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1.
Nat Commun ; 11(1): 4997, 2020 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-33020472

RESUMO

Despite a deeper molecular understanding, human glioblastoma remains one of the most treatment refractory and fatal cancers. It is known that the presence of macrophages and microglia impact glioblastoma tumorigenesis and prevent durable response. Herein we identify the dual function cytokine IL-33 as an orchestrator of the glioblastoma microenvironment that contributes to tumorigenesis. We find that IL-33 expression in a large subset of human glioma specimens and murine models correlates with increased tumor-associated macrophages/monocytes/microglia. In addition, nuclear and secreted functions of IL-33 regulate chemokines that collectively recruit and activate circulating and resident innate immune cells creating a pro-tumorigenic environment. Conversely, loss of nuclear IL-33 cripples recruitment, dramatically suppresses glioma growth, and increases survival. Our data supports the paradigm that recruitment and activation of immune cells, when instructed appropriately, offer a therapeutic strategy that switches the focus from the cancer cell alone to one that includes the normal host environment.


Assuntos
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Glioma/metabolismo , Glioma/patologia , Interleucina-33/metabolismo , Animais , Neoplasias Encefálicas/mortalidade , Carcinogênese , Núcleo Celular/metabolismo , Citocinas/metabolismo , Glioblastoma/metabolismo , Glioblastoma/mortalidade , Glioblastoma/patologia , Glioma/mortalidade , Humanos , Inflamação , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Camundongos SCID , Microglia , Análise de Sobrevida , Linfócitos T/metabolismo , Linfócitos T/patologia , Microambiente Tumoral/imunologia
2.
Nat Commun ; 11(1): 4786, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32963227

RESUMO

Evidence points to an indispensable function of macrophages in tissue regeneration, yet the underlying molecular mechanisms remain elusive. Here we demonstrate a protective function for the IL-33-ST2 axis in bronchial epithelial repair, and implicate ST2 in myeloid cell differentiation. ST2 deficiency in mice leads to reduced lung myeloid cell infiltration, abnormal alternatively activated macrophage (AAM) function, and impaired epithelial repair post naphthalene-induced injury. Reconstitution of wild type (WT) AAMs to ST2-deficient mice completely restores bronchial re-epithelialization. Central to this mechanism is the direct effect of IL-33-ST2 signaling on monocyte/macrophage differentiation, self-renewal and repairing ability, as evidenced by the downregulation of key pathways regulating myeloid cell cycle, maturation and regenerative function of the epithelial niche in ST2-/- mice. Thus, the IL-33-ST2 axis controls epithelial niche regeneration by activating a large multi-cellular circuit, including monocyte differentiation into competent repairing AAMs, as well as group-2 innate lymphoid cell (ILC2)-mediated AAM activation.


Assuntos
Bronquíolos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Células Epiteliais/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-33/metabolismo , Interleucina-33/farmacologia , Animais , Bronquíolos/lesões , Bronquíolos/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Células Epiteliais/patologia , Feminino , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Pulmão/patologia , Ativação Linfocitária , Linfócitos/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais
3.
Nat Commun ; 11(1): 4718, 2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32948777

RESUMO

Disturbances in glucose homeostasis and low-grade chronic inflammation culminate into metabolic syndrome that increase the risk for the development of type 2 diabetes mellitus (T2DM). The recently discovered group 2 innate lymphoid cells (ILC2s) are capable of secreting copious amounts of type 2 cytokines to modulate metabolic homeostasis in adipose tissue. In this study, we have established that expression of Death Receptor 3 (DR3), a member of the TNF superfamily, on visceral adipose tissue (VAT)-derived murine and peripheral blood human ILC2s is inducible by IL-33. We demonstrate that DR3 engages the canonical and/or non-canonical NF-κB pathways, and thus stimulates naïve and co-stimulates IL-33-activated ILC2s. Importantly, DR3 engagement on ILC2s significantly ameliorates glucose tolerance, protects against insulin-resistance onset and remarkably reverses already established insulin-resistance. Taken together, these results convey the potent role of DR3 as an ILC2 regulator and introduce DR3 agonistic treatment as a novel therapeutic avenue for treating T2DM.


