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1.
J Transl Med ; 22(1): 176, 2024 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-38369466

RESUMO

BACKGROUND: The need for radiotherapy among the elderly rises with increasing life expectancy and a corresponding increase of elderly cancer patients. Radiation-induced skin injury is one of the most frequent adverse effects in radiotherapy patients, severely limiting their life quality. Re-epithelialization and collagen deposition have essential roles in the recovery of skin injuries induced by high doses of ionizing radiation. At the same time, radiation-induced senescent cells accumulate in irradiated tissues. However, the effects and mechanisms of senescent cells on re-epithelialization and collagen deposition in radiation-induced skin injury have not been fully elucidated. RESULTS: Here, we identified a role for a population of senescent cells expressing p16 in promoting re-epithelialization and collagen deposition in radiation-induced skin injury. Targeted ablation of p16+ senescent cells or treatment with Senolytics resulted in the disruption of collagen structure and the retardation of epidermal coverage. By analyzing a publicly available single-cell sequencing dataset, we identified fibroblasts as a major contributor to the promotion of re-epithelialization and collagen deposition in senescent cells. Notably, our analysis of publicly available transcriptome sequencing data highlighted IL-33 as a key senescence-associated secretory phenotype produced by senescent fibroblasts. Neutralizing IL-33 significantly impedes the healing process. Finally, we found that the effect of IL-33 was partly due to the modulation of macrophage polarization. CONCLUSIONS: In conclusion, our data suggested that senescent fibroblasts accumulated in radiation-induced skin injury sites participated in wound healing mainly by secreting IL-33. This secretion regulated the local immune microenvironment and macrophage polarization, thus emphasizing the importance of precise regulation of senescent cells in a phased manner.


Assuntos
Interleucina-33 , Lesões por Radiação , Humanos , Idoso , Interleucina-33/farmacologia , Pele , Colágeno/farmacologia , Fibroblastos , Macrófagos , Senescência Celular
2.
Int J Mol Sci ; 25(3)2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38339008

RESUMO

MCs are tissue-resident immune cells that strategically reside in barrier organs and respond effectively to a wide range of stimuli, such as IL-33, a mediator released upon epithelial damage. Adenosine triphosphate (ATP) accumulates at sites of tissue injury and is known to modulate MC activities. This study investigated how an inflammatory tissue environment rich in IL-33 modulates the ATP-mediated activation of MCs. Human primary MCs primed with IL-33 displayed a strongly increased response to ATP but not ADP. This resulted in increased degranulation, IL-8 release, and pERK1/2 signalling. Such effects are unique to IL-33 stimulation and not shared by the epithelial alarmin, TSLP. MC exposure to IL-33 also increased membrane expression of purinergic and ATP-binding P2X receptors. The use of selective P2X receptor inhibitors identified P2X7 receptor as the key mediator of the enhanced ATP-induced ERK1/2 signalling and degranulation in IL-33-primed MCs. Whilst the inhibition of P2X1 and P2X4 receptors had no effect on MC degranulation, inhibiting these receptors together with P2X7 resulted in further decreased MC-mediated degranulation. These data therefore point toward the potential mechanisms by which IL-33 contributes to the modulation of ATP-mediated activation in human MCs.


Assuntos
Degranulação Celular , Interleucina-33 , Receptores Purinérgicos P2X7 , Humanos , Trifosfato de Adenosina/farmacologia , Trifosfato de Adenosina/metabolismo , Degranulação Celular/genética , Degranulação Celular/fisiologia , Interleucina-33/farmacologia , Interleucina-33/metabolismo , Mastócitos/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Transdução de Sinais
3.
Am J Physiol Heart Circ Physiol ; 326(4): H1006-H1016, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38363211

RESUMO

Preeclampsia (PE), a leading cause of maternal/fetal morbidity and mortality, is a hypertensive pregnancy disorder with end-organ damage that manifests after 20 wk of gestation. PE is characterized by chronic immune activation and endothelial dysfunction. Clinical studies report reduced IL-33 signaling in PE. We use the Reduced Uterine Perfusion Pressure (RUPP) rat model, which mimics many PE characteristics including reduced IL-33, to identify mechanisms mediating PE pathophysiology. We hypothesized that IL-33 supplementation would improve blood pressure (BP), inflammation, and oxidative stress (ROS) during placental ischemia. We implanted intraperitoneal mini-osmotic pumps infusing recombinant rat IL-33 (1 µg/kg/day) into normal pregnant (NP) and RUPP rats from gestation day 14 to 19. We found that IL-33 supplementation in RUPP rats reduces maternal blood pressure and improves the uterine artery resistance index (UARI). In addition to physiological improvements, we found decreased circulating and placental cytolytic Natural Killer cells (cNKs) and decreased circulating, placental, and renal TH17s in IL-33-treated RUPP rats. cNK cell cytotoxic activity also decreased in IL-33-supplemented RUPP rats. Furthermore, renal ROS and placental preproendothelin-1 (PPET-1) decreased in RUPP rats treated with IL-33. These findings demonstrate a role for IL-33 in controlling vascular function and maternal BP during pregnancy by decreasing inflammation, renal ROS, and PPET-1 expression. These data suggest that IL-33 may have therapeutic potential in managing PE.NEW & NOTEWORTHY Though decreased IL-33 signaling has been clinically associated with PE, the mechanisms linking this signaling pathway to overall disease pathophysiology are not well understood. This study provides compelling evidence that mechanistically links reduced IL-33 with the inflammatory response and vascular dysfunction observed in response to placental ischemia, such as in PE. Data presented in this study submit the IL-33 signaling pathway as a possible therapeutic target for the treatment of PE.


