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1.
J Biomed Mater Res B Appl Biomater ; 112(6): e35411, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38773758

RESUMO

The ultimate goal of tissue engineering is to repair and regenerate damaged tissue or organ. Achieving this goal requires blood vessel networks to supply oxygen and nutrients to new forming tissues. Macrophages are part of the immune system whose behavior plays a significant role in angiogenesis and blood vessel formation. On the other hand, macrophages are versatile cells that change their behavior in response to environmental stimuli. Given that implantation of a biomaterial is followed by inflammation; therefore, we reasoned that this inflammatory condition in tissue spaces modulates the final phenotype of macrophages. Also, we hypothesized that anti-inflammatory glucocorticoid dexamethasone improves modulating macrophages behavior. To check these concepts, we investigated the macrophages that had matured in an inflammatory media. Furthermore, we examined macrophages' behavior after maturation on a dexamethasone-containing scaffold and analyzed how the behavioral change of maturing macrophages stimulates other macrophages in the same environment. In this study, the expression of pro-inflammatory markers TNFa and NFκB1 along with pro-healing markers IL-10 and CD163 were investigated to study the behavior of macrophages. Our results showed that macrophages that were matured in the inflammatory media in vitro increase expression of IL-10, which in turn decreased the expression of pro-inflammatory markers TNFa and NFκB in maturing macrophages. Also, macrophages that were matured on dexamethasone-containing scaffolds decreased the expression of IL-10, TNFa, and NFκB and increase the expression of CD163 compared to the control group. Moreover, the modulation of anti-inflammatory response in maturing macrophages on dexamethasone-containing scaffold resulted in increased expression of TNFa and CD163 by other macrophages in the same media. The results obtained in this study, proposing strategies to improve healing through controlling the behavior of maturing macrophages and present a promising perspective for inflammation control using tissue engineering scaffolds.


Assuntos
Dexametasona , Interleucina-10 , Macrófagos , Poliésteres , Alicerces Teciduais , Dexametasona/farmacologia , Interleucina-10/metabolismo , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Alicerces Teciduais/química , Poliésteres/química , Poliésteres/farmacologia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Humanos , Animais , Inflamação/metabolismo , Camundongos
2.
FASEB J ; 38(9): e23638, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38713098

RESUMO

Diabetic retinopathy (DR) is associated with ocular inflammation leading to retinal barrier breakdown, vascular leakage, macular edema, and vision loss. DR is not only a microvascular disease but also involves retinal neurodegeneration, demonstrating that pathological changes associated with neuroinflammation precede microvascular injury in early DR. Macrophage activation plays a central role in neuroinflammation. During DR, the inflammatory response depends on the polarization of retinal macrophages, triggering pro-inflammatory (M1) or anti-inflammatory (M2) activity. This study aimed to determine the role of macrophages in vascular leakage through the tight junction complexes of retinal pigment epithelium, which is the outer blood-retinal barrier (BRB). Furthermore, we aimed to assess whether interleukin-10 (IL-10), a representative M2-inducer, can decrease inflammatory macrophages and alleviate outer-BRB disruption. We found that modulation of macrophage polarization affects the structural and functional integrity of ARPE-19 cells in a co-culture system under high-glucose conditions. Furthermore, we demonstrated that intravitreal IL-10 injection induces an increase in the ratio of anti-inflammatory macrophages and effectively suppresses outer-BRB disruption and vascular leakage in a mouse model of early-stage streptozotocin-induced diabetes. Our results suggest that modulation of macrophage polarization by IL-10 administration during early-stage DR has a promising protective effect against outer-BRB disruption and vascular leakage. This finding provides valuable insights for early intervention in DR.


Assuntos
Barreira Hematorretiniana , Diabetes Mellitus Experimental , Retinopatia Diabética , Interleucina-10 , Macrófagos , Camundongos Endogâmicos C57BL , Animais , Retinopatia Diabética/metabolismo , Retinopatia Diabética/patologia , Barreira Hematorretiniana/metabolismo , Barreira Hematorretiniana/patologia , Interleucina-10/metabolismo , Camundongos , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/metabolismo , Masculino , Humanos , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Epitélio Pigmentado da Retina/efeitos dos fármacos , Estreptozocina , Ativação de Macrófagos/efeitos dos fármacos , Modelos Animais de Doenças , Polaridade Celular/efeitos dos fármacos
3.
JCI Insight ; 9(9)2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38716729

RESUMO

Atopic dermatitis (AD) is an inflammatory skin condition with a childhood prevalence of up to 25%. Microbial dysbiosis is characteristic of AD, with Staphylococcus aureus the most frequent pathogen associated with disease flares and increasingly implicated in disease pathogenesis. Therapeutics to mitigate the effects of S. aureus have had limited efficacy and S. aureus-associated temporal disease flares are synonymous with AD. An alternative approach is an anti-S. aureus vaccine, tailored to AD. Experimental vaccines have highlighted the importance of T cells in conferring protective anti-S. aureus responses; however, correlates of T cell immunity against S. aureus in AD have not been identified. We identify a systemic and cutaneous immunological signature associated with S. aureus skin infection (ADS.aureus) in a pediatric AD cohort, using a combined Bayesian multinomial analysis. ADS.aureus was most highly associated with elevated cutaneous chemokines IP10 and TARC, which preferentially direct Th1 and Th2 cells to skin. Systemic CD4+ and CD8+ T cells, except for Th2 cells, were suppressed in ADS.aureus, particularly circulating Th1, memory IL-10+ T cells, and skin-homing memory Th17 cells. Systemic γδ T cell expansion in ADS.aureus was also observed. This study suggests that augmentation of protective T cell subsets is a potential therapeutic strategy in the management of S. aureus in AD.