Assuntos
Tecido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Linfócitos/metabolismo , Membro 25 de Receptores de Fatores de Necrose Tumoral/metabolismo , Adipócitos/metabolismo , Adolescente , Adulto , Idoso , Animais , Citocinas/metabolismo , Proteínas de Ligação a DNA/genética , Feminino , Glucose/metabolismo , Homeostase , Humanos , Imunidade Inata , Resistência à Insulina , Interleucina-33/metabolismo , Gordura Intra-Abdominal/metabolismo , Masculino , Síndrome Metabólica/complicações , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Membro 25 de Receptores de Fatores de Necrose Tumoral/uso terapêutico , Adulto Jovem
4.
Nat Commun ; 11(1): 3998, 2020 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-32778730

RESUMO

Allergic asthma is a leading chronic disease associated with airway hyperreactivity (AHR). Type-2 innate lymphoid cells (ILC2s) are a potent source of T-helper 2 (Th2) cytokines that promote AHR and lung inflammation. As the programmed cell death protein-1 (PD-1) inhibitory axis regulates a variety of immune responses, here we investigate PD-1 function in pulmonary ILC2s during IL-33-induced airway inflammation. PD-1 limits the viability of ILC2s and downregulates their effector functions. Additionally, PD-1 deficiency shifts ILC2 metabolism toward glycolysis, glutaminolysis and methionine catabolism. PD-1 thus acts as a metabolic checkpoint in ILC2s, affecting cellular activation and proliferation. As the blockade of PD-1 exacerbates AHR, we also develop a human PD-1 agonist and show that it can ameliorate AHR and suppresses lung inflammation in a humanized mouse model. Together, these results highlight the importance of PD-1 agonistic treatment in allergic asthma and underscore its therapeutic potential.


Assuntos
Asma/imunologia , Asma/metabolismo , Imunidade Inata/imunologia , Linfócitos/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Animais , Citocinas/metabolismo , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Humanos , Inflamação/imunologia , Subunidade gama Comum de Receptores de Interleucina/genética , Interleucina-33/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Receptor de Morte Celular Programada 1/genética , Células Th2/metabolismo , Transcriptoma
5.
PLoS One ; 15(7): e0236744, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32730309

RESUMO

Repeated exposures to environmental allergens in susceptible individuals drive the development of type 2 inflammatory conditions such as asthma, which have been traditionally considered to be mainly mediated by Th2 cells. However, emerging evidence suggest that a new innate cell type, group 2 innate lymphoid cells (ILC2), plays a central role in initiating and amplifying a type 2 response, even in the absence of adaptive immunity. At present, the regulatory mechanisms for controlling ILC2 activation remain poorly understood. Here we report that respiratory delivery of immunogenic extracellular RNA (exRNAs) derived from RNA- and DNA-virus infected cells, was able to activate a protective response against acute type 2 lung immunopathology and airway hyperresponsiveness (AHR) induced by IL-33 and a fungal allergen, A. flavus, in mice. Mechanistically, we found that the innate immune responses triggered by exRNAs had a potent suppressive effect in vivo on the proliferation and function of ILC2 without the involvement of adaptive immunity. We further provided the loss-of-function genetic evidence that the TLR3- and MAVS-mediated signaling axis is essential for the inhibitory effects of exRNAs in mouse lungs. Thus, our results indicate that the host detection of extracellular immunostimulatory RNAs generated during respiratory viral infections have an important function in the regulation of ILC2-driven acute lung inflammation.


Assuntos
Armadilhas Extracelulares/imunologia , Imunidade Inata/imunologia , Linfócitos/imunologia , Pneumonia/imunologia , RNA/imunologia , Hipersensibilidade Respiratória/imunologia , Imunidade Adaptativa , Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Proteínas Adaptadoras de Transporte Vesicular/fisiologia , Alérgenos/imunologia , Alérgenos/metabolismo , Animais , Citocinas/metabolismo , Armadilhas Extracelulares/metabolismo , Interleucina-33/imunologia , Interleucina-33/metabolismo , Linfócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pneumonia/metabolismo , Pneumonia/patologia , RNA/metabolismo , Hipersensibilidade Respiratória/metabolismo , Hipersensibilidade Respiratória/patologia , Transdução de Sinais , Células Th2/imunologia , Células Th2/metabolismo , Receptor 3 Toll-Like/fisiologia
6.
Science ; 369(6501)2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32675345

