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1.
Am J Rhinol Allergy ; : 19458924241269686, 2024 Aug 02.
Artículo en Inglés | MEDLINE | ID: mdl-39093621

RESUMEN

BACKGROUND: The Th2 cell polarization is a crucial factor in the pathogenesis of allergic diseases. The underlying mechanism requires further investigation. Telomerase has an immune-regulating ability. The aim of this study is to elucidate the association between telomerase and Th2 cell polarization in patients with allergic rhinitis (AR). METHODS: CD4+ T cells were isolated from blood samples collected from AR patients and healthy control subjects. RNA sequencing was employed to analyze RNA samples extracted from CD4+ T cells. An AR mouse model was established using the ovalbumin-alum protocol. RESULTS: High telomerase gene activity and high endoplasmic reticulum (ER) stress status were observed in CD4+ T-cells in patients with AR. Positive correlation between the telomerase reverse transcriptase (TERT) gene expression in CD4+ T cells and AR response in patients with AR. TERT facilitated the degradation of Foxp3 proteins in CD4+ T cells, resulting in the polarization of Th2 cells. Sensitization with the ovalbumin-alum protocol enhanced the Tert expression in CD4+ T cells by exacerbating ER stress. Conditional inhibition of the Tert or eukaryotic translation initiation factor 2-α (Eif2a) expression in CD4+ T cells effectively attenuated experimental AR in mice. CONCLUSIONS: Elevated amounts of telomerase in CD4+ T cells were found in CD4+ T cells of subjects with AR. Telomerase promoted Th2 cell polarization by inducing Foxp3 protein degradation and promotes GATA3 activation. Inhibition of TERT or eIF2a alleviated experimental AR.

2.
Cell Biosci ; 14(1): 95, 2024 Jul 21.
Artículo en Inglés | MEDLINE | ID: mdl-39034406

RESUMEN

BACKGROUND: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder that has been found to be associated with dysregulation of gastrointestinal functions and gut microbial homeostasis (the so-called "gut-brain axis"). ASD is often accompanied by poor performances in social interaction and repetitive behaviors. Studies on the gut-brain axis provide novel insights and candidate targets for ASD therapeutics and diagnosis. Based on the ASD mice model, this work aims to reveal the mechanisms behind the interaction of intestinal barrier function and probiotics in ASD mouse models. RESULTS: We found an altered intestinal barrier in both BTBR T+ Itpr3tf/J (BTBR) and valproic acid (VPA) mice, including increased intestinal permeability, decreased expression of intestinal tight junction proteins (claudin1, claudin3, and occludin), and increased levels of IL-6, TNF-α, and IFN-γ. Based on intestinal microbial alternation, C. butyricum can drive reduced expression of histone deacetylases 1 (HDAC1) and enhanced intestinal barrier function, significantly promoting behavioral abnormalities of ASD in BTBR mice. In parallel, we confirmed that C. butyricum was involved in the regulation of intestinal function by the Trek1 channel, indicating that it is a target of C. butyricum/butyric acid to improve intestinal barrier function in ASD mice. CONCLUSIONS: Our finding provides solid evidence for the gut microbiota involved in ASD through the brain-gut axis. In addition, the probiotics C. butyricum hold promise to improve gut health and ameliorate behavioral abnormalities associated with ASD.

3.
Immunol Res ; 2024 Jul 22.
Artículo en Inglés | MEDLINE | ID: mdl-39034374

RESUMEN

BACKGROUND: The cause of food allergy (FA) is still a mystery. Telomerases are involved in the regulation of immune responses. This study aims to gain an understanding of the contribution of telomerase reverse transcriptase (TERT) to the pathogenesis of FA. METHODS: A murine FA model was established with ovalbumin as the specific antigen. The role of TERT in regulating dendritic cell (DC) immune tolerogenic functions was evaluated in this murine model. RESULTS: We observed that the Tert promoter was at demethylation status and the Tert expression was elevated in DCs of FA mice. The Tert expression in DCs had a positive correlation with the FA response. TERT prevented the induction of Il10 expression in DCs. The immune tolerogenic functions of DCs were diminished by TERT. The immune tolerogenic functions of DC were restored by CpG by boosting the Tert promoter methylation. Administration of CpG promoted the therapeutic effects of allergen specific immunotherapy in FA mice. CONCLUSIONS: Low levels of Il10 expression and high levels of Tert expression were observed in intestinal DCs of FA mice. CpG exposure restored the expression of Il10 and increased the therapeutic benefits of allergen-specific immunotherapy.