Assuntos
Dermatite Atópica , Infecções Cutâneas Estafilocócicas , Staphylococcus aureus , Dermatite Atópica/imunologia , Dermatite Atópica/microbiologia , Humanos , Staphylococcus aureus/imunologia , Criança , Feminino , Infecções Cutâneas Estafilocócicas/imunologia , Infecções Cutâneas Estafilocócicas/microbiologia , Masculino , Pré-Escolar , Pele/microbiologia , Pele/imunologia , Pele/patologia , Quimiocina CXCL10/imunologia , Quimiocina CXCL10/metabolismo , Células Th1/imunologia , Células Th2/imunologia , Células Th17/imunologia , Teorema de Bayes , Linfócitos T CD8-Positivos/imunologia , Interleucina-10/metabolismo , Interleucina-10/imunologia , Linfócitos Intraepiteliais/imunologia , Antígenos de Diferenciação de Linfócitos T , Glicoproteínas de Membrana
4.
BMC Gastroenterol ; 24(1): 163, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38745150

RESUMO

BACKGROUND: The liver regeneration is a highly complicated process depending on the close cooperations between the hepatocytes and non-parenchymal cells involving various inflammatory cells. Here, we explored the role of myeloid-derived suppressor cells (MDSCs) in the processes of liver regeneration and liver fibrosis after liver injury. METHODS: We established four liver injury models of mice including CCl4-induced liver injury model, bile duct ligation (BDL) model, concanavalin A (Con A)-induced hepatitis model, and lipopolysaccharide (LPS)-induced hepatitis model. The intrahepatic levels of MDSCs (CD11b+Gr-1+) after the liver injury were detected by flow cytometry. The effects of MDSCs on liver tissues were analyzed in the transwell co-culture system, in which the MDSCs cytokines including IL-10, VEGF, and TGF-ß were measured by ELISA assay and followed by being blocked with specific antibodies. RESULTS: The intrahepatic infiltrations of MDSCs with surface marker of CD11b+Gr-1+ remarkably increased after the establishment of four liver injury models. The blood served as the primary reservoir for hepatic recruitment of MDSCs during the liver injury, while the bone marrow appeared play a compensated role in increasing the number of MDSCs at the late stage of the inflammation. The recruited MDSCs in injured liver were mainly the M-MDSCs (CD11b+Ly6G-Ly6Chigh) featured by high expression levels of cytokines including IL-10, VEGF, and TGF-ß. Co-culture of the liver tissues with MDSCs significantly promoted the proliferation of both hepatocytes and hepatic stellate cells (HSCs). CONCLUSIONS: The dramatically and quickly infiltrated CD11b+Gr-1+ MDSCs in injured liver not only exerted pro-proliferative effects on hepatocytes, but also accounted for the activation of profibrotic HSCs.


Assuntos
Antígeno CD11b , Cirrose Hepática , Regeneração Hepática , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides , Animais , Células Supressoras Mieloides/metabolismo , Células Supressoras Mieloides/imunologia , Camundongos , Cirrose Hepática/patologia , Cirrose Hepática/metabolismo , Regeneração Hepática/fisiologia , Antígeno CD11b/metabolismo , Masculino , Modelos Animais de Doenças , Fígado/patologia , Fígado/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Tetracloreto de Carbono , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Concanavalina A , Ligadura , Lipopolissacarídeos , Interleucina-10/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Células Estreladas do Fígado/metabolismo , Técnicas de Cocultura , Hepatócitos/metabolismo , Hepatócitos/patologia , Ductos Biliares
5.
J Immunother Cancer ; 12(5)2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38782541

RESUMO

BACKGROUND: Accumulating evidence demonstrates that an increased tumor-associated macrophage abundance is often associated with poor prognosis in colorectal cancer (CRC). The mechanism underlying the effect of tumor-derived exosomes on M2 macrophage polarization remains elusive. RESULTS: The novel circular RNA circPOLQ exhibited significantly higher expression in CRC tissues than in paired normal tissues. Higher circPOLQ expression was associated with poorer prognosis in patients with CRC. In vitro and in vivo experiments showed that tumor-derived exosomal circPOLQ did not directly regulate CRC cell development but promoted CRC metastatic nodule formation by enhancing M2 macrophage polarization. circPOLQ activated the interleukin-10/signal transducer and activator of transcription 3 axis by targeting miR-379-3 p to promote M2 macrophage polarization. CONCLUSION: circPOLQ can enter macrophages via CRC cell-derived exosomes and promote CRC metastatic nodule formation by enhancing M2 macrophage polarization. These findings reveal a tumor-derived exosome-mediated tumor-macrophage interaction potentially affecting CRC metastatic nodule formation.