Assuntos
Hipertensão , Interleucina-33 , Pré-Eclâmpsia , Artéria Uterina , Animais , Feminino , Gravidez , Ratos , Pressão Sanguínea/efeitos dos fármacos , Suplementos Nutricionais , Modelos Animais de Doenças , Hipertensão/tratamento farmacológico , Inflamação/metabolismo , Interleucina-33/farmacologia , Isquemia/metabolismo , Placenta/irrigação sanguínea , Pré-Eclâmpsia/tratamento farmacológico , Pré-Eclâmpsia/metabolismo , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Artéria Uterina/efeitos dos fármacos , Artéria Uterina/metabolismo
4.
mBio ; 15(3): e0333823, 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38376154

RESUMO

Innate lymphoid cells (ILCs) play a critical role in maintaining intestinal health in homeostatic and diseased conditions. During Clostridium difficile infection (CDI), IL-33 activates ILC2 to protect from colonic damage and mortality. The function of IL-33 and ILC is tightly regulated by the intestinal microbiota. We set out to determine the impact of antibiotic-induced disruption of the microbiome on ILC function. Our goal was to understand antibiotic-induced changes in ILC function on susceptibility to C. difficile colitis in a mouse model. We utilized high-throughput single-cell RNAseq to investigate the phenotypic features of colonic ILC at baseline, after antibiotic administration with or without IL-33 treatment. We identified a heterogeneous landscape of colonic ILCs with gene signatures of inflammatory, anti-inflammatory, migratory, progenitor, plastic, and antigen-presenting ILCs. Antibiotic treatment decreased ILC2 while coordinately increasing ILC1 and ILC3 phenotypes. Notably, Ifng+, Ccl5+, and Il23r+ ILC increased after antibiotics. IL-33 treatment counteracted the antibiotic effect by downregulating ILC1 and ILC3 and activating ILC2. In addition, IL-33 treatment markedly induced the expression of type 2 genes, including Areg and Il5. Finally, we identified amphiregulin, produced by ILC2, as protective during C. difficile infection. Together, our data expand our understanding of how antibiotics induce susceptibility to C. difficile colitis through their impact on ILC subsets and function.IMPORTANCEClostridium difficile infection (CDI) accounts for around 500,000 symptomatic cases and over 20,000 deaths annually in the United States alone. A major risk factor of CDI is antibiotic-induced dysbiosis of the gut. Microbiota-regulated IL-33 and innate lymphoid cells (ILCs) are important in determining the outcomes of C. difficile infection. Understanding how antibiotic and IL-33 treatment alter the phenotype of colon ILCs is important to identify potential therapeutics. Here, we performed single-cell RNAseq of mouse colon ILCs collected at baseline, after antibiotic treatment, and after IL-33 treatment. We identified heterogeneous subpopulations of all three ILC subtypes in the mouse colon. Our analysis revealed several potential pathways of antibiotic-mediated increased susceptibility to intestinal infection. Our discovery that Areg is abundantly expressed by ILCs, and the protection of mice from CDI by amphiregulin treatment, suggests that the amphiregulin-epidermal growth factor receptor pathway is a potential therapeutic target for treating intestinal colitis.


Assuntos
Clostridioides difficile , Infecções por Clostridium , Colite , Enterocolite Pseudomembranosa , Camundongos , Animais , Imunidade Inata , Linfócitos , Antibacterianos/farmacologia , Interleucina-33/metabolismo , Interleucina-33/farmacologia , Anfirregulina/metabolismo , Anfirregulina/farmacologia , Disbiose , Infecções por Clostridium/metabolismo
5.
Neurochem Int ; 172: 105645, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38016520

RESUMO

Our prior investigations have demonstrated the pivotal role of IL-33 in facilitating the maturation of oligodendrocytes (OLs), prompting our interest in exploring its potential therapeutic effects. In this study, our focus was directed towards deciphering the functions of interleukin-33 (IL-33) in established demyelinating mouse model induced by the feeding of cuprizone (CPZ)-containing diet. We observed the reduction in corpus callosal adenomatous polyposis coli (APC)+ OLs with IL-33 expression in mice subjected to CPZ feeding for durations of 6 and 8 weeks. In parallel, the levels of IL-33 in the corpus callosum declined after CPZ-containing diet. Furthermore, we conducted experiments utilizing primary oligodendrocyte precursor cells (OPCs) and mature OLs, which were exposed to CPZ. A decrease in the expression of myelin basic protein (MBP) was evident in the cultures of mature OLs after treatment with CPZ. Additionally, both IL-33 mRNA and protein levels exhibited downregulation. To counteract the diminished IL-33 levels induced by CPZ, we employed a lentiviral vector to overexpress IL-33 in OLs. Intriguingly, the overexpression of IL-33 (IL33OE) in OLs resulted in a more distinct membranous morphology following CPZ treatment when compared to that observed in OL Mock cultures. Moreover, MBP protein levels in the presence of CPZ were higher in IL33OE OLs than that detected in OL Mock cultures. These findings collectively indicate that IL-33 possesses the capability to mitigate CPZ-induced damage and bolster OL homeostasis. In summary, our study underscores the importance of IL-33 in the context of demyelinating diseases, shedding light on its potential therapeutic implications for fostering remyelination and preserving OL function.