4.
Mol Immunol ; 173: 71-79, 2024 Jul 26.
Artículo en Inglés | MEDLINE | ID: mdl-39067087

RESUMEN

BACKGROUND: The treatment of food allergy (FA) needs improvement. The treatment of immune disorders can be improved by regulating epigenetic marks, which is a promising method. The objective of this research is to alleviate experimental FA by employing an inhibitor of DNA methyltransferase-1 (DNMT1). METHODS: Ovalbumin was used as the specific antigen to establish a mouse model of FA. Intestinal IL-35+ regulatory B cells (Breg cells) were isolated from FA mice, and characterized using immunological approaches. RESULTS: FA mice had a lower frequency of IL-35+ Breg cells, which was inversely correlated with their FA response. The quantity of IL-35 was lower in intestinal Breg cells from FA mice. Hypermethylation status was detected in the Il35 promoter, which was accompanied with high levels of H3K9me3. Enforced expression of DNMT1 hindered the promoter activity of the IL35 gene. Administration of an inhibitor of DNMT1 (RG108) restored the immune regulatory capacity of FA intestinal Bregs, and effectively suppressed the expression of DNMT1, and attenuated experimental FA. CONCLUSIONS: The elevated quantity of DNMT1 in intestinal Breg cells compromises the expression of IL-35 and affects the immune regulatory functions, which facilitates the development of FA. The immune regulatory functions of intestinal Breg cells are restored and experimental FA is attenuated by inhibiting DNMT1.

5.
iScience ; 27(6): 110067, 2024 Jun 21.
Artículo en Inglés | MEDLINE | ID: mdl-38883815

RESUMEN

Dendritic cells (DC) play a crucial role in the initiation of immune responses. TRIM41, an E3 ubiquitin ligase, can facilitate targeting protein degradation. The purpose of this study is to analyze the role of TRIM41 in the pathogenesis of airway allergy (AA) and the impact of regulating TRIM41 on suppressing AA. We observed that the airway DCs of AA mice had a higher expression of Trim41. The expression of Trim41 in airway DCs was associated with the DCs' tolerogenic functions of AA mice. The AA responses, including increased amounts of eosinophil peroxidase, mast cell protease-1, Th2 cytokines, and specific IgE in bronchoalveolar lavage fluids, were positively correlated with the Trim41 expression in mouse airway DCs. TRIM41 induced c-Maf degradation and interfered with the Il10 expression in airway DCs, which could be counteracted by inhibiting TRIM41. Regulation of TRIM41 mitigated experimental AA responses.

6.
Immunology ; 2024 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-38859694

RESUMEN

SET domain-containing 2 (SETD2) is a histone methyltransferase. It regulates the activity of H3K36me3 to enhance gene transcription. Macrophages (Mϕs) are one of the cell types involved in immune response. The purpose of this study is to clarify the role of SETD2 in regulating the immune property of Mϕ. The Mφs were isolated from the bronchoalveolar lavage fluid (BALF) and analysed through flow cytometry and RNA sequencing. A mouse strain carrying Mφs deficient in SETD2 was used. A mouse model of airway allergy was established with the ovalbumin/alum protocol. Less expression of SETD2 was observed in airway Mϕs in patients with allergic asthma. SETD2 of M2 cells was associated with the asthmatic clinical response. Sensitization reduced the expression of SETD2 in mouse respiratory tract M2 cells, which is associated with the allergic reaction. Depletion of SETD2 in Mφs resulted in Th2 pattern inflammation in the lungs. SETD2 maintained the immune regulatory ability in airway M2 cells. SETD2 plays an important role in the maintenance of immune regulatory property of airway Mφs.