Assuntos
Neoplasias Colorretais , Exossomos , Interleucina-10 , Macrófagos , RNA Circular , Fator de Transcrição STAT3 , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/genética , Humanos , Exossomos/metabolismo , Fator de Transcrição STAT3/metabolismo , Camundongos , Animais , Interleucina-10/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , Macrófagos/metabolismo , Ativação de Macrófagos , Masculino , Feminino , Transdução de Sinais , Linhagem Celular Tumoral , Macrófagos Associados a Tumor/metabolismo
6.
Ren Fail ; 46(1): 2356023, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38785317

RESUMO

Glycyrrhizin (GL) has immunoregulatory effects on various inflammatory diseases including hepatitis and nephritis. However, the mechanisms underlying the anti-inflammatory effect of GL on renal inflammation are not fully understood. Hepatorenal syndrome (HRS) is a functional acute renal impairment that occurs in severe liver disease, and we found that kidney injury also occurs in Con A-induced experimental hepatitis in mice. We previously found that GL can alleviate Con A-induced hepatitis by regulating the expression of IL-25 in the liver. We wanted to investigate whether GL can alleviate Con A-induced nephritis by regulating IL-25. IL-25 regulates inflammation by modulating type 2 immune responses, but the mechanism by which IL-25 affects kidney disease remains unclear. In this study, we found that the administration of GL enhanced the expression of IL-25 in renal tissues; the latter promoted the generation of type 2 macrophages (M2), which inhibited inflammation in the kidney caused by Con A challenge. IL-25 promoted the secretion of the inhibitory cytokine IL-10 by macrophages but inhibited the expression of the inflammatory cytokine IL-1ß by macrophages. Moreover, IL-25 downregulated the Con A-mediated expression of Toll-like receptor (TLR) 4 on macrophages. By comparing the roles of TLR2 and TLR4, we found that TLR4 is required for the immunoregulatory effect of IL-25 on macrophages. Our data revealed that GL has anti-inflammatory effects on Con A-induced kidney injury and that the GL/IL-25/M2 axis participates in the anti-inflammatory process. This study suggested that GL is a potential therapeutic for protecting against acute kidney injury.


Assuntos
Modelos Animais de Doenças , Ácido Glicirrízico , Rim , Macrófagos , Animais , Ácido Glicirrízico/farmacologia , Ácido Glicirrízico/uso terapêutico , Camundongos , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Masculino , Rim/patologia , Rim/metabolismo , Receptor 2 Toll-Like/metabolismo , Interleucinas/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Inflamação/metabolismo , Interleucina-10/metabolismo , Receptor 4 Toll-Like/metabolismo , Transdução de Sinais/efeitos dos fármacos , Interleucina-1beta/metabolismo , Síndrome Hepatorrenal/etiologia , Síndrome Hepatorrenal/tratamento farmacológico , Síndrome Hepatorrenal/metabolismo , Camundongos Endogâmicos C57BL , Nefrite/tratamento farmacológico , Nefrite/metabolismo , Nefrite/etiologia , Nefrite/prevenção & controle
7.
Front Immunol ; 15: 1404297, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38751432

RESUMO

Introduction: Recently, the use of botanicals as an alternative to coccidiostats has been an appealing approach for controlling coccidiosis. Therefore, this study was conducted to evaluate the potential role of aqueous methanolic extract (200 mg/kg) of Krameria lappacea (roots) (KLRE) against infection induced by Eimeria papillata. Methods: A total of 25 male C57BL/6 mice were divided into five groups (I, II, III, IV, and V). On 1st day of the experiment, all groups except groups I (control) and II (non-infected-treated group with KLRE), were inoculated orally with 103 sporulated E. papillata oocysts. On the day of infection, group IV was treated with KLRE. Group V served as an infected-treated group and was treated with amprolium (coccidiostat). Results: Treatment with extract and coccidiostat was continued for five consecutive days. While not reaching the efficacy level of the reference drug (amprolium), KLRE exhibited notable anticoccidial activity as assessed by key criteria, including oocyst suppression rate, total parasitic stages, and maintenance of nutrient homeostasis. The presence of phenolic and flavonoid compounds in KLRE is thought to be responsible for its positive effects. The Eimeria infection increased the oxidative damage in the jejunum. KLRE treatment significantly increased the activity of catalase and superoxide dismutase. On the contrary, KLRE decreased the level of malondialdehyde and nitric oxide. Moreover, KLRE treatment decreased macrophage infiltration in the mice jejunal tissue, as well as the extent of CD4 T cells and NFkB. E. papillata caused a state of systemic inflammatory response as revealed by the upregulation of inducible nitric oxide synthase (iNOs)-mRNA. Upon treatment with KLRE, the activity of iNOs was reduced from 3.63 to 1.46 fold. Moreover, KLRE was able to downregulate the expression of pro-inflammatory cytokines interferon-γ, nuclear factor kappa B, and interleukin-10 -mRNA by 1.63, 1.64, and 1.38 fold, respectively. Moreover, KLRE showed a significant reduction in the expression of IL-10 protein level from 104.27 ± 8.41 pg/ml to 62.18 ± 3.63 pg/ml. Conclusion: Collectively, K. lappacea is a promising herbal medicine that could ameliorate the oxidative stress and inflammation of jejunum, induced by E. papillata infection in mice.