RESUMO

Targeting the cross-talk between tumor-initiating cells (TICs) and the niche microenvironment is an attractive avenue for cancer therapy. We show here, using a mouse model of squamous cell carcinoma, that TICs play a crucial role in creating a niche microenvironment that is required for tumor progression and drug resistance. Antioxidant activity in TICs, mediated by the transcription factor NRF2, facilitates the release of a nuclear cytokine, interleukin-33 (IL-33). This cytokine promotes differentiation of macrophages that express the high-affinity immunoglobulin E receptor FcεRIα and are in close proximity to TICs. In turn, these IL-33-responding FcεRIα+ macrophages send paracrine transforming growth factor ß (TGF-ß) signals to TICs, inducing invasive and drug-resistant properties and further upregulating IL-33 expression. This TIC-driven, IL-33-TGF-ß feedforward loop could potentially be exploited for cancer treatment.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Interleucina-33/metabolismo , Células-Tronco Neoplásicas/patologia , Fator de Crescimento Transformador beta/metabolismo , Animais , Progressão da Doença , Humanos , Células-Tronco Neoplásicas/metabolismo , Transdução de Sinais , Microambiente Tumoral
7.
Nat Immunol ; 21(7): 756-765, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32572240

RESUMO

The molecular basis for the propensity of a small number of environmental proteins to provoke allergic responses is largely unknown. Herein, we report that mite group 13 allergens of the fatty acid-binding protein (FABP) family are sensed by an evolutionarily conserved acute-phase protein, serum amyloid A1 (SAA1), that promotes pulmonary type 2 immunity. Mechanistically, SAA1 interacted directly with allergenic mite FABPs (Der p 13 and Blo t 13). The interaction between mite FABPs and SAA1 activated the SAA1-binding receptor, formyl peptide receptor 2 (FPR2), which drove the epithelial release of the type-2-promoting cytokine interleukin (IL)-33 in a SAA1-dependent manner. Importantly, the SAA1-FPR2-IL-33 axis was upregulated in nasal epithelial cells from patients with chronic rhinosinusitis. These findings identify an unrecognized role for SAA1 as a soluble pattern recognition receptor for conserved FABPs found in common mite allergens that initiate type 2 immunity at mucosal surfaces.


Assuntos
Asma/imunologia , Rinite Alérgica/imunologia , Proteína Amiloide A Sérica/metabolismo , Transdução de Sinais/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alérgenos/imunologia , Animais , Antígenos de Dermatophagoides/imunologia , Asma/patologia , Células Cultivadas , Modelos Animais de Doenças , Células Epiteliais , Proteínas de Ligação a Ácido Graxo/imunologia , Feminino , Humanos , Imunidade Humoral , Imunidade Inata , Interleucina-33/metabolismo , Pulmão/citologia , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Cultura Primária de Células , Receptores de Formil Peptídeo/metabolismo , Receptores de Lipoxinas/metabolismo , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Rinite Alérgica/patologia , Proteína Amiloide A Sérica/genética , Regulação para Cima , Adulto Jovem
8.
PLoS One ; 15(4): e0232230, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32340025

RESUMO

BACKGROUND: Proinflammatory interleukin-33 (IL-33) binds to its receptor ST2L and is involved in inflammation and the malignant behavior of cancer cells. However, the role of IL-33-ST2L and the IL-33 decoy receptor sST2 in the tumor microenvironment of pancreatic cancer is unclear. Because we previously reported that sST2 derived from colon cancer cells profoundly influences malignant tumor growth, we hypothesized that sST2 released from pancreatic cancer cells also modulates IL-33-ST2L signaling in the tumor microenvironment, thereby influencing tumor growth. METHODS: ST2 (ST2L and sST2) expression in mouse pancreatic cancer Panc02 cells was downregulated by shRNAs. mRNA expression levels of IL-33, ST2, cytokines and chemokines in the cells and tumor tissues were examined using real-time PCR. sST2 secretion and the amount of CXCL3 in tumor tissues were measured using ELISA. Tumor growth was investigated after injection of the cells into the pancreas of C57BL/6 mice. MPO+, F4/80+ and CD20+ cells in tumor tissues were detected using immunohistochemistry. RESULTS: Some but not all human and mouse pancreatic cancer cell lines preferentially expressed sST2. Then, we investigated the role of sST2 in orthotopic tumor growth of sST2-expressing mouse pancreatic cancer Panc02 cells in immunocompetent mice. shRNA-mediated knockdown of sST2 expression in the cells suppressed orthotopic tumor growth, which was partially recovered by overexpression of shRNA-resistant sST2 mRNA but was not evident in IL-33 knockout mice. This was associated with decreases in Cxcl3 expression, vessel density and accumulation of cancer-associated neutrophils but not cancer-associated macrophages. Administration of SB225002, an inhibitor of the CXCL3 receptor CXCR2, induced similar effects. CONCLUSIONS: Cancer cell-derived sST2 enhances tumor growth through upregulation of CXCL3 via inhibition of IL-33-ST2L signaling in the tumor microenvironment of pancreatic cancer. These results suggest that the sST2 and the CXCL3-CXCR2 axis could be therapeutic targets.