Assuntos
Cuprizona , Doenças Desmielinizantes , Interleucina-33 , Animais , Camundongos , Corpo Caloso , Cuprizona/toxicidade , Doenças Desmielinizantes/tratamento farmacológico , Modelos Animais de Doenças , Interleucina-33/metabolismo , Interleucina-33/farmacologia , Interleucina-33/uso terapêutico , Camundongos Endogâmicos C57BL , Bainha de Mielina , Oligodendroglia
6.
BMC Nephrol ; 24(1): 361, 2023 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-38053041

RESUMO

OBJECTIVE: Diabetic nephropathy (DN) is a serious chronic complication of diabetes mellitus (DM). Endoplasmic reticulum (ER) stress is an important factor in the regulation of pathological processes in DN, and excessive ER stress can lead to apoptosis. Although the IL-33/ST2 axis is known to be involved in diabetic kidney disease or related nephropathy, its role and molecular mechanisms remain poorly understood in terms of DN. The purpose of this study was to investigate the effects of IL-33/ST2 signaling on DN and to characterize the roles that ER stress and apoptosis play in DN. METHODS: To investigate this study, mice were randomly assigned into DN (induced by 0.1% STZ) and Control groups. Biochemical indices (FBG, BUN, UPR, UCE) were measured in serum and urine samples to reflect blood glucose and kidney damage. Quantitative real-time PCR, western blot, and immunofluorescence were used to assess gene and protein expression of the IL-33/ST2 axis and ER stress relative signaling molecule. Apoptosis was analyzed by flow cytometry. RESULTS: IL-33 levels are significantly increased in the kidneys of patients and mice with DN. Double immunofluorescence staining showed that IL-33 colocalized with CD31-positive endothelial cells. Treatment with IL-33 attenuated kidney injury in Streptozotocin (STZ)-treated mice. In vitro, we showed that IL-33 attenuated ER stress and apoptosis in glomerular endothelial cells. However, sST2 treatment significantly reversed these effects of IL-33. CONCLUSION: Together, these data suggest that IL-33/ST2 signaling mitigates STZ-induced renal damage, partly at least, by suppressing ER stress and apoptosis. Therefore, IL-33 may be an effective therapeutic target in DN.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Ratos , Humanos , Camundongos , Animais , Nefropatias Diabéticas/patologia , Células Endoteliais/metabolismo , Interleucina-33/farmacologia , Interleucina-33/uso terapêutico , Proteína 1 Semelhante a Receptor de Interleucina-1 , Ratos Sprague-Dawley , Diabetes Mellitus Experimental/metabolismo , Estresse do Retículo Endoplasmático , Apoptose
7.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 39(12): 1094-1099, 2023 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-38140869

RESUMO

Objective To investigate the effect of calcitonin gene-related peptide (CGRP) on the regulation of group 2 innate lymphoid cells (ILC2) in the peripheral blood of patients with allergic rhinitis (AR). Methods Peripheral blood mononuclear cells (PBMCs) were extracted from normal healthy individuals and AR patients, then stimulated with CGRP, interleukin 33 (IL-33) and CGRP combined with IL-33 for 3 days, with blank stimulus as control. The percentage of ILC2 in the four groups was measured by flow cytometry. After being sorted, ILC2 was given to CGRP, IL-33 and CGRP combined with IL-33 stimulation for 3 days, with blank stimulus as control. The percentage of IL-5 and IL-13 positive cells in ILC2 was detected by flow cytometry, and the levels of IL-5 and IL-13 in ILC2 supernatant were measured by ELISA. Results The percentage of ILC2 in the peripheral blood of AR patients was significantly higher than that of the control group. The levels of IL-5+ILC2 and IL-13+ILC2 were significantly increased by IL-33 single stimulation after culturing PBMCs. After adding IL-33 combined with CGRP stimulation, the levels of IL-5+ILC2 and IL-13+ILC2 in PBMCs were significantly reduced; after CGRP single stimulation, the levels of IL-5+ILC2 and IL-13+ILC2 in PBMCs were further decreased. After ILC2 was sorted and cultured, the levels of IL-5+ILC2 and IL-13+ILC2 showed significant increase after IL-33 single stimulation. The levels of IL-5+ILC2 and IL-13+ILC2 were decreased by IL-33 and CGRP co-stimulation, and they were further reduced after CGRP single stimulation. Compared to IL-33 single stimulation, IL-5 and IL-13 levels dropped significantly due to the IL-33 and CGRP co-stimulation. The levels of IL-5 and IL-13 were further reduced by CGRP single stimulation. Conclusion CGRP inhibits the proliferation and activation of peripheral blood ILC2 in AR and exert anti-inflammatory effects in AR.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina , Rinite Alérgica , Humanos , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Leucócitos Mononucleares , Imunidade Inata , Interleucina-33/farmacologia , Interleucina-13 , Linfócitos , Interleucina-5/farmacologia , Proliferação de Células
8.
J Neuroinflammation ; 20(1): 264, 2023 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-37968698