Assuntos
Antioxidantes , Linfócitos T CD4-Positivos , Coccidiose , Coccidiostáticos , Eimeria , Interleucina-10 , Camundongos Endogâmicos C57BL , Extratos Vegetais , Raízes de Plantas , Animais , Extratos Vegetais/farmacologia , Coccidiose/tratamento farmacológico , Coccidiose/imunologia , Coccidiose/parasitologia , Camundongos , Masculino , Interleucina-10/metabolismo , Antioxidantes/farmacologia , Eimeria/efeitos dos fármacos , Raízes de Plantas/química , Coccidiostáticos/farmacologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Modelos Animais de Doenças
8.
Int J Mol Sci ; 25(9)2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38732106

RESUMO

Type 2 diabetes (T2D) is characterized by muscle metabolic dysfunction that exercise can minimize, but some patients do not respond to an exercise intervention. Myokine secretion is intrinsically altered in patients with T2D, but the role of myokines in exercise resistance in this patient population has never been studied. We sought to determine if changes in myokine secretion were linked to the response to an exercise intervention in patients with T2D. The participants followed a 10-week aerobic exercise training intervention, and patients with T2D were grouped based on muscle mitochondrial function improvement (responders versus non-responders). We measured myokines in serum and cell-culture medium of myotubes derived from participants pre- and post-intervention and in response to an in vitro model of muscle contraction. We also quantified the expression of genes related to inflammation in the myotubes pre- and post-intervention. No significant differences were detected depending on T2D status or response to exercise in the biological markers measured, with the exception of modest differences in expression patterns for certain myokines (IL-1ß, IL-8, IL-10, and IL-15). Further investigation into the molecular mechanisms involving myokines may explain exercise resistance with T2D; however, the role in metabolic adaptations to exercise in T2D requires further investigation.


Assuntos
Diabetes Mellitus Tipo 2 , Exercício Físico , Fibras Musculares Esqueléticas , Treinamento Resistido , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/terapia , Masculino , Exercício Físico/fisiologia , Pessoa de Meia-Idade , Feminino , Fibras Musculares Esqueléticas/metabolismo , Interleucina-1beta/metabolismo , Interleucina-1beta/sangue , Citocinas/metabolismo , Citocinas/sangue , Interleucina-8/metabolismo , Interleucina-8/sangue , Interleucina-10/metabolismo , Interleucina-10/sangue , Idoso , Interleucina-15/metabolismo , Interleucina-15/sangue , Terapia por Exercício/métodos , Contração Muscular , Músculo Esquelético/metabolismo , Miocinas
9.
Int J Rheum Dis ; 27(5): e15174, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38720423

RESUMO

OBJECTIVES: This study investigates the role of TNF-induced protein 3 (TNFAIP3) and CCAAT/enhancer-binding protein ß (C/EBPß) in alveolar macrophages (AMs) of patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) and their influence on pulmonary fibrosis. METHODS: Transfection of HEK293T cells and AMs with plasmids carrying TNFAIP3 and C/EBPß was performed, followed by co-culturing AMs with pulmonary fibroblasts. Immunoblotting analysis was then utilized to assess the expression of TNFAIP3, C/EBPß, and collagen type 1 (Col1). Quantitative PCR analysis was conducted to quantify the mRNA levels of C/EBPß, IL-10, and TGF-ß1. STRING database analysis, and immunoprecipitation assays were employed to investigate the interactions between TNFAIP3 and C/EBPß. RESULTS: TNFAIP3 expression was significantly reduced in SSc-ILD AMs, correlating with increased Col1 production in fibroblasts. Overexpression of TNFAIP3 inhibited this pro-fibrotic activity. Conversely, C/EBPß expression was elevated in SSc-ILD AMs, and its reduction through TNFAIP3 restoration decreased pro-fibrotic cytokines IL-10 and TGFß1 levels. Protein-protein interaction studies confirmed the regulatory relationship between TNFAIP3 and C/EBPß. CONCLUSIONS: This study highlights the important role of TNFAIP3 in regulating pulmonary fibrosis in SSc-ILD by modulating C/EBPß expression in AMs. These findings suggest that targeting TNFAIP3 could be a potential therapeutic strategy for managing SSc-ILD patients.


Assuntos
Proteína beta Intensificadora de Ligação a CCAAT , Técnicas de Cocultura , Fibroblastos , Doenças Pulmonares Intersticiais , Macrófagos Alveolares , Escleroderma Sistêmico , Proteína 3 Induzida por Fator de Necrose Tumoral alfa , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Proteína beta Intensificadora de Ligação a CCAAT/genética , Colágeno Tipo I/metabolismo , Colágeno Tipo I/genética , Fibroblastos/metabolismo , Células HEK293 , Interleucina-10/metabolismo , Interleucina-10/genética , Pulmão/metabolismo , Pulmão/patologia , Doenças Pulmonares Intersticiais/metabolismo , Doenças Pulmonares Intersticiais/etiologia , Macrófagos Alveolares/metabolismo , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/etiologia , Escleroderma Sistêmico/metabolismo , Escleroderma Sistêmico/complicações , Transdução de Sinais , Fator de Crescimento Transformador beta1/metabolismo , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/metabolismo , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Adulto , Idoso
10.
Cell Commun Signal ; 22(1): 284, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38783329