Assuntos
Proliferação de Células/fisiologia , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-33/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células PC-3 , Pâncreas/metabolismo , Pâncreas/patologia , Receptores de Interleucina-1/metabolismo , Transdução de Sinais/fisiologia , Microambiente Tumoral/fisiologia , Regulação para Cima/fisiologia
9.
Arterioscler Thromb Vasc Biol ; 40(5): 1256-1274, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32160773

RESUMO

OBJECTIVE: In view of our previous observations on differential expression of LMCD1 (LIM and cysteine-rich domains 1) in human versus rodents, we asked the question whether LMCD1 plays a species-specific role in the development of vascular lesions. Approach and Results: A combination of genetic, molecular, cellular, and disease models were used to test species-specific role of LMCD1 in the pathogenesis of vascular lesions. Here, we report species-specific regulation of LMCD1 expression in mediating vascular smooth muscle cell proliferation and migration during vascular wall remodeling in humans versus mice. Thrombin induced LMCD1 expression in human aortic smooth muscle cells but not mouse aortic smooth muscle cells via activation of Par1 (protease-activated receptor 1)-Gαq/11 (Gα protein q/11)-PLCß3 (phospholipase Cß3)-NFATc1 (nuclear factor of activated T cells 1) signaling. Furthermore, although LMCD1 mediates thrombin-induced proliferation and migration of both human aortic smooth muscle cells and mouse aortic smooth muscle cells via influencing E2F1 (E2F transcription factor 1)-mediated CDC6 (cell division cycle 6) expression and NFATc1-mediated IL (interleukin)-33 expression, respectively, in humans, it acts as an activator, and in mice, it acts as a repressor of these transcriptional factors. Interestingly, LMCD1 repressor activity was nullified by N-myristoyltransferase 2-mediated myristoylation in mouse. Besides, we found increased expression of LMCD1 in human stenotic arteries as compared to nonstenotic arteries. On the other hand, LMCD1 expression was decreased in neointimal lesions of mouse injured arteries as compared to noninjured arteries. CONCLUSIONS: Together, these observations reveal that LMCD1 acts as an activator and repressor of E2F1 and NFATc1 in humans and mice, respectively, in the induction of CDC6 and IL-33 expression during development of vascular lesions. Based on these findings, LMCD could be a potential target for drug development against restenosis and atherosclerosis in humans.


Assuntos
Proteínas Correpressoras/metabolismo , Fator de Transcrição E2F1/metabolismo , Interleucina-33/metabolismo , Proteínas com Domínio LIM/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Fatores de Transcrição NFATC/metabolismo , Remodelação Vascular , Lesões do Sistema Vascular/metabolismo , Animais , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Movimento Celular , Proliferação de Células , Células Cultivadas , Proteínas Correpressoras/genética , Modelos Animais de Doenças , Fator de Transcrição E2F1/genética , Feminino , Regulação da Expressão Gênica , Humanos , Interleucina-33/genética , Proteínas com Domínio LIM/genética , Masculino , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Ácido Mirístico/metabolismo , Fatores de Transcrição NFATC/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Processamento de Proteína Pós-Traducional , Transdução de Sinais , Especificidade da Espécie , Trombina/farmacologia , Remodelação Vascular/efeitos dos fármacos , Lesões do Sistema Vascular/genética , Lesões do Sistema Vascular/patologia
10.
Cancer Res ; 80(10): 1981-1990, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32156776

RESUMO

Recurrence and treatment resistance are major causes of cancer-associated death. There has been a growing interest in better understanding epithelial-mesenchymal transition, stemness of cancer cells, and exhaustion and dysfunction of the immune system for which numerous genomic, proteomic, microenvironmental, and immunologic mechanisms have been demonstrated. However, practical treatments for such patients have not yet been established. Here we identified IL33 as a key driver of polyploidy, followed by rapid proliferation after treatment. IL33 induction transformed tumor cells into polyploid giant cells, showing abnormal cell cycle without cell division accompanied by Snail deregulation and p53 inactivation; small progeny cells were generated in response to treatment stress. Simultaneously, soluble IL33 was released from tumor cells, leading to expansion of receptor ST2-expressing cells including IL17RB+GATA3+ cells, which promoted tumor progression and metastasis directly and indirectly via induction of immune exhaustion and dysfunction. Blocking IL33 with a specific mAb in murine IL33+ metastatic tumor models abrogated negative consequences and successfully elicited antitumor efficacy induced by other combined treatments. Ex vivo assays using tumor tissues and peripheral blood mononuclear cells of patients with cancer validated the clinical relevancy of these findings. Together, these data suggest that targeting the IL33-ST2 axis is a promising strategy for diagnosis and treatment of patients likely to be resistant to treatments in the clinical settings. SIGNIFICANCE: These findings indicate that the functional role of IL33 in cancer polyploidy contributes to intrinsic and extrinsic mechanisms underlying treatment failure.