RESUMO

BACKGROUND: Lipid metabolism has a crucial role in neural repair in neurodegenerative diseases. We recently revealed that lipogenesis-mediated interleukin-33 (IL-33) upregulation lead to blood-brain barrier (BBB) repair after ischemic stroke. However, manipulating the key enzyme fatty acid synthase (FASN) to enhance lipogenesis was very challenging. Glyceryl triacetate (GTA) was used as a donor of acetate and precursor of acetyl coenzyme A, the key substrate for de novo lipogenesis catalyzed by FASN. Therefore, we hypothesized that GTA would promote lipogenesis the peri-infarct after ischemic stroke and contribute to the BBB repair through IL-33. METHODS: Middle cerebral artery occlusion (MCAO) was performed on C57BL mice and GTA was gavage administrated (4 g/kg) on day 2 and 4 after MCAO. Lipogenesis was evaluated by assessment of the protein level of FASN, lipid droplets, and fatty acid products through liquid chromatography-mass spectrometry in the peri-infarct area on day 3 after MCAO, respectively. BBB permeability was determined by extravasation of Evans blue, IgG and dextran, and levels of tight junction proteins in the peri-infarct area on day 7 after MCAO, respectively. Infarct size and neurological defects were assessed on day 7 after MCAO. Brain atrophy on day 30 and long-term sensorimotor abilities after MCAO were analyzed as well. The inhibitor of FASN, C75 and the virus-delivered FASN shRNA were used to evaluate the role of FASN-driven lipogenesis in GTA-improved BBB repair. Finally, the therapeutic potential of recombinant IL-33 on BBB repair and neurological recovery was evaluated. RESULTS: We found that treatment with GTA increased the lipogenesis as evidenced by lipid droplets level and lauric acid content, but not the FASN protein level. Treatment with GTA increased the IL-33 level in the peri-infarct area and decreased the BBB permeability after MCAO. However, infarct size and neurological defect score were unchanged on day 7 after MCAO, while the long-term recovery of sensorimotor function and brain atrophy were improved by GTA. Inhibition of lipogenesis using C75 or FASN shRNA reversed the beneficial effect of GTA. Finally, exogenous IL-33 improved BBB repair and long-term functional recovery after stroke. CONCLUSION: Collectively, we concluded that treatment with GTA improved the BBB repair and functional recovery after ischemic stroke, probably by the enhancement of lipogenesis and IL-33 expression.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Camundongos , Animais , AVC Isquêmico/patologia , Barreira Hematoencefálica , Interleucina-33/farmacologia , Lipogênese , Camundongos Endogâmicos C57BL , Acidente Vascular Cerebral/patologia , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/patologia , RNA Interferente Pequeno/metabolismo , Atrofia/patologia , Isquemia Encefálica/metabolismo
9.
Endocrinology ; 165(1)2023 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-37972259

RESUMO

Interleukin 33 (IL-33) signaling regulates most of the key processes of pregnancy, including decidualization, trophoblast proliferation and invasion, vascular remodeling, and placental growth. Accordingly, dysregulation of IL-33, its membrane-bound receptor (ST2L, transducer of IL-33 signaling), and its soluble decoy receptor (sST2, inhibitor of IL-33 signaling) has been linked to a wide range of adverse pregnancy outcomes that are common in women with obesity and polycystic ovary syndrome, that is, conditions associated with hyperandrogenism, insulin resistance, and compensatory hyperinsulinemia. To reveal if androgens and insulin might modulate uteroplacental IL-33 signaling, we investigated the effect of dihydrotestosterone (DHT) and/or insulin on the expression of ST2L and sST2 (along with the activity of their promoter regions), IL-33 and sIL1RAP (heterodimerization partner of sST2), during in vitro decidualization of endometrial stromal cells from 9 healthy women. DHT and insulin markedly upregulated sST2 secretion, in addition to the upregulation of its messenger RNA (mRNA) expression, while the proximal ST2 promoter, from which the sST2 transcript originates, was upregulated by insulin, and in a synergistic manner by DHT and insulin combination treatment. On the other hand, sIL1RAP was slightly downregulated by insulin and IL-33 mRNA expression was not affected by any of the hormones, while ST2L mRNA expression and transcription from its promoter region (distal ST2 promoter) could not be detected or showed a negligibly low level. We hypothesize that high levels of androgens and insulin might lead to subfertility and pregnancy complications, at least partially, through the sST2-dependent downregulation of uteroplacental IL-33 signaling.


Assuntos
Insulina , Interleucina-33 , Humanos , Feminino , Gravidez , Interleucina-33/genética , Interleucina-33/metabolismo , Interleucina-33/farmacologia , Insulina/farmacologia , Di-Hidrotestosterona/farmacologia , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Transdução de Sinais , Placenta/metabolismo , Androgênios/farmacologia , RNA Mensageiro , Células Estromais/metabolismo
10.
Int J Mol Sci ; 24(19)2023 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-37834290

RESUMO

The differentiation and function of osteocytes are controlled by surrounding cells and mechanical stress; however, the detailed mechanisms are unknown. Recent findings suggest that IL-33 is highly expressed in periodontal tissues in orthodontic tooth movement. The present study aimed to elucidate the effect of IL-33 on the expression of regulatory factors for bone remodeling and their molecular mechanisms in the osteocyte-like cell line MLO-Y4. MLO-Y4 cells were treated with IL-33, and the activation of intracellular signaling molecules and transcriptional factors was determined using Western blot analysis and chromatin immunoprecipitation assay. IL-33 treatment enhanced the expression of IL-6 in MLO-Y4 cells, which was suppressed by the knockdown of the IL-33 receptor ST2L. Additionally, IL-33 treatment induced activation of NF-κB, JNK/AP-1, and p38 MAPK signaling pathways in MLO-Y4 cells. Moreover, pretreatment with specific inhibitors of NF-κB, p38 MAPK, and JNK/AP-1 attenuated the IL-33-induced expression of IL-6. Furthermore, chromatin immunoprecipitation indicated that IL-33 increased c-Jun recruitment to the IL-6 promoter. Overall, these results suggest that IL-33 induces IL-6 expression and regulates osteocyte function via activation of the NF-κB, JNK/AP-1, and p38 MAPK pathways through interaction with ST2L receptors on the plasma membrane.