RESUMO

BACKGROUND: To elucidate the mechanism of dysfunction of tolerogenic dendritic cells (DCs) is of significance. Telomerase involves the regulation of the cell fate and activities. The objective of this study is to investigate the role of telomerase reverse transcriptase (TERT) in regulating the tolerogenic feature of DCs. METHODS: The telomerase was assessed in DCs, which were collected from patients with allergic rhinitis (AR), healthy control (HC) subjects, and mice. RNAs were extracted from DCs, and analyzed by RNA sequencing (RNAseq), real-time quantitative RT-PCR, and Western blotting. RESULTS: The results showed that expression of TERT was higher in peripheral DCs of AR patients. The expression of IL10 in DCs was negatively correlated with the levels of TERT expression. Importantly, the levels of TERT mRNA in DCs were associated with the AR response in patients with AR. Endoplasmic reticulum (ER) stress promoted the expression of Tert in DCs. Sensitization with the ovalbumin-aluminum hydroxide protocol increased the expression of Tert in DCs by exacerbating ER stress. TERT interacting with c-Maf (the transcription factor of IL-10) inducing protein (CMIP) in DCs resulted in CMIP ubiquitination and degradation, and thus, suppressed the production of IL-10. Inhibition of Tert in DCs mitigated experimental AR. CONCLUSIONS: Elevated amounts of TERT were detected in DCs of patients with AR. The tolerogenic feature of DCs was impacted by TERT. Inhibited TERT attenuated experimental AR.


Assuntos
Células Dendríticas , Tolerância Imunológica , Interleucina-10 , Telomerase , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Telomerase/metabolismo , Telomerase/genética , Animais , Humanos , Interleucina-10/metabolismo , Interleucina-10/genética , Camundongos , Rinite Alérgica/imunologia , Feminino , Masculino , Estresse do Retículo Endoplasmático , Camundongos Endogâmicos BALB C , Adulto
11.
Cells ; 13(10)2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38786036

RESUMO

Inflammation contributes to the onset and exacerbation of numerous age-related diseases, often manifesting as a chronic condition during aging. Given that cellular senescence fosters local and systemic inflammation, senotherapeutic interventions could potentially aid in managing or even reducing inflammation. Here, we investigated the immunomodulatory effects of the senotherapeutic Peptide 14 (Pep 14) in human peripheral blood mononuclear cells (PBMCs), monocytes, and macrophages. We found that, despite failing to significantly influence T cell activation and proliferation, the peptide promoted a Th2/Treg gene expression and cytokine signature in PBMCs, characterized by increased expression of the transcription factors GATA3 and FOXP3, as well as the cytokines IL-4 and IL-10. These observations were partially confirmed through ELISA, in which we observed increased IL-10 release by resting and PHA-stimulated PBMCs. In monocytes from the U-937 cell line, Pep 14 induced apoptosis in lipopolysaccharide (LPS)-stimulated cells and upregulated IL-10 expression. Furthermore, Pep 14 prevented LPS-induced activation and promoted an M2-like polarization in U-937-derived macrophages, evidenced by decreased expression of M1 markers and increased expression of M2 markers. We also showed that the conditioned media from Pep 14-treated macrophages enhanced fibroblast migration, indicative of a functional M2 phenotype. Taken together, our findings suggest that Pep 14 modulates immune cell function towards an anti-inflammatory and regenerative phenotype, highlighting its potential as a therapeutic intervention to alleviate immunosenescence-associated dysregulation.


Assuntos
Macrófagos , Monócitos , Células Th1 , Humanos , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/metabolismo , Peptídeos/farmacologia , Lipopolissacarídeos/farmacologia , Citocinas/metabolismo , Interleucina-10/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Apoptose/efeitos dos fármacos
12.
Cells ; 13(10)2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38786082

RESUMO

Lung transplantation results are compromised by ischemia-reperfusion injury and alloimmune responses. Ex vivo lung perfusion (EVLP) is used to assess marginal donor lungs before transplantation but is also an excellent platform to apply novel therapeutics. We investigated donor lung immunomodulation using genetically engineered mesenchymal stromal cells with augmented production of human anti-inflammatory hIL-10 (MSCsIL-10). Pig lungs were placed on EVLP for 6 h and randomized to control (n = 7), intravascular delivery of 20 × 106 (n = 5, low dose) or 40 × 106 human MSCs IL-10 (n = 6, high dose). Subsequently, single-lung transplantation was performed, and recipient pigs were monitored for 3 days. hIL-10 secretion was measured during EVLP and after transplantation, and immunological effects were assessed by cytokine profile, T and myeloid cell characterization and mixed lymphocyte reaction. MSCIL-10 therapy rapidly increased hIL-10 during EVLP and resulted in transient hIL-10 elevation after lung transplantation. MSCIL-10 delivery did not affect lung function but was associated with dose-related immunomodulatory effects, with the low dose resulting in a beneficial decrease in apoptosis and lower macrophage activation, but the high MSCIL-10 dose resulting in inflammation and cytotoxic CD8+ T cell activation. MSCIL-10 therapy during EVLP results in a rapid and transient perioperative hIL-10 increase and has a therapeutic window for its immunomodulatory effects.


Assuntos
Imunomodulação , Interleucina-10 , Transplante de Pulmão , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Transplante de Pulmão/métodos , Animais , Interleucina-10/metabolismo , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/imunologia , Células-Tronco Mesenquimais/citologia , Suínos , Transplante de Células-Tronco Mesenquimais/métodos , Humanos , Engenharia Genética , Pulmão/metabolismo , Pulmão/patologia , Pulmão/imunologia
13.
Nat Commun ; 15(1): 4232, 2024 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-38762479

RESUMO

Toll-like receptor 9 (TLR9) recognizes bacterial, viral and self DNA and play an important role in immunity and inflammation. However, the role of TLR9 in obesity is less well-studied. Here, we generate B-cell-specific Tlr9-deficient (Tlr9fl/fl/Cd19Cre+/-, KO) B6 mice and model obesity using a high-fat diet. Compared with control mice, B-cell-specific-Tlr9-deficient mice exhibited increased fat tissue inflammation, weight gain, and impaired glucose and insulin tolerance. Furthermore, the frequencies of IL-10-producing-B cells and marginal zone B cells were reduced, and those of follicular and germinal center B cells were increased. This was associated with increased frequencies of IFNγ-producing-T cells and increased follicular helper cells. In addition, gut microbiota from the KO mice induced a pro-inflammatory state leading to immunological and metabolic dysregulation when transferred to germ-free mice. Using 16 S rRNA gene sequencing, we identify altered gut microbial communities including reduced Lachnospiraceae, which may play a role in altered metabolism in KO mice. We identify an important network involving Tlr9, Irf4 and Il-10 interconnecting metabolic homeostasis, with the function of B and T cells, and gut microbiota in obesity.


Assuntos
Linfócitos B , Dieta Hiperlipídica , Disbiose , Microbioma Gastrointestinal , Inflamação , Interleucina-10 , Camundongos Knockout , Obesidade , Receptor Toll-Like 9 , Animais , Obesidade/imunologia , Obesidade/microbiologia , Obesidade/metabolismo , Disbiose/imunologia , Disbiose/microbiologia , Receptor Toll-Like 9/metabolismo , Receptor Toll-Like 9/genética , Linfócitos B/imunologia , Linfócitos B/metabolismo , Inflamação/metabolismo , Camundongos , Dieta Hiperlipídica/efeitos adversos , Interleucina-10/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Fatores Reguladores de Interferon
14.
Immunity ; 57(5): 1105-1123.e8, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38703775

RESUMO

Immunosuppressive macrophages restrict anti-cancer immunity in glioblastoma (GBM). Here, we studied the contribution of microglia (MGs) and monocyte-derived macrophages (MDMs) to immunosuppression and mechanisms underlying their regulatory function. MDMs outnumbered MGs at late tumor stages and suppressed T cell activity. Molecular and functional analysis identified a population of glycolytic MDM expressing GLUT1 with potent immunosuppressive activity. GBM-derived factors promoted high glycolysis, lactate, and interleukin-10 (IL-10) production in MDMs. Inhibition of glycolysis or lactate production in MDMs impaired IL-10 expression and T cell suppression. Mechanistically, intracellular lactate-driven histone lactylation promoted IL-10 expression, which was required to suppress T cell activity. GLUT1 expression on MDMs was induced downstream of tumor-derived factors that activated the PERK-ATF4 axis. PERK deletion in MDM abrogated histone lactylation, led to the accumulation of intratumoral T cells and tumor growth delay, and, in combination with immunotherapy, blocked GBM progression. Thus, PERK-driven glucose metabolism promotes MDM immunosuppressive activity via histone lactylation.


Assuntos
Glioblastoma , Glucose , Histonas , Macrófagos , Glioblastoma/imunologia , Glioblastoma/metabolismo , Glioblastoma/patologia , Animais , Histonas/metabolismo , Camundongos , Macrófagos/imunologia , Macrófagos/metabolismo , Glucose/metabolismo , Humanos , Linhagem Celular Tumoral , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Transportador de Glucose Tipo 1/metabolismo , Transportador de Glucose Tipo 1/genética , Interleucina-10/metabolismo , Glicólise , Microglia/metabolismo , Microglia/imunologia , Camundongos Endogâmicos C57BL , Linfócitos T/imunologia , Linfócitos T/metabolismo , Tolerância Imunológica
15.
Cancer Rep (Hoboken) ; 7(5): e2064, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38711262

RESUMO

BACKGROUND: Breast cancer (BC) is the most commonly diagnosed female cancer. Homeobox protein MEIS2, a key transcription factor, is involved in the regulation of many developmental and cellular processes. However, the role of MEIS2 in the development of breast cancer is still unclear. AIMS: We aimed to examine the role of myeloid ecotropic insertion site (MEIS2) in breast cancer and the association of MEIS2 with breast cancer clinical stages and pathological grades. We revealed the underlying mechanism by which MEIS2 affected breast cancer cell growth and tumor development. METHODS AND RESULTS: Using human BC cell lines, clinical samples and animal xenograft model, we reveal that MEIS2 functions as a tumor suppressor in breast cancer. The expression of MEIS2 is inversely correlated with BC clinical stages and pathological grades. MEIS2 knockdown (MEIS2-KD) promotes while MEIS2 overexpression suppresses breast cancer cell proliferation and tumor development in vitro and in animal xenograft models, respectively. To determine the biological function of MEIS2, we screen the expression of a group of MEIS2 potential targeting genes in stable-established cell lines. Results show that the knockdown of MEIS2 in breast cancer cells up-regulates the IL10 expression, but MEIS2 overexpression opposed the effect on IL10 expression. Furthermore, the suppressive role of MEIS2 in breast cancer cell proliferation is associated with the IL10 expression and myeloid cells infiltration. CONCLUSION: Our study demonstrates that the tumor suppressor of MEIS2 in breast cancer progression is partially via down regulating the expression of IL10 and promoting myeloid cells infiltration. Targeting MEIS2 would be a potentially therapeutic avenue for BC.


Assuntos
Neoplasias da Mama , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio , Interleucina-10 , Fatores de Transcrição , Humanos , Feminino , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Animais , Camundongos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Interleucina-10/metabolismo , Interleucina-10/genética , Linhagem Celular Tumoral , Regulação para Baixo , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Nus
16.
PLoS One ; 19(5): e0292028, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38691538

RESUMO

APRIL (A Proliferation-Inducing Ligand), a member of the TNF superfamily, was initially described for its ability to promote proliferation of tumor cells in vitro. Moreover, this cytokine has been related to the pathogenesis of different chronic inflammatory diseases, such as rheumatoid arthritis. This study aimed to evaluate the ability of APRIL in regulating B cell-mediated immune response in the antigen-induced arthritis (AIA) model in mice. AIA was induced in previously immunized APRIL-transgenic (Tg) mice and their littermates by administration of antigen (mBSA) into the knee joints. Different inflammatory cell populations in spleen and draining lymph nodes were analyzed using flow cytometry and the assay was performed in the acute and chronic phases of the disease, while cytokine levels were assessed by ELISA. In the acute AIA, APRIL-Tg mice developed a less severe condition and a smaller inflammatory infiltrate in articular tissues when compared with their littermates. We also observed that the total cellularity of draining lymph nodes was decreased in APRIL-Tg mice. Flow cytometry analysis revealed an increase of CD19+IgM+CD5+ cell population in draining lymph nodes and an increase of CD19+CD21hiCD23hi (B regulatory) cells in APRIL-Tg mice with arthritis as well as an increase of IL-10 and CXCL13 production in vitro.


Assuntos
Artrite Experimental , Linfócitos B Reguladores , Camundongos Transgênicos , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral , Animais , Camundongos , Artrite Experimental/imunologia , Artrite Experimental/patologia , Linfócitos B Reguladores/imunologia , Interleucina-10/metabolismo , Linfonodos/imunologia , Linfonodos/patologia , Baço/imunologia , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética
17.
Cytokine ; 179: 156622, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38648681

RESUMO

Tuberculosis is caused by Mycobacterium tuberculosis (M tb), which is recognized by macrophages and produces inflammatory cytokines, and chemokines at the site of infection. The present study was proposed to understand the interaction of M tb antigens, cytokines, and chemokines. We have evaluated the chemokine MCP-1 levels and its expression in PBMCs stimulated with M tb antigens Ag85A, ESAT6 and recombinant cytokines rhTNF-α, rhIFN-γ, rhTGF-ß, and rhIL-10 in active pulmonary TB (APTB) patients, household contacts (HHC) at 0 months, 6 months and healthy controls (HC). We have observed low levels of MCP-1 with Ag85A, ESAT6, and rhTNF-α stimulations in APTB 0M compared to HHC and HC (p < 0.0067, p < 0.0001, p < 0.01, p < 0.005, p < 0.0065, p < 0.0001) and significantly increased after treatment with rhTNF-α. The MCP-1 levels with rhIFN-γ were high in APTB, HHC at 0 M and significant between APTB 0 M vs. 6 M, HHC vs. HC, and HHC 0M vs. 6M (p < 0.0352, p < 0.0252, p < 0.00062). The rhTGF-ß, rhIL-10 induced high MCP-1 levels in APTB, HHC compared to HC (p < 0.0414, p < 0.0312, p < 0.004, p < 0.0001) and significantly decreased after treatment with rhIL-10 (p < 0.0001). The MCP-1 expression was low with all the stimulations in APTB 0M when compared to HC and after treatment. Whereas, HHC shown low MCP-1 expression with rhTNF-α, rhIFN-γ and Ag85A and high with rhTGF-ß, rhIL-10 and ESAT6. In conclusion, the study determined the differential expression and production of MCP-1 with M tb antigens and recombinant cytokines. Further, cohort studies are required to study these interaction to identify the high risk individuals, which might help for TB control.


Assuntos
Antígenos de Bactérias , Quimiocina CCL2 , Citocinas , Mycobacterium tuberculosis , Proteínas Recombinantes , Humanos , Antígenos de Bactérias/imunologia , Quimiocina CCL2/imunologia , Quimiocina CCL2/metabolismo , Masculino , Mycobacterium tuberculosis/imunologia , Feminino , Proteínas Recombinantes/imunologia , Adulto , Citocinas/metabolismo , Proteínas de Bactérias/imunologia , Pessoa de Meia-Idade , Interferon gama/imunologia , Interferon gama/metabolismo , Tuberculose Pulmonar/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-10/metabolismo , Interleucina-10/imunologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Tuberculose/imunologia , Fator de Crescimento Transformador beta/imunologia
18.
J Immunotoxicol ; 21(1): 2332172, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38563602

RESUMO

Efficacious therapeutic options capable of resolving inflammatory lung disease associated with environmental and occupational exposures are lacking. This study sought to determine the preclinical therapeutic potential of lung-delivered recombinant interleukin (IL)-10 therapy following acute organic dust exposure in mice. Here, C57BL/6J mice were intratracheally instilled with swine confinement organic dust extract (ODE) (12.5%, 25%, 50% concentrations) with IL-10 (1 µg) treatment or vehicle control intratracheally-administered three times: 5 hr post-exposure and then daily for 2 days. The results showed that IL-10 treatment reduced ODE (25%)-induced weight loss by 66% and 46% at Day 1 and Day 2 post-exposure, respectively. IL-10 treatment reduced ODE (25%, 50%)-induced lung levels of TNFα (-76%, -83% [reduction], respectively), neutrophil chemoattractant CXCL1 (-51%, -60%), and lavage fluid IL-6 (-84%, -89%). IL-10 treatment reduced ODE (25%, 50%)-induced lung neutrophils (-49%, -70%) and recruited CD11cintCD11b+ monocyte-macrophages (-49%, -70%). IL-10 therapy reduced ODE-associated expression of antigen presentation (MHC Class II, CD80, CD86) and inflammatory (Ly6C) markers and increased anti-inflammatory CD206 expression on CD11cintCD11b+ cells. ODE (12.5%, 25%)-induced lung pathology was also reduced with IL-10 therapy. In conclusion, the studies here showed that short-term, lung-delivered IL-10 treatment induced a beneficial response in reducing inflammatory consequences (that were also associated with striking reduction in recruited monocyte-macrophages) following acute complex organic dust exposure.


Assuntos
Pneumopatias , Pneumonia , Animais , Camundongos , Suínos , Interleucina-10/metabolismo , Camundongos Endogâmicos C57BL , Pneumonia/tratamento farmacológico , Pulmão/patologia , Pneumopatias/induzido quimicamente , Pneumopatias/tratamento farmacológico , Poeira
19.
Front Cell Infect Microbiol ; 14: 1361326, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38572322

RESUMO

Spinal tuberculosis is a common extrapulmonary type that is often secondary to pulmonary or systemic infections. Mycobacterium tuberculosis infection often leads to the balance of immune control and bacterial persistence. In this study, 64 patients were enrolled and the clinicopathological and immunological characteristics of different age groups were analyzed. Anatomically, spinal tuberculosis in each group mostly occurred in the thoracic and lumbar vertebrae. Imaging before preoperative anti-tuberculosis therapy showed that the proportion of abscesses in the older group was significantly lower than that in the younger and middle-aged groups. However, pathological examination of surgical specimens showed that the proportion of abscesses in the older group was significantly higher than that in the other groups, and there was no difference in the granulomatous inflammation, caseous necrosis, inflammatory necrosis, acute inflammation, exudation, granulation tissue formation, and fibrous tissue hyperplasia. B cell number was significantly lower in the middle-aged and older groups compared to the younger group, while the number of T cells, CD4+ T cells, CD8+ T cells, macrophages, lymphocytes, plasma cells, and NK cells did not differ. Meaningfully, we found that the proportion of IL-10 high expression and TGF-ß1 positive in the older group was significantly higher than that in the younger group. TNF-α, CD66b, IFN-γ, and IL-6 expressions were not different among the three groups. In conclusion, there are some differences in imaging, pathological, and immune features of spinal tuberculosis in different age groups. The high expression of IL-10 and TGF-ß1 in older patients may weaken their anti-tuberculosis immunity and treatment effectiveness.


Assuntos
Mycobacterium tuberculosis , Tuberculose da Coluna Vertebral , Pessoa de Meia-Idade , Humanos , Idoso , Interleucina-10/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Tuberculose da Coluna Vertebral/tratamento farmacológico , Tuberculose da Coluna Vertebral/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Abscesso/tratamento farmacológico , Abscesso/metabolismo , Antituberculosos/uso terapêutico , Necrose/tratamento farmacológico , Necrose/metabolismo , Linfócitos T CD4-Positivos , Citocinas/metabolismo
20.
Front Immunol ; 15: 1369117, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38601165

RESUMO

There is an urgent need for alternative therapies targeting human dendritic cells (DCs) that could reverse inflammatory syndromes in many autoimmune and inflammatory diseases and organ transplantations. Here, we describe a bispecific antibody (bsAb) strategy tethering two pathogen-recognition receptors at the surface of human DCs. This cross-linking switches DCs into a tolerant profile able to induce regulatory T-cell differentiation. The bsAbs, not parental Abs, induced interleukin 10 and transforming growth factor ß1 secretion in monocyte-derived DCs and human peripheral blood mononuclear cells. In addition, they induced interleukin 10 secretion by synovial fluid cells in rheumatoid arthritis and gout patients. This concept of bsAb-induced tethering of surface pathogen-recognition receptors switching cell properties opens a new therapeutic avenue for controlling inflammation and restoring immune tolerance.


Assuntos
Anticorpos Biespecíficos , Linfócitos T Reguladores , Humanos , Interleucina-10/metabolismo , Anticorpos Biespecíficos/farmacologia , Anticorpos Biespecíficos/metabolismo , Leucócitos Mononucleares , Células Dendríticas
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