7.
Cell Signal ; 121: 111257, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38857681

RESUMEN

Epithelial barrier dysfunction plays an important role in the pathogenesis of Th2 bias. The mechanism requires further clarification. NEMO is associated with regulating apoptotic activities in the cell. The purpose of this study is to investigate the role of insufficient Nemo signals in developing Th2 bias in the respiratory tract. Nemof/fEpcam-Cre mice (A mouse strain carrying NEMO-deficient epithelial cells. NemoKO mice, in short) was generated. An airway Th2 bias mouse model was established with the ovalbumin/alum protocol. The NemoKO mice exhibited spontaneous airway Th2 bias. Respiratory tract epithelial barrier integrity was compromised in NemoKO mice. Apoptosis was found in approximately 10% of the epithelial cells of the respiratory tract in NemoKO mice. The reconstruction of the Nemo expression restored homeostasis within the epithelial barrier of the airways. Restoration of Nemo gene expression in epithelial cells by Nemo mRNA vaccination alleviated Th2 bias in mice with airway allergy. To sum up, NEMO plays an important role in maintaining the integrity of the epithelial barrier in the respiratory tract. Administration of NEMO mRNA vaccines can restore epithelial barrier functions and alleviate Th2 bias in the airways.


Asunto(s)
ARN Mensajero , Células Th2 , Animales , Ratones , ARN Mensajero/metabolismo , ARN Mensajero/genética , Células Th2/inmunología , Células Th2/metabolismo , Vacunación , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Ovalbúmina/inmunología , Células Epiteliales/metabolismo , Apoptosis , Ratones Endogámicos C57BL , Hipersensibilidad Respiratoria , Hipersensibilidad , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/inmunología , Modelos Animales de Enfermedad , Ratones Noqueados
9.
Cell Commun Signal ; 22(1): 284, 2024 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-38783329

RESUMEN

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.


Asunto(s)
Células Dendríticas , Tolerancia Inmunológica , Interleucina-10 , Telomerasa , Adulto , Animales , Femenino , Humanos , Masculino , Ratones , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Estrés del Retículo Endoplásmico , Interleucina-10/metabolismo , Interleucina-10/genética , Ratones Endogámicos BALB C , Rinitis Alérgica/inmunología , Telomerasa/metabolismo , Telomerasa/genética
10.
Immunol Lett ; 267: 106867, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38754636

RESUMEN

Chronic inflammation is the pathological feature of inflammatory bowel diseases (IBD), but its etiology is unknown. Macrophages are one of the major immune cell fractions in the colon. The objectives of this study are to characterize the immune regulatory functions of macrophages in the colon of patients with ulcerative colitis (UC). UC patients (n = 30) were recruited into this study. Colon lavage fluid (CLF) was collected. Macrophages are isolated from the cellular components of CLF. The immune suppressive functions of macrophages were assessed using immunological approaches. We observed that macrophages occupied about half of the proportions of the cellular components in CLF. Lower amounts of IL10 mRNA and proteins were detected in macrophages of the UC group than the normal control (NC) group. The expression of IL10 in CLF macrophages was positively correlated with the UC-associated cytokines, including tumor necrosis factor-α, interleukin (IL)-1ß, IFN-γ, eosinophil-derived mediators, in CLF. The immune suppressive functions of CLF macrophages in UC patients were impaired. The inducibility of IL10 expression of UC M0 cells was defective as compared with NC M0 cells. Exposure to CpG restored the inducibility of IL10 expression in UC M0 cells, and gain the potential to acquire the immune suppressive functions. To sum up, the immune suppressive functions of UC macrophages are impaired. The inducibility of IL10 expression of M0 cells is impaired, which can be restored by the treatment with CpG.


Asunto(s)
Colitis Ulcerosa , Citocinas , Interleucina-10 , Macrófagos , Humanos , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Femenino , Masculino , Adulto , Interleucina-10/metabolismo , Persona de Mediana Edad , Citocinas/metabolismo , Células Cultivadas , Colon/inmunología , Colon/patología , Colon/metabolismo
11.
Innate Immun ; 30(2-4): 55-65, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38725177