Assuntos
Interleucina-6 , NF-kappa B , NF-kappa B/metabolismo , Interleucina-6/metabolismo , Interleucina-33/farmacologia , Interleucina-33/metabolismo , Fator de Transcrição AP-1/metabolismo , Proteínas de Transporte/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Osteócitos/metabolismo
11.
Int J Mol Sci ; 24(15)2023 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-37569890

RESUMO

Fallopia japonica (Asian knotweed) is a medicinal herb traditionally used to treat inflammation, among other conditions. However, the effects of F. japonica root extract (FJE) on airway inflammation associated with combined allergic rhinitis and asthma (CARAS) and the related mechanisms have not been investigated. This study examined the effect of FJE against CARAS in an ovalbumin (OVA)-induced CARAS mouse model. Six-week-old male BALB/c mice were randomly segregated into six groups. Mice were sensitized intraperitoneally with OVA on days 1, 8, and 15, and administered saline, Dexamethasone (1.5 mg/kg), or FJE (50, 100, or 200 mg/kg) once a day for 16 days. Nasal symptoms, inflammatory cells, OVA-specific immunoglobulins, cytokine production, mast cell activation, and nasal histopathology were assessed. Administration of FJE down-regulated OVA-specific IgE and up-regulated OVA-specific IgG2a in serum. FJE reduced the production of T helper (Th) type 2 cytokines, and the Th1 cytokine levels were enhanced in nasal and bronchoalveolar lavage fluid. Moreover, FJE positively regulated allergic responses by reducing the accumulation of inflammatory cells, improving nasal and lung histopathological characteristics, and inhibiting inflammation-associated cytokines. FJE positively modulated the IL-33/TSLP/NF-B signaling pathway, which is involved in regulating inflammatory cells, immunoglobulin levels, and pro-inflammatory cytokines at the molecular level.


Assuntos
Asma , Fallopia japonica , Rinite Alérgica , Animais , Masculino , Camundongos , Asma/induzido quimicamente , Asma/tratamento farmacológico , Asma/metabolismo , Líquido da Lavagem Broncoalveolar , Citocinas/metabolismo , Modelos Animais de Doenças , Fallopia japonica/química , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-33/farmacologia , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Ovalbumina , Rinite Alérgica/metabolismo , Transdução de Sinais
12.
Curr Eye Res ; 48(12): 1100-1111, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37615401

RESUMO

PURPOSE: To characterize the in vivo effects of Dermatophagoides pteronyssinus 1 (DerP1) in mice and determine the underlying NLRP3 inflammasome-mediated pyroptosis signaling mechanisms in the human corneal epithelial cells (HCECs). METHODS: DerP1 was used to induce allergic conjunctivitis in C57 mice. HCECs were sensitized with DerP1 in vitro to mimic their condition observed in allergic conjunctivitis in vivo. Transmission electron microscopy was used to evaluate pyroptosis in the HCECs, enzyme-linked immunosorbent assays to assess interleukin (IL)-33, IL-1ß and IL-4 levels, flow cytometry to detect the proportion of Th2 cells, MTT assays to assess cell metabolic activity, immunofluorescence to evaluate the effects of DerP1 on functional HCEC phenotypes, and Western blot assays to detect the expression of NOD-like receptor family pyrin domain-containing 3 (NLRP3), gasdermin D (GSDMD), N-terminal fragment of GSDMD (GSDMD-N), pro-caspase-1, cleaved caspase-1, IL-1ß, and IL-33. IL-33 expression in the HCECs was knocked down via lentivirus transfection. RESULTS: In vivo, DerP1 promotes pyroptosis, production of Th2 inflammatory cytokines and IL-33, and NLRP3 activation in mouse corneas. In vitro, pyroptotic bodies were found in the HCECs after sensitization with DerP1. Various concentrations of DerP1 increased the expression levels of NLRP3, GSDMD, GSDMD-N, pro-caspase-1, cleaved caspase-1, and IL-1ß in the HCECs, with the largest increase observed after exposure to 20 µM DerP1. In vitro, recombinant human IL-33 mediated the expression of pyroptotic biomarkers in the HCECs, whereas IL-33 silencing diminished 20 µM DerP1-induced increase in their expression levels. CONCLUSIONS: DerP1 induces pyroptosis and allergic conjunctivitis, the expression of Th2 inflammatory cytokines, NLRP3 activation, and IL-33 in mouse corneas in our model. These effects would attribute to its activating NLRP3-GSDMD signaling pathway axis via enhancing IL-33 expression in HCECs.