Assuntos
Resistencia a Medicamentos Antineoplásicos/fisiologia , Interleucina-33/metabolismo , Neoplasias/metabolismo , Animais , Humanos , Camundongos , Camundongos Endogâmicos C57BL
11.
Proc Natl Acad Sci U S A ; 117(10): 5402-5408, 2020 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-32102913

RESUMO

A distinct population of Foxp3+CD4+ regulatory T (Treg) cells promotes repair of acutely or chronically injured skeletal muscle. The accumulation of these cells depends critically on interleukin (IL)-33 produced by local mesenchymal stromal cells (mSCs). An intriguing physical association among muscle nerves, IL-33+ mSCs, and Tregs has been reported, and invites a deeper exploration of this cell triumvirate. Here we evidence a striking proximity between IL-33+ muscle mSCs and both large-fiber nerve bundles and small-fiber sensory neurons; report that muscle mSCs transcribe an array of genes encoding neuropeptides, neuropeptide receptors, and other nerve-related proteins; define muscle mSC subtypes that express both IL-33 and the receptor for the calcitonin-gene-related peptide (CGRP); and demonstrate that up- or down-tuning of CGRP signals augments or diminishes, respectively, IL-33 production by muscle mSCs and later accumulation of muscle Tregs. Indeed, a single injection of CGRP induced much of the genetic program elicited in mSCs early after acute skeletal muscle injury. These findings highlight neural/stromal/immune-cell crosstalk in tissue repair, suggesting future therapeutic approaches.


Assuntos
Células-Tronco Mesenquimais/fisiologia , Músculo Esquelético/lesões , Músculo Esquelético/fisiologia , Nociceptores/fisiologia , Regeneração , Linfócitos T Reguladores/imunologia , Animais , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Comunicação Celular , Interleucina-33/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/efeitos dos fármacos , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos
12.
Mol Med Rep ; 21(3): 1658-1666, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32016471

RESUMO

Resveratrol (RSV), a natural polyphenol found in grapes and other herbal plants, has been reported to possess anti­inflammatory, anti­oxidative and anti­proliferative activities. The aim of the present study was to investigate the effect of RSV on interleukin (IL)­33­induced inflammatory responses in mast cells and identify the underlying molecular mechanisms. Rat basophilic leukemia (RBL­2H3) cells were stimulated with IL­33 in the presence or absence of RSV. MTT, ELISA, reverse transcription­quantitative PCR and western blot analyses were then performed in order to assess cytotoxicity, inflammatory cytokine production, suppression of tumorigenicity 2 receptor expression, protein expression involved in mitogen­activated protein kinase (MAPK) and nuclear factor (NF)­κB signaling, respectively. Finally, rats were used to determine the biological effect of RSV in vivo. The results revealed that RSV inhibited cell viability and increased cytotoxicity in a dose­dependent manner. Medium concentration of RSV (10 µM) treatment attenuated inflammatory cytokine production, such as IL­6, IL­13, tumor necrosis factor­α and monocyte chemotactic protein­1, and curbed IL­33­induced enhancement of immunoglobulin E­mediated responses in RBL­2H3 cells, which were associated with the suppression of NF­κB­mediated transcription and inhibition of P38 phosphorylation in response to IL­33 stimulation, but not extracellular signal regulated kinase or JNK. Notably, RSV application also decreased the levels of inflammatory cytokines in rats induced by IL­33 injection, which was similar to the anti­inflammatory effect in vitro. The data from the present study demonstrated that RSV played a regulatory role in antagonizing the effects of IL­33 on mast cells both in vitro and in vivo, suggesting that it has therapeutic potential in IL­33­mediated inflammatory diseases that are associated with mast cells.