RESUMEN

Th2 polarization is essential for the pathogenesis of allergic rhinitis (AR). Th2 polarization's mechanism requires further understanding. IL-4 is the primary cytokine involved in Th2 response. Fibroblasts play a role in immune regulation. This study aims to elucidate the role of nasal mucosal fibroblast-derived IL-4 in the induction of Th2 responses. Nasal mucosal tissues were obtained from surgically removed samples from patients with nasal polyps, whether with or without AR. Fibroblasts were isolated from the tissues by flow cytometry cell sorting, and analyzed by RNA sequencing (RNAseq). The data from RNAseq showed that nasal fibroblasts expressed genes of GATA3, CD80, CD83, CD86, STAT6, IL2, IL4, IL5, IL6, IL13 and costimulatory factor. The data were verified by RT-qPCR. The level of gene activity was positively correlated with those of AR-related cytokines present in nasal secretions. Nasal fibroblasts release IL-4 upon activation. Nasal fibroblasts had the ability to transform naive CD4+ T cells into Th2 cells, which can be eliminated by inhibiting IL-4 receptor or CD28 in CD4+ T cells. To sum up, nasal mucosal fibroblasts produce IL-4, which can induce Th2 cell development. The data implicate that nasal fibroblasts are involved in the pathogenesis of nasal allergy.


Asunto(s)
Fibroblastos , Interleucina-4 , Mucosa Nasal , Rinitis Alérgica , Células Th2 , Humanos , Células Th2/inmunología , Fibroblastos/inmunología , Fibroblastos/metabolismo , Mucosa Nasal/inmunología , Mucosa Nasal/metabolismo , Interleucina-4/metabolismo , Rinitis Alérgica/inmunología , Rinitis Alérgica/metabolismo , Células Cultivadas , Femenino , Masculino , Adulto , Persona de Mediana Edad , Pólipos Nasales/inmunología , Activación de Linfocitos , Diferenciación Celular
12.
Cell Immunol ; 401-402: 104829, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38754338

RESUMEN

Eosinophils account for a significant portion of immune cells in the body. It is well known that eosinophils play a role in the pathogenesis of many diseases. In which the interaction between eosinophils and other immune cells is incompletely understood. The aim of this study is to characterize the immune suppressive functions of eosinophils. In this study, an irway allergy mouse model was established. Eosinophils were isolated from the airway tissues using flow cytometry cell sorting. The RAW264.7 cell line was used to test the immune suppressive functions of eosinophils. We observed that eosinophils had immune suppressive functions manifesting inhibiting immune cell proliferation and cytokine release from other immune cells. The eosinophil's immune suppressive functions were mediated by eosinophil-derived molecules, such as eosinophil peroxidase (EPX) and major basic protein (MBP). The expression of Ras-like protein in the brain 27a (Rab27a) was detected in eosinophils, which controlled the release of MBP and EPX by eosinophils. Eosinophil mediators had two contrast effects on inducing inflammatory responses or rendering immune suppressive effects, depending on the released amounts. Administration of an inhibitor of Rab27a at proper dosage could alleviate experimental airway allergy. To sum up, eosinophils have immune suppressive functions and are also inflammation inducers. Rab27a governs the release of EPX and MBP from eosinophils, which leads to immune suppression or inflammation. Modulation of Rab27a can alleviate airway allergy responses by modulating eosinophil's immune suppressive functions, which has the translational potential for the management of eosinophil-related diseases.


Asunto(s)
Peroxidasa del Eosinófilo , Eosinófilos , Animales , Eosinófilos/inmunología , Eosinófilos/metabolismo , Ratones , Células RAW 264.7 , Peroxidasa del Eosinófilo/metabolismo , Ratones Endogámicos BALB C , Citocinas/metabolismo , Citocinas/inmunología , Modelos Animales de Enfermedad , Proteína Mayor Básica del Eosinófilo/metabolismo , Proteína Mayor Básica del Eosinófilo/inmunología , Femenino , Hipersensibilidad/inmunología , Proliferación Celular , Inflamación/inmunología
14.
Immunology ; 172(4): 588-599, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38634546

RESUMEN

Allergic asthma is characterized by the polarization of Th2 cells and impaired immune regulation. Macrophages occupy the largest proportion of airway immune cells. This study aims to discover the mechanism that hinders the immune regulatory functions of airway macrophages. In this study, macrophages were isolated from cells in bronchoalveolar lavage fluids (BALF) collected from asthma patients and normal control (NC) subjects. The results indicated that macrophages occupied the largest portion of the cellular components in BALF. The frequency of IL-10+ macrophage was significantly lower in asthma patients than in NC subjects. The expression of IL-10 in macrophages of BALF was associated with the levels of asthma-related parameters. The immune-suppressive functions of BALF M0 cells were defective in asthma patients. The inducibility of IL-10 expression was impaired in BALF macrophages of asthma patients, which could be restored by exposing to CpG. In conclusion, the induction of IL-10 in macrophages of BALF in asthma patients was impaired, and it could be restored by exposure to CpG.