Assuntos
Conjuntivite Alérgica , Proteína 3 que Contém Domínio de Pirina da Família NLR , Camundongos , Humanos , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Interleucina-33/farmacologia , Dermatophagoides pteronyssinus/metabolismo , Piroptose/fisiologia , Caspase 1/metabolismo , Células Epiteliais/metabolismo , Citocinas
13.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 39(8): 693-700, 2023 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-37515335

RESUMO

Objective To investigate the effects and mechanism of Interleukin-33 (IL-33) mediated proliferation and differentiation of pulmonary myofibroblasts (MFbs) in pulmonary fibrosis (PF). Methods C57BL/6 mice were randomly divided into four groups: a control group, a bleomycin (BLM) group, a BLM combined with IL-33 group and a BLM combined with anti-IL-33 antibody group, 12 mice in each group. The PF model was induced by intratracheal injection of BLM (5000 U/kg). The degrees of fibrosis were examined using HE and Masson staining. ELISA was used to measure the plasma levels of IL-33. Immunohistochemical staining was used to measure the expression of alpha smooth muscle actin (α-SMA) in lung tissue. Primary pulmonary fibroblasts were isolated and cultured from lung tissues of mice. The cells were divided into four groups: a control group, an IL-33 group, an IL-33 combined with dimethyl sulfoxide (DMSO) group and an IL-33 combined with pyrrolidine dithiocarbamate (PDTC) group. The cells were treated with DMSO or PDTC for 1 hour and then with IL-33 for 48 hours. Cell proliferation was measured by 5-ethynyl-2'-deoxyuridine (EdU) assay and cell cycle was measured by flow cytometry. TranswellTM assay was used to analyze cell migration. Real-time quantitative PCR was used to measure the expression of collagen type I (Col1), Col3 and α-SMA mRNA. The protein levels of IL-33, Col1, Col3, α-SMA, eukaryotic initiation factor 3a (eIF3a), phosphorylated IκBα (p-IκBα) (total lysate), p-NF-κB p65(total lysate) and NF-κB p65 (nucleus) were measured by Western blot analysis. Results In vivo, compared with the control group, the expressions of IL-33, p-IκBα (total lysate), p-NF-κB p65 (total lysate), NF-κB p65(nucleus), eIF3a, α-SMA, Col1 and Col3 in the BLM group significantly increased. Compared with the BLM group, the expressions of p-IκBα (total lysate), p-NF-κB p65 (total lysate), NF-κB p65 (nucleus), eIF3a, α-SMA, Col1 and Col3 in the IL-33 group increased further and the PF was further aggravated. But the effect of anti-IL-33 antibody was just opposite to that of IL-33. In vitro, IL-33 markedly induced the proliferation and migration of pulmonary fibroblasts, and significantly up-regulated the expression of p-IκBα (total lysate), p-NF-κB p65(total lysate), NF-κB p65 (nucleus), eIF3a, α-SMA, Col1 and Col3. But all these effects of IL-33 were reversed by pyrrolidine dithiocarbamate. Conclusion The results suggest that IL-33 may promote the expression of eIF3a by activating NF-κB signaling pathway, thus inducing the proliferation and differentiation of MFbs and promoting the occurrence and development of PF.


Assuntos
Fibrose Pulmonar , Animais , Camundongos , Bleomicina/efeitos adversos , Bleomicina/metabolismo , Diferenciação Celular , Proliferação de Células , Dimetil Sulfóxido/farmacologia , Fibroblastos , Interleucina-33/metabolismo , Interleucina-33/farmacologia , Camundongos Endogâmicos C57BL , Miofibroblastos/metabolismo , NF-kappa B/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , Transdução de Sinais
14.
Hum Cell ; 36(5): 1689-1702, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37308740

RESUMO

The impact of volcanic airborne products on airway epithelium homeostasis is largely unknown. This study assessed the effects of volcanic Fumarole Condensates (FC) alone or combined with Cigarette Smoke Extracts (CSE) on airway epithelial cells (16HBE and A549). Chemical composition of FC was analyzed by gas chromatography and HPLC. Cells were exposed to FC and IL-33 and IL-8 were assessed. The effects of FC and CSE on cell injury were evaluated assessing cell metabolism/cell viability, mitochondrial stress, cell apoptosis/cell necrosis, and cell proliferation. FC contained: water vapor (70-97%), CO2 (3-30%), acid gases (H2S, SO2, HCl, HF) around 1%. FC increased the intracellular IL-33 but differently modulated IL-33 and IL-8 gene expression and IL-8 release in the tested cell lines. FC without/with CSE: (a) increased cell metabolism/cell viability in 16HBE, while decreased it in A549; (b) increased mitochondrial stress in both cell types. FC with CSE increased cell necrosis in A549 in comparison to CSE alone. CSE reduced cell proliferation in 16HB,E while increased it in A549 and FC counteracted these effects in both cell types. Overall, FC induce a pro-inflammatory profile associated to a metabolic reprogramming without a relevant toxicity also in presence of CSE in airway epithelial cells.


Assuntos
Fumar Cigarros , Interleucina-33 , Humanos , Interleucina-33/metabolismo , Interleucina-33/farmacologia , Interleucina-8/metabolismo , Células Epiteliais/metabolismo , Necrose/metabolismo
15.
Allergy ; 78(7): 1878-1892, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37163231