Assuntos
Inflamação/etiologia , Inflamação/metabolismo , Interleucina-33/metabolismo , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , NF-kappa B/metabolismo , Resveratrol/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Imunoglobulina E/imunologia , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Mastócitos/imunologia , Ratos , Transdução de Sinais/efeitos dos fármacos
13.
Adv Exp Med Biol ; 1240: 83-93, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32060890

RESUMO

Suppression of tumorigenicity 2 (ST2), also known as interleukin-1 receptor-like 1 (IL1RL1), is one of the natural receptors of IL-33. Three major isoforms, ST2L (transmembrane form), sST2 (soluble form), and ST2V, are generated by alternative splicing. Damage to stromal cells induces necrosis and release of IL-33, which binds to heterodimeric ST2L/IL-1RAcP complex on the membrane of a variety of immune cells. This IL-33/ST2L signal induces transcription of the downstream inflammatory and anti-inflammatory genes by activating diverse intracellular kinases and factors to mount an adequate immune response, even in tumor microenvironment. For example, activation of IL-33/ST2L signal may trigger Th2-dependent M2 macrophage polarization to facilitate tumor progression. Notably, sST2 is a soluble form of ST2 that lacks a transmembrane domain but preserves an extracellular domain similar to ST2L, which acts as a "decoy" receptor for IL-33. sST2 has been shown to involve in the inflammatory tumor microenvironment and the progression of colorectal cancer, non-small cell lung cancer, and gastric cancer. Therefore, targeting the IL-33/ST2 axis becomes a promising new immunotherapy for treatment of many cancers. This chapter reviews the recent findings on IL-33/ST2L signaling in tumor microenvironment, the trafficking mode of sST2, and the pharmacological strategies to target IL-33/ST2 axis for cancer treatment.


Assuntos
Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Transdução de Sinais , Microambiente Tumoral , Animais , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1/antagonistas & inibidores , Proteína 1 Semelhante a Receptor de Interleucina-1/imunologia , Interleucina-33/antagonistas & inibidores , Interleucina-33/imunologia , Interleucina-33/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Transdução de Sinais/imunologia , Microambiente Tumoral/imunologia
14.
J Leukoc Biol ; 107(4): 663-671, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32017227

RESUMO

This study tests the hypothesis that activation of MAPK by physiologically relevant concentrations of IL-33 contributes to enhanced cytokine expression by IL-12 stimulated human NK cells. While IL-33 canonically triggers type 2 cytokine responses, this cytokine can also synergize with type 1 cytokines like IL-12 to provoke IFN-γ. We show that picogram concentrations of IL-12 and IL-33 are sufficient to promote robust secretion of IFN-γ by human NK cells that greatly exceeds resposes to either cytokine alone. Nanogram doses of IL-33, potentially consistent with levels in tissue microenvironments, synergize with IL-12 to induce secretion of additional cytokines, including TNF and GM-CSF. IL-33-induced activation of the p38 MAPK pathway in human NK cells is crucial for enhanced release of IFN-γ and TNF in response to IL-12. Mechanistically, IL-33-induced p38 MAPK signaling enhances stability of IFNG transcripts and triggers A disintegrin and metalloproteinase domain 17 (ADAM17) mediated cleavage of TNF from the cell surface. These data support our hypothesis and suggest that altered sensitivity of NK cells to IL-12 in the presence of IL-33 may have important consequences in diseases associated with mixed cytokine milieus, like asthma and chronic obstructive pulmonary disease.


Assuntos
Citocinas/metabolismo , Interleucina-33/metabolismo , Células Matadoras Naturais/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Proteína ADAM17/metabolismo , Linhagem Celular , Humanos , Interferon gama/genética , Interferon gama/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-12/metabolismo , Fosforilação , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fator de Transcrição STAT4/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
15.
Arch Oral Biol ; 112: 104663, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31986333

RESUMO

OBJECTIVE: This study aims to uncover the role of interleukin-33 on cementoblast-mediated cementum repair. METHODS: 6-8-week-old C57BL/6 mice were used to establish the model of orthodontic tooth movement. Interleukin-33 and suppression of tumorigenicity2 (ST2) expressions were immunohistochemically detected in the periodontal tissue. In vitro, cementoblast-like (OCCM-30) cells were cultured in the presence of recombinant mouse interleukin-33 protein (rmIL-33) at a 1-14 d time frame. ST2 expressions were immunofluorescently labeled and quantitatively examined. The effects of interleukin-33 on cementoblast differentiation, mineralization and proliferation were examined by alkaline phosphatase, alizarin red staining and cell counting kit-8, respectively. To further clarify the effect of interleukin-33 on cementogenesis-related protein expressions, runt-related transcription factor 2 (RUNX2), osterix, osteopontin, bone sialoprotein(BSP), osteocalcin, osteoprotegerin (OPG) and receptor activator of NF-КB ligand (RANKL) expressions were examined by western blot. RESULTS: Orthodontic load of high magnitude induces external apical root resorption, and increases interleukin-33 expression in the periodontal tissue of mice. Cells in the cementum express ST2. Interleukin-33 initially down-regulates but later recovers ST2 mRNA and protein levels in OCCM-30 cells. Interleukin-33 abates cementoblast differentiation and mineralization, and suppresses RUNX2, osterix, BSP and osteopontin expressions in OCCM-30 cells at the later stage of the culture period. Interleukin-33 enhances RANKL expression, and reduces the ratio of OPG/RANKL in OCCM-30 cells. CONCLUSION: Orthodontic load of high magnitude induces interleukin-33 expression in the periodontal tissue. Interleukin-33 has a negative effect on cementogenesis via suppressing cementoblast differentiation, mineralization and cementogenesis-related protein expressions.