Asunto(s)
Asma , Líquido del Lavado Bronquioalveolar , Interleucina-10 , Oligodesoxirribonucleótidos , Humanos , Asma/inmunología , Oligodesoxirribonucleótidos/farmacología , Oligodesoxirribonucleótidos/inmunología , Líquido del Lavado Bronquioalveolar/inmunología , Líquido del Lavado Bronquioalveolar/citología , Femenino , Masculino , Interleucina-10/metabolismo , Adulto , Macrófagos/inmunología , Macrófagos/metabolismo , Persona de Mediana Edad , Macrófagos Alveolares/inmunología , Células Cultivadas , Células Th2/inmunología
15.
Arch Biochem Biophys ; 755: 109984, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38588908

RESUMEN

BACKGROUND: Allergen specific immunotherapy (AIT) has been widely used in allergy clinics. The therapeutic effects of it are to be improved. Macrophages occupy the largest proportion of airway immune cells. The aim of this study is to measure the effects of nasal instillation AIT (nAIT) on airway allergy by regulating macrophage functions. METHODS: An airway allergy mouse model was established with the ovalbumin-alum protocol. nAIT was conducted for mice with airway allergy through nasal instillation. The effects of nAIT were compared with subcutaneous injection AIT (SCIT) and sublingual AIT (SLIT). RESULTS: Mice with airway allergy showed the airway allergic response, including lung inflammation, airway hyper responsiveness, serum specific IgE, increase in the amounts of eosinophil peroxidase, mouse mast cell protease-1, and Th2 cytokines in bronchoalveolar lavage fluid. nAIT had a much better therapeutic effect on the airway allergic response than SCIT and SLIT. Mechanistically, we observed better absorption of allergen in macrophages, better production of IL-10 by macrophages, and better immune suppressive functions in macrophages in mice received nAIT than SCIT and SLIT. CONCLUSIONS: The nAIT has a much better therapeutic effect on suppressing the airway allergic response, in which macrophages play a critical role.

16.
Biomed Pharmacother ; 174: 116510, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38554528

RESUMEN

BACKGROUND: CpG oligodeoxynucleotide (CpG-ODN; CpG, in short) has been employed as an adjuvant in allergen specific immunotherapy (AIT) to treat allergic diseases. The underlying mechanism needs to be further explained. The aim of this study is to examine the mechanism by which CpG and dust mite extracts (DME, a specific antigen) alleviate experimental airway allergy. METHODS: DME was used as the specific allergen to establish an airway allergy mouse model. The mice were directly exposed to DME and CpG through nasal instillations (the CpG.DME therapy). The response of DCs and allergic responses in the airways were assessed using immunological approaches. RESULTS: The airway allergy reaction was effectively suppressed by CpG.DME therapy. The administration of CpG or DME alone did not have any significant suppressive effects on the airway allergic response. Direct exposure to CpG.DME induced type 1 DCs (DC1s) and plasmacytoid DCs (pDCs), while CpG alone induced DC1s and DME alone induced DC2s in the airway tissues. Both DC1s and pDCs were required for the induction of type 1 regulatory T cells in the airway tissues by CpG.DME therapy. Depletion of either pDCs or DC1s abolished the induction of Tr1 cells, and abolished the suppressive effects on airway allergic response by the CpG.DME therapy. CONCLUSIONS: Direct exposure to CpG.DME induces DC1s and pDCs in the airway tissues. DC1s in synergy with pDCs induce type 1 regulatory T cells. The CpG.DME therapy is effective in suppressing allergic responses in mice with airway allergy.