RESUMO

INTRODUCTION: Epidemiological studies demonstrated that cleaning work and frequent use of cleaning products are risk factors for asthma. Laundry detergents have been reported to have epithelial barrier-opening effects. However, whether laundry detergents directly induce airway inflammation and its mechanisms in vivo remain to be elucidated. METHODS: Two commercial laundry detergents and two commonly used surfactants for cleaning and cosmetics (sodium lauryl sulfate and sodium dodecyl benzene sulfonate) were intranasally administered to mice. Lungs were analyzed using flow cytometry, histology, ELISA, and quantitative PCR. Human bronchial epithelial cells were stimulated with laundry detergents and analyzed using quantitative PCR and western blotting. Involvement of oxidative stress was assessed using an antioxidant. Dust samples from homes were analyzed to determine their detergent content by measuring their critical micelle concentration (CMC). RESULTS: The administered laundry detergents and surfactants-induced eosinophilic airway inflammation accompanied by increased IL-33 expression and activation of group 2 innate lymphoid cells (ILC2s). Detergent-induced eosinophilic airway inflammation was significantly attenuated in Rag2-/- Il2rg-/- , Il33-/- mice, and also in wild-type mice treated with NAC. Detergent-induced IL-33 expression in airways was attenuated by NAC treatment, both in vivo and in vitro. CMCs were found in all of the tested dust extracts, and they differed significantly among the homes. CONCLUSION: The laundry detergents and surfactants-induced eosinophilic airway inflammation in vivo through epithelial cell and ILC2 activation. They induced IL-33 expression in airway epithelial cells through oxidative stress. Furthermore, detergent residues were present in house dust and are presumably inhaled into the airway in daily life.


Assuntos
Detergentes , Imunidade Inata , Humanos , Camundongos , Animais , Detergentes/efeitos adversos , Tensoativos/efeitos adversos , Linfócitos , Interleucina-33/farmacologia , Poeira , Inflamação
16.
Cell Stress Chaperones ; 28(4): 363-374, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37166618

RESUMO

Kawasaki disease (KD) is a form of idiopathic vasculitis frequently accompanied by coronary artery lesions, which involves endothelial dysfunction. Recent studies have demonstrated that circular RNAs (circRNAs) are implicated in many cardiovascular diseases. However, few studies have examined the role of circRNAs on endothelial dysfunction in KD. In this study, we investigated the role of circ7632 on endothelial-mesenchymal transition (EndoMT) in KD and then explored the underlying mechanism. Children diagnosed with KD and age-matched healthy controls (HC) were included. Sera samples were collected. Primary human umbilical vein endothelial cells (HUVECs) were obtained and incubated with 15% HC and KD serum for 48 h. The mRNA and protein expression of mesenchymal markers vimentin and α-smooth muscle actin (α-SMA) and endothelial marker zonula occludens-1 (ZO-1) in HUVECs transfected with plasmid-circ7632 and si-circ7632 were detected by RT-qPCR and Western blot analysis. CCK8, scratch test, and migration test were performed to examine the effect of circ7632 on the cell proliferation and migration. The circ7632 level was higher in HUVECs treated by KD serum than in HUVECs treated with HC serum. Overexpression of circ7632 significantly increased vimentin and α-SMA expression, decreased ZO-1 expression, and also decreased cell proliferation. Down-regulation of circ7632 expression got the opposite results. RNA-seq analysis, and confirmatory experiment displayed that down-regulation of circ7632 decreased IL-33 expression, and IL-33 silencing mitigated KD serum-mediated EndoMT. Our study revealed that circ7632 level was elevated in KD serum-treated HUVECs. Circ7632 down-regulation could alleviate EndoMT likely through decreasing IL-33 expression. The circ7632 may become a potential therapeutic target for KD.


Assuntos
Síndrome de Linfonodos Mucocutâneos , Criança , Humanos , Síndrome de Linfonodos Mucocutâneos/genética , Síndrome de Linfonodos Mucocutâneos/patologia , Vimentina/genética , Vimentina/metabolismo , Vimentina/farmacologia , Regulação para Baixo , Interleucina-33/genética , Interleucina-33/metabolismo , Interleucina-33/farmacologia , RNA Circular/genética , RNA Circular/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo
17.
Acta Neuropathol Commun ; 11(1): 61, 2023 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-37024941

RESUMO

The persistent dysregulation and accumulation of poisonous proteins from destructive neural tissues and cells activate pathological mechanisms after traumatic brain injury (TBI). The lymphatic drainage system of the brain, composed of the glymphatic system and meningeal lymphatic vessels (MLVs), plays an essential role in the clearance of toxic waste after brain injury. The neuroprotective effect of interleukin 33 (IL-33) in TBI mice has been demonstrated; however, its impact on brain lymphatic drainage is unclear. Here, we established a fluid percussion injury model to examine the IL-33 administration effects on neurological function and lymphatic drainage in the acute brain of TBI mice. We verified that exogenous IL-33 could improve the motor and memory skills of TBI mice and demonstrated that in the acute phase, it increased the exchange of cerebrospinal and interstitial fluid, reversed the dysregulation and depolarization of aquaporin-4 in the cortex and hippocampus, improved the drainage of MLVs to deep cervical lymph nodes, and reduced tau accumulation and glial activation. We speculate that the protective effect of exogenous IL-33 on TBI mice's motor and cognitive functions is related to the enhancement of brain lymphatic drainage and toxic metabolite clearance from the cortex and hippocampus in the acute stage. These data further support the notion that IL-33 therapy may be an effective treatment strategy for alleviating acute brain injury after TBI.