Assuntos
Cementogênese , Cemento Dentário/citologia , Interleucina-33/metabolismo , Técnicas de Movimentação Dentária , Animais , Diferenciação Celular , Células Cultivadas , Cemento Dentário/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Recombinantes
16.
PLoS One ; 15(1): e0226701, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31940364

RESUMO

IgE-primed mast cells in peripheral tissues, including the skin, lung, and intestine, are key initiators of allergen-triggered edema and inflammation. Particularly in severe forms of allergy, this inflammation becomes strongly neutrophil dominated, and yet how mast cells coordinate this type of response is unknown. We and others have reported that activated mast cells--a hematopoietic cell type--can produce IL-33, a cytokine known to participate in allergic responses but generally considered as being of epithelial origin and driving Type 2 immune responses (e.g., ILC2 and eosinophil activation). Using models of skin anaphylaxis, our data reveal that mast cell-derived IL-33 also initiates neutrophilic inflammation. We demonstrate a cellular crosstalk mechanism whereby activated mast cells crosstalk to IL-33 receptor-bearing basophils, driving these basophils to adopt a unique response signature rich in neutrophil-associated molecules. We further establish that basophil expression of CXCL1 is necessary for IgE-driven neutrophilic inflammation. Our findings thus unearth a new mechanism by which mast cells initiate local inflammation after antigen triggering and might explain the complex inflammatory phenotypes observed in severe allergic diseases. Moreover, our findings (i) establish a functional link from IL-33 to neutrophilic inflammation that extends IL-33-mediated biology well beyond that of Type 2 immunity, and (ii) demonstrate the functional importance of hematopoietic cell-derived IL-33 in allergic pathogenesis.


Assuntos
Basófilos/patologia , Hipersensibilidade/imunologia , Hipersensibilidade/metabolismo , Interleucina-33/metabolismo , Mastócitos/patologia , Animais , Comunicação Celular , Quimiocina CXCL1/metabolismo , Regulação da Expressão Gênica/imunologia , Hipersensibilidade/complicações , Inflamação/complicações , Camundongos , Infiltração de Neutrófilos
17.
Chem Biol Interact ; 315: 108897, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31726037

RESUMO

Type 2 diabetes mellitus (T2DM) is a disease with a drastically growing worldwide prevalence. It is usually associated with numerous complications of which; diabetic nephropathy (DN); is a main complication of microvasculature and more seriously, a common cause of end-stage renal disease (ESRD). Unfortunately, both the lack of a definitive remedy alongside the economic and the social burden on DN patients enforces considerable impetus for developing alternative therapies. IL-33 is a newly discovered member of the IL-1 cytokine family. IL33/ST2 signaling plays a crucial role in acute and chronic kidney diseases. Calycosin is an isoflavone with reported IL33 signaling inhibitory activity. The present study aimed to investigate if calycosin possess renal protective effect in high-fat diet/STZ-induced T2DM model and to clarify the potential underlying mechanisms. HFD-STZ control rats showed functional and structural renal damage confirmed by increased serum creatinine, blood urea nitrogen and albuminuria associated with marked renal glomerulosclerosis and interstitial fibrosis. Initiation of inflammation, oxidative stress, and fibrosis was evident as depicted by elevated renal levels of IL33/ST2 mRNA as well as increased renal NF-κBp65, TNF-α, IL-1ß, MDA, and TGF-ß contents with suppressed Nrf2 and TAC. Calycosin treatment markedly improved the aforementioned makers of renal injury and dysfunction, modulated IL33/ST2 signaling, inflammatory cytokines, oxidative stress and fibrotic processes. This was accompanied by improvement of T2DM-induced renal ultramicroscopic and histopathological alterations.


