated DNA oxidation on 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) represents a novel epigenetic modification that regulates dynamic gene expression during embryonic stem cells (ESCs) differentiation. Through the role of Tet on 5hmC regulation in stem cell development is relatively defined, how the Tet family is regulated and impacts on ESCs lineage development remains elusive. In this study, we show non-coding RNA regulation on Tet family may contribute to epigenetic regulation during ESCs differentiation, which is suggested by microRNA-29b (miR-29b) binding sites on the Tet1 3' untranslated region (3' UTR). We demonstrate miR-29b increases sharply after embyoid body (EB) formation, which causes Tet1 repression and reduction of cellular 5hmC level during ESCs differentiation. Importantly, we show this miR-29b/Tet1 regulatory axis promotes the mesendoderm lineage formation both in vitro and in vivo by inducing the Nodal signaling pathway and repressing the key target of the active demethylation pathway, Tdg. Taken together, our findings underscore the contribution of small non-coding RNA mediated regulation on DNA demethylation dynamics and the differential expressions of key mesendoderm regulators during ESCs lineage specification. MiR-29b could potentially be applied to enrich production of mesoderm and endoderm derivatives and be further differentiated into desired organ-specific cells.
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Diferenciación Celular/genética , Proteínas de Unión al ADN/metabolismo , Epigénesis Genética , MicroARNs/metabolismo , Células Madre Embrionarias de Ratones/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , 5-Metilcitosina/análogos & derivados , Animales , Células Cultivadas , Citosina/análogos & derivados , Citosina/metabolismo , Proteínas de Unión al ADN/antagonistas & inhibidores , Proteínas de Unión al ADN/genética , Dioxigenasas , Ectodermo/citología , Cuerpos Embrioides/citología , Endodermo/citología , Células HEK293 , Humanos , Factores de Determinación Derecha-Izquierda/genética , Mesodermo/citología , Ratones , MicroARNs/biosíntesis , Células Madre Embrionarias de Ratones/citología , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/genética , Timina ADN Glicosilasa/metabolismoRESUMEN
Chimeric antigen receptor (CAR)-immune cell therapy has revolutionized the anti-tumor field, achieving efficient and precise tumor clearance by directly guiding immune cell activity to target tumors. In addition, the use of CAR-immune cells to influence the composition and function of the immune system and ultimately achieve virus clearance and immune system homeostasis has attracted the interest of researchers. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggered a global pandemic of coronavirus disease 2019 (COVID-19). To date, the rapidly mutating SARS-CoV-2 continues to challenge existing therapies and has raised public concerns regarding reinfection. In patients with COVID-19, the interaction of SARS-CoV-2 with the immune system influences the course of the disease, and the coexistence of over-activated immune system components, such as macrophages, and severely compromised immune system components, such as natural killer cells, reveals a dysregulated immune system. Dysregulated immune-induced inflammation may impair viral clearance and T-cell responses, causing cytokine storms and ultimately leading to patient death. Here, we summarize the research progress on the use of CAR-immune cells against SARS-CoV-2 infection. Furthermore, we discuss the feasibility, challenges and prospect of CAR-immune cells as a new immune candidate therapy against SARS-CoV-2.