Asunto(s)
Células Dendríticas , Ratones Endogámicos BALB C , Oligodesoxirribonucleótidos , Hipersensibilidad Respiratoria , Animales , Células Dendríticas/inmunología , Células Dendríticas/efectos de los fármacos , Oligodesoxirribonucleótidos/farmacología , Ratones , Hipersensibilidad Respiratoria/inmunología , Hipersensibilidad Respiratoria/terapia , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Femenino , Adyuvantes Inmunológicos/farmacología , Alérgenos/inmunología , Antígenos Dermatofagoides/inmunología , Hipersensibilidad/inmunología , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Pyroglyphidae/inmunología
17.
Int Immunopharmacol ; 130: 111778, 2024 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-38432147

RESUMEN

OBJECTIVE: To investigate the mechanism of action of fatty acid receptors, FFAR1 and FFAR4, on ulcerative colitis (UC) through fatty acid metabolism and macrophage polarization. METHODS: Dextran sulfate sodium (DSS)-induced mouse model of UC mice was used to evaluate the efficacy of FFAR1 (GW9508) and FFAR4 (GSK137647) agonists by analyzing body weight, colon length, disease activity index (DAI), and histological scores. Real-time PCR and immunofluorescence analysis were performed to quantify the levels of fatty acid metabolizing enzymes and macrophage makers. FFA-induced lipid accumulation in RAW264.7 cells was visualized by Oil Red O staining analysis, and cells were collected to detect macrophage polarization by flow cytometry. RESULTS: The combination of GW9508 and GSK137647 significantly improved DSS-induced UC symptoms, caused recovery in colon length, and decreased histological injury. GW9508 + GSK137647 treatment upregulated the expressions of CD206, lipid oxidation enzyme (CPT-1α) and anti-inflammatory cytokines (IL-4, IL-10, IL-13) but downregulated those of CD86, lipogenic enzymes (ACC1, FASN, SCD1), and pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α). Combining the two agonists decreased FFA-induced lipid accumulation and increased CD206 expression in cell-based experiments. CONCLUSION: Activated FFAR1 and FFAR4 ameliorates DSS-induced UC by promoting fatty acid metabolism to reduce lipid accumulation and mediate M2 macrophage polarization.


Asunto(s)
Colitis Ulcerosa , Ácidos Grasos no Esterificados , Macrófagos , Receptores Acoplados a Proteínas G , Animales , Ratones , Compuestos de Anilina/farmacología , Compuestos de Anilina/uso terapéutico , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/tratamiento farmacológico , Colon/patología , Citocinas/metabolismo , Sulfato de Dextran , Modelos Animales de Enfermedad , Ácidos Grasos no Esterificados/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Metilaminas/farmacología , Metilaminas/uso terapéutico , Ratones Endogámicos C57BL , Propionatos/farmacología , Propionatos/uso terapéutico , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Receptores Acoplados a Proteínas G/agonistas
18.
J Leukoc Biol ; 115(5): 893-901, 2024 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-38517856

RESUMEN

Interleukin (IL)-33 is a key driver of T helper 2 (Th2) cell polarization. Endoplasmic reticulum (ER) stress plays a role in the skewed T cell activation. The objective of this project is to elucidate the role of IL-33 derived from macrophages in inducing Th2 polarization in the airways. In this study, bronchoalveolar lavage fluids (BALF) were collected from patients with asthma and healthy control subjects. Macrophages were isolated from the BALF by flow cytometry cell sorting. An asthmatic mouse model was established using the ovalbumin/alum protocol. The results showed that increased IL33 gene activity and ER stress-related molecules in BALF-derived M2a macrophages was observed in asthmatic patients. Levels of IL33 gene activity in M2a cells were positively correlated with levels of asthma response in asthma patients. Sensitization exacerbated the ER stress in the airway macrophages, which increased the expression of IL-33 in macrophages of airway in sensitized mice. Conditional ablation of Il33 or Perk or Atf4 genes in macrophages prevented induction of airway allergy in mice. In conclusion, asthma airway macrophages express high levels of IL-33 and at high ER stress status. Inhibition of IL-33 or ER stress in macrophages can effectively alleviate experimental asthma.