Assuntos
Fibrose/tratamento farmacológico , Interleucina-33/metabolismo , Isoflavonas/farmacologia , Rim/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Receptores de Interleucina-1/metabolismo , Animais , Citocinas/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Fibrose/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Rim/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Estreptozocina/farmacologia
18.
Immunol Lett ; 218: 5-10, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31863784

RESUMO

Interleukin (IL)-33 is an alarmin factor that is highly secreted in a variety of autoimmune diseases, induces maturation of dendritic cells (DCs) and differentiation of T helper 17 (Th17) cells. As the balance between Th17 cells and regulatory T cells (Tregs) is important to maintain immune homeostasis, in this study, we investigated the effects of IL-33 on Treg cell response. We observed that direct treatment with IL-33 had no effect on Treg differentiation, whereas IL-33-matured DCs (IL33-matDCs) inhibited the differentiation of CD4+ T cells to Tregs by decreasing the expression of Foxp3. Furthermore, co-culture with IL-33-matDCs changed stable Tregs (CD25hiCD4+ Tregs) to IL-17-producing cells, whereas IL-33-matDCs had little effects on unstable Tregs (CD25loCD4+ Tregs). The stable Tregs were demonstrated to express high levels of IL-6 receptors. Blocking of IL-6 secreted from IL-33-matDCs suppressed the conversion of Tregs to Th17 cells, indicating the greater propensity to convert stable Tregs to Th17 cells is due to IL-6 signaling. Taken together, these results demonstrate that IL-33 inhibits Treg differentiation and the conversion of stable Tregs to Th17 cells via DCs.


Assuntos
Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Interleucina-33/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Animais , Biomarcadores , Comunicação Celular , Diferenciação Celular/imunologia , Plasticidade Celular/imunologia , Técnicas de Cocultura , Feminino , Imunofenotipagem , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Ativação Linfocitária/imunologia , Camundongos , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
19.
J Recept Signal Transduct Res ; 39(4): 359-367, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31755331

RESUMO

Context: IL-33 is a pro-inflammatory cytokine that is involved in the development of chronic inflammatory diseases and the initiation of allergic inflammation in response to pathogens and acts an alarmin.Objective: Present study aims to explore the IL-33 mediated effects of histamine induced allergic inflammation in human mast cells.Materials and methods: In this study, cord blood derived CD34+ mast cells and HMC-1 cells were primed with IL-33 followed by the stimulation with histamine. We investigated the functional activation of mast cell by intracellular calcium release using calcium mobilization assay, release of granular content using degranulation assay, profiling of various inflammatory and regulatory cytokines as well as chemokines by Luminex Bioplex assay and its signaling mechanisms involved using western blot analysis.Results: In our study, we found that the IL-33 acts as a mediator in the allergic inflammation induced by the histamine. IL-33 potentiates the release of intracellular calcium and degranulation content in human mast cells. Also, it enhances the production of Th2, Th1 cytokines and chemokines and down-regulates the production of regulatory cytokine. Furthermore, it enhanced the phosphorylation of the signaling molecules such as ERK, Akt, and NFκB in activated mast cells. Therefore, IL-33 acts as a potent activator of mast cells and it can elicit inflammatory response synergistically with histamine.Conclusions: Taken together, IL-33 acts as a potent mediator by inducing the inflammatory response in activated mast cells, hence increasing their responsiveness to antigens and amplifying the allergic response.


Assuntos
Hipersensibilidade/imunologia , Inflamação/imunologia , Interleucina-33/metabolismo , Mastócitos/imunologia , Células Cultivadas , Citocinas/metabolismo , Histamina/administração & dosagem , Agonistas dos Receptores Histamínicos/administração & dosagem , Humanos , Hipersensibilidade/etiologia , Hipersensibilidade/metabolismo , Hipersensibilidade/patologia , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Interleucina-33/genética , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Mastócitos/patologia , NF-kappa B/metabolismo , Transdução de Sinais
20.
Mediators Inflamm ; 2019: 7158014, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31736655

RESUMO

Background: IL-33 belongs to the IL-1 family, playing a role in several biologic processes as well as in the pathogenesis of different diseases, including skin pathologies. It acts as an alarmin, released by damaged cells. Binding to a ST2 receptor, it stimulates many immune cells such as ILC2 and Th2 cells. IL-33/ST2 axis seems to be involved in Th17 response. According to this, a review was performed to analyze if IL-33 even interplay in the onset of psoriasis, a Th1/Th17 inflammatory disease. Methods: Data obtained from the included articles are study author name, publication date, group studied, clinical and