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COVID-19 , SARS-CoV-2 , Humanos , COVID-19/terapia , Inflamación , Inmunoterapia Adoptiva , Tratamiento Basado en Trasplante de Células y TejidosRESUMEN
OBJECTIVE: The specific role of fibroblast-like synoviocytes (FLSs) in the pathogenesis of rheumatoid arthritis (RA) is still not fully elucidated. This study aimed to explore the molecular mechanisms of epigenetic pathways, including three epigenetic factors, microRNA (miRNA)-22 (MIR22), ten-eleven translocation methylcytosine dioxygenase 3 (TET3), and MT-RNR2 like 2 (MTRNR2L2), in RA-FLSs. METHODS: The expression of MIR22, TET3, and MTRNR2L2 in the synovium of patients with RA and arthritic mice were determined by fluorescence in situ hybridization, quantitative polymerase chain reaction (qPCR), immunohistochemistry, and Western blot. Mir22-/- and Tet3+/- mice were used to establish a collagen antibody-induced arthritis (CAIA) model. Mir22 angomir and Tet3 small interfering RNA (siRNA) were used to illustrate the therapeutic effects on arthritis using a collagen-induced (CIA) model. Bioinformatics, luciferase reporter assay, 5-hydroxymethylcytosine (5hmC) dot blotting, chromatin immunoprecipitation-qPCR, and hydroxymethylated DNA immunoprecipitation were conducted to show the direct repression of MIR22 on the TET3 and transcriptional activation of TET3 on MTRNR2L2. RESULTS: The Mir22-/- CAIA model and RA-FLS-related in vitro experiments demonstrated the inhibitory effect of MIR22 on inflammation. MIR22 can directly inhibit the translation of TET3 in RA-FLSs by binding to its 3' untranslated region in TET3. The Tet3+/- mice-established CAIA model showed less severe symptoms of arthritis in vivo. In vitro experiments further confirmed the proinflammatory effect of TET3 in RA. In addition, the CIA model was used to validate the therapeutic effects of Mir22 angomir and Tet3 siRNA. Finally, TET3 exerts its proinflammatory effect by promoting 5hmC production in the promoter of its target MTRNR2L2 in RA-FLSs. CONCLUSION: The key role of the MIR22-TET3-MTRNR2L2 pathway in RA-FLSs provided an experimental basis for further studies into the pathogenesis and related targets of RA from the perspective of FLSs.
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Artritis Experimental , Artritis Reumatoide , Dioxigenasas , Epigénesis Genética , MicroARNs , Sinoviocitos , Artritis Reumatoide/genética , Artritis Reumatoide/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Animales , Ratones , Humanos , Artritis Experimental/genética , Artritis Experimental/metabolismo , Sinoviocitos/metabolismo , Inflamación/genética , Inflamación/metabolismo , Fibroblastos/metabolismo , Masculino , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Membrana Sinovial/metabolismo , Ratones Endogámicos DBARESUMEN
Glioma is the most common tumor of the primary central nervous system, and its malignant phenotype has been shown to be closely related to glioma stem cells (GSCs). Although temozolomide has significantly improved the therapeutic outcome of glioma with a high penetration rate of the blood-brain barrier, resistance is often present in patients. Moreover, evidence has shown that the crosstalk between GSCs and tumor-associated microglia/macrophages (TAMs) affect the clinical occurrence, growth, and multi-tolerance of chemoradiotherapy in gliomas. Here, we highlight its vital roles in the maintenance of the stemness of GSCs and the ability of GSCs to recruit TAMs to the tumor microenvironment and promote their polarization into tumor-promoting macrophages, hence providing groundwork for future research into new treatment strategies of cancer.
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Neoplasias Encefálicas , Glioma , Microglía , Células Madre Neoplásicas , Macrófagos Asociados a Tumores , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Macrófagos Asociados a Tumores/efectos de los fármacos , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/patología , Microglía/efectos de los fármacos , Microglía/inmunología , Microglía/patología , Humanos , Animales , Glioma/tratamiento farmacológico , Glioma/inmunología , Glioma/patología , Glioma/radioterapia , Transducción de Señal , Activación de Macrófagos , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/radioterapia , Microambiente TumoralRESUMEN
Rheumatoid arthritis (RA) is a multisystemic and inflammatory autoimmune disease characterized by joint destruction. The C-C motif chemokine receptor 2 (CCR2) is mainly expressed in monocytes and T cells, initiating their migration to sites of inflammation, ultimately leading to cartilage damage and bone destruction. CCR2 has long been considered a prospective target for treating autoimmune diseases. However, clinical studies on inhibitors or neutralizing antibodies against CCR2 in RA have exhibited limited efficacy. Recent evidence indicates that CCR2 may play different roles in RA. Hence, a comprehensive understanding regarding the role of CCR2 may facilitate the development of targeted drugs and provide novel insights for improving CCL2-mediated inflammatory diseases. This review summarizes the biological characteristics of CCR2, the related signaling pathways, and recent developments in CCR2-targeting therapeutics.