Asunto(s)
Asma , Estrés del Retículo Endoplásmico , Interleucina-33 , Macrófagos , Células Th2 , Adulto , Animales , Femenino , Humanos , Masculino , Ratones , Asma/inmunología , Asma/metabolismo , Asma/patología , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Polaridad Celular , Modelos Animales de Enfermedad , Estrés del Retículo Endoplásmico/inmunología , Interleucina-33/metabolismo , Macrófagos/metabolismo , Macrófagos/inmunología , Ratones Endogámicos C57BL , Células Th2/inmunología , Células Th2/metabolismo , Adulto Joven , Persona de Mediana Edad
19.
Immunology ; 172(2): 210-225, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38366844

RESUMEN

Numerous diseases of the immune system can be traced back to the malfunctioning of the regulatory T cells. The aetiology is unclear. Psychological stress can cause disruption to the immune regulation. The synergistic effects of psychological stress and immune response on immune regulation have yet to be fully understood. The intention of this study is to analyse the interaction between psychological stress and immune responses and how it affects the functional status of type 1 regulatory T (Tr1) cells. In this study, ovalbumin peptide T-cell receptor transgenic mice were utilised. Mice were subjected to restraint stress to induce psychological stress. An airway allergy murine model was established, in which a mouse strain with RING finger protein 20 (Rnf20)-deficient CD4+ T cells were used. The results showed that concomitant exposure to restraint stress and immune response could exacerbate endoplasmic reticulum stress in Tr1 cells. Corticosterone was responsible for the elevated expression of X-box protein-1 (XBP1) in mouse Tr1 cells after exposure to both restraint stress and immune response. XBP1 mediated the effects of corticosterone on inducing Rnf20 in Tr1 cells. The reduction of the interleukin-10 expression in Tr1 cells was facilitated by Rnf20. Inhibition of Rnf20 alleviated experimental airway allergy by restoring the immune regulatory ability of Tr1 cells. In conclusion, the functions of Tr1 cells are negatively impacted by simultaneous exposure to psychological stress and immune response. Tr1 cells' immune suppressive functions can be restored by inhibiting Rnf20, which has the translational potential for the treatment of diseases of the immune system.


Asunto(s)
Interleucina-10 , Ratones Transgénicos , Ovalbúmina , Estrés Psicológico , Linfocitos T Reguladores , Animales , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Ovalbúmina/inmunología , Estrés Psicológico/inmunología , Ratones , Interleucina-10/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores de Antígenos de Linfocitos T/inmunología , Proteína 1 de Unión a la X-Box/metabolismo , Proteína 1 de Unión a la X-Box/genética , Corticosterona/sangre , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Estrés del Retículo Endoplásmico/inmunología , Modelos Animales de Enfermedad , Restricción Física , Ratones Noqueados , Ratones Endogámicos C57BL , Hipersensibilidad Respiratoria/inmunología
20.
Inflamm Res ; 73(3): 381-392, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38265686

RESUMEN

BACKGROUND: A variety of stimuli can cause endoplasmic reticulum (ER) stress, which is a common cellular reaction. It is not yet clear how ER stress contributes to the pathogenesis of ulcerative colitis (UC). The deregulation of regulatory T cell (Treg) is associated with UC. The goal of this study is to shed light on how ER stress affects Treg's development. METHODS: CD4+ CD25- T cells were isolated from blood samples collected from UC patients and healthy control (HC) subjects. ER stress-associated molecule expression in CD4+ CD25- T cell was assessed by RNA sequencing and RT-qPCR. RESULTS: The presence of ER stress in peripheral CD4+ CD25- T cells was observed in patients with UC compared to HC subjects. The induction of ER stress in HC CD4+ CD25- T cells by polyclonal activation was made worse by the presence of 3-methyl-4-nitrophenol (MNP; a common environmental pollutant). Exposure to MNP in culture resulted in an increase in the expression of ring finger protein 20 (Rnf20) in CD4+ CD25- T cells. The synergistic effects of MNP and ER stress on the reduction of IL-10 levels in CD4+ CD25- T cells are mediated by Rnf20, which prevents the development of Tr1 cells. Inhibition of Rnf20 resulted in the development of Tr1 cells from CD4+ CD25- T cells in UC patients. CONCLUSIONS: The synergistic effects of ER stress and MNP interfere with the development of Tr1 cells. The development of Tr1 from CD4+ CD25- T cells in patients with UC is re-established by Rnf20 inhibition.


Asunto(s)
Colitis Ulcerosa , Humanos , Colitis Ulcerosa/patología , Linfocitos T Reguladores
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