Assuntos
Lesões Encefálicas Traumáticas , Lesões Encefálicas , Interleucina-33 , Animais , Camundongos , Encéfalo/patologia , Lesões Encefálicas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Interleucina-33/farmacologia , Sistema Linfático/metabolismo
18.
Int J Mol Sci ; 24(6)2023 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-36982304

RESUMO

Receptor-interacting protein kinase (RIP) family 1 signaling has complex effects on inflammatory processes and cell death, but little is known concerning allergic skin diseases. We examined the role of RIP1 in Dermatophagoides farinae extract (DFE)-induced atopic dermatitis (AD)-like skin inflammation. RIP1 phosphorylation was increased in HKCs treated with DFE. Nectostatin-1, a selective and potent allosteric inhibitor of RIP1, inhibited AD-like skin inflammation and the expression of histamine, total IgE, DFE-specific IgE, IL-4, IL-5, and IL-13 in an AD-like mouse model. The expression of RIP1 was increased in ear skin tissue from a DFE-induced mouse model with AD-like skin lesions and in the lesional skin of AD patients with high house dust mite sensitization. The expression of IL-33 was down-regulated after RIP1 inhibition, and the levels of IL-33 were increased by over-expression of RIP1 in keratinocytes stimulated with DFE. Nectostatin-1 reduced IL-33 expression in vitro and in the DFE-induced mouse model. These results suggest that RIP1 can be one of the mediators that regulate IL-33-mediated atopic skin inflammation by house dust mites.


Assuntos
Dermatite Atópica , Animais , Camundongos , Antígenos de Dermatophagoides , Citocinas/farmacologia , Dermatite Atópica/patologia , Dermatophagoides farinae , Modelos Animais de Doenças , Imunoglobulina E , Inflamação/patologia , Interleucina-33/farmacologia , Extratos Vegetais/farmacologia , Pyroglyphidae , Pele/patologia
19.
Am J Physiol Regul Integr Comp Physiol ; 324(4): R556-R567, 2023 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-36847598

RESUMO

Preeclampsia (PE) is a pregnancy-specific hypertensive disorder with end-organ damage that presents after 20 wk of gestation. PE pathophysiology often includes vascular dysfunction and increased inflammation that continues to damage patient health even after PE resolves. Currently, there is no cure for PE beyond delivery of the fetal-placental unit. Previous clinical studies have identified elevated placental NLRP3 expression in patients with PE and suggest NLRP3 as a potential therapeutic target. In this study, we examined the effect of NLRP3 inhibition on PE pathophysiology in the reduced uterine perfusion pressure (RUPP) model rat using MCC950 (20 mg/kg/day) or esomeprazole (3.5 mg/kg/day). We hypothesized that increased NLRP3 in response to placental ischemia impairs anti-inflammatory IL-33 signaling to induce T-helper 17 cell (TH17) and cytolytic NK cell (cNK) activation, which is known to mediate oxidative stress and vascular dysfunction leading to maternal HTN and intrauterine growth restriction. RUPP rats had significantly higher placental NLRP3 expression, maternal blood pressure, fetal reabsorption rate, vascular resistance, oxidative stress, cNKs and TH17s, and decreased IL-33 compared with normal pregnant (NP) rats. NLRP3 inhibition, with either treatment, significantly reduced placental NLRP3 expression, maternal blood pressure, fetal reabsorption rates, vascular resistance, oxidative stress, cNK, and TH17 populations in RUPP rats. Based on our findings, NLRP3 inhibition reduces PE pathophysiology and esomeprazole may be a potential therapeutic for PE treatment.


Assuntos
Hipertensão , Pré-Eclâmpsia , Humanos , Gravidez , Ratos , Feminino , Animais , Placenta/metabolismo , Interleucina-33/metabolismo , Interleucina-33/farmacologia , Interleucina-33/uso terapêutico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Esomeprazol/metabolismo , Esomeprazol/farmacologia , Esomeprazol/uso terapêutico , Ratos Sprague-Dawley , Pressão Sanguínea , Isquemia , Inflamação/metabolismo
20.
Allergy ; 78(5): 1292-1306, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36609802

RESUMO

BACKGROUND: Staphylococcus (S) aureus colonization is known to cause skin barrier disruption in atopic dermatitis (AD) patients. However, it has not been studied how S. aureus induces aberrant epidermal lipid composition and skin barrier dysfunction. METHODS: Skin tape strips (STS) and swabs were obtained from 24 children with AD (6.0 ± 4.4 years) and 16 healthy children (7.0 ± 4.5 years). Lipidomic analysis of STS samples was performed by mass spectrometry. Skin levels of methicillin-sensitive and methicillin-resistant S. aureus (MSSA and MRSA) were evaluated. The effects of MSSA and MRSA were evaluated in primary human keratinocytes (HEKs) and organotypic skin cultures. RESULTS: AD and organotypic skin colonized with MRSA significantly increased the proportion of lipid species with nonhydroxy fatty acid sphingosine ceramide with palmitic acid ([N-16:0 NS-CER], sphingomyelins [16:0-18:0 SM]), and lysophosphatidylcholines [16:0-18:0 LPC], but significantly reduced the proportion of corresponding very long-chain fatty acids (VLCFAs) species (C22-28) compared to the skin without S. aureus colonization. Significantly increased transepidermal water loss (TEWL) was found in MRSA-colonized AD skin. S. aureus indirectly through interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, IL-6, and IL-33 inhibited expression of fatty acid elongase enzymes (ELOVL3 and ELOVL4) in HEKs. ELOVL inhibition was more pronounced by MRSA and resulted in TEWL increase in organotypic skin. CONCLUSION: Aberrant skin lipid profiles and barrier dysfunction are associated with S. aureus colonization in AD patients. These effects are attributed to the inhibition of ELOVLs by S. aureus-induced IL-1ß, TNF-α, IL-6, and IL-33 seen in keratinocyte models and are more prominent in MRSA than MSSA.


Assuntos
Dermatite Atópica , Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Criança , Humanos , Staphylococcus aureus , Interleucina-33/farmacologia , Interleucina-6 , Dermatite Atópica/patologia , Lipídeos
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