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Artritis Reumatoide , Receptores CCR2 , Humanos , Quimiocina CCL2/metabolismo , Inflamación/tratamiento farmacológico , Monocitos , Receptores CCR2/metabolismoRESUMEN
G protein-coupled receptor kinase 2 (GRK2) is one of the cytosolic enzymes, and GRK2 translocation induces prostaglandin E2 receptor 4 (EP4) over-desensitization and reduces the level of cyclic adenosine monophosphate (cAMP) to regulate macrophage polarization. However, the role of GRK2 in the pathophysiology of ulcerative colitis (UC) remains unclear. In this study, we investigated the role of GRK2 in macrophage polarization in UC, using biopsies from patients, a GRK2 heterozygous mouse model with dextran sulfate sodium (DSS)-induced colitis, and THP-1 cells. The results showed that a high level of prostaglandin E2 (PGE2) stimulated the receptor EP4 and enhanced the transmembrane activity of GRK2 in colonic lamina propria mononuclear cells (LPMCs), resulting in a down-regulation of membrane EP4 expression. Then, the suppression of cAMP-cyclic AMP responsive element-binding (CREB) signal inhibited M2 polarization in UC. Paroxetine is acknowledged as one of the selective serotonin reuptake inhibitors (SSRI), which is also considered as a potent GRK2 inhibitor with a high selectivity for GRK2. We found that paroxetine could alleviate symptoms of DSS-induced colitis in mice by regulating GPCR signaling to affect macrophage polarization. Taken together, the current results show that GRK2 may act as a novel therapeutic target in UC by regulating macrophage polarization, and paroxetine as a GRK2 inhibitor may have therapeutic effect on mice with DSS-induced colitis.
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Epitope vaccine based on the enzyme urease of Helicobacter pylori is a promising option for prophylactic and therapeutic vaccination against H. pylori infection. In our previous study, the epitope vaccine CTB-UA, which was composed of the mucosal adjuvant cholera toxin B subunit (CTB) and an epitope (UreA183â203) from the H. pylori urease A subunit (UreA) was constructed. This particular vaccine was shown to have good immunogenicity and immunoreactivity and could induce specific neutralizing antibodies, which exhibited effectively inhibitory effects on the enzymatic activity of H. pylori urease. In this study, the prophylactic and therapeutic efficacy of the epitope vaccine CTB-UA was evaluated in a BALB/c mice model. The experimental results indicated that oral prophylactic or therapeutic immunization with CTB-UA significantly decreased H. pylori colonization compared with oral immunization with PBS. The results also revealed that the protection was correlated with antigen-specific IgG, IgA, and mucosal secretory IgA antibody responses. CTB-UA may be a promising vaccine candidate for the control of H. pylori infection.
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Proteínas Bacterianas/inmunología , Vacunas Bacterianas/inmunología , Toxina del Cólera/inmunología , Infecciones por Helicobacter/prevención & control , Helicobacter pylori/inmunología , Ureasa/inmunología , Animales , Anticuerpos Antibacterianos/inmunología , Proteínas Bacterianas/administración & dosificación , Proteínas Bacterianas/genética , Vacunas Bacterianas/administración & dosificación , Vacunas Bacterianas/genética , Toxina del Cólera/administración & dosificación , Toxina del Cólera/genética , Modelos Animales de Enfermedad , Infecciones por Helicobacter/tratamiento farmacológico , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/microbiología , Helicobacter pylori/enzimología , Helicobacter pylori/genética , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ureasa/administración & dosificación , Ureasa/genética , VacunaciónRESUMEN
Rheumatoid arthritis (RA) is a chronic autoimmune disease that endangers the health of approximately 1% of the global population. Current RA medications on the market mainly include non-steroidal anti-inflammatory drugs, biological agents, and disease-modifying drugs. These drugs aim to inhibit the overactivated immune response or inflammation of RA, but they cannot cure RA. A better understanding of the pathogenesis of RA will provide a new understanding to search for RA targets and for drug development. The infiltration of T cells and hyper-proliferation of fibroblast-like synoviocytes (FLS) in the synovium of patients with RA are significantly upregulated. Furthermore, the abnormal activation of these two types of cells has been confirmed to promote development of the course of A by many studies. This article systematically summarizes the interactions between T cells and FLS in RA synovial tissues, including one-way/mutual regulation and direct/indirect regulation between the two. It further aims to investigate the pathogenesis of RA from the perspective of mutual regulation between T cells and FLS and to provide new insights into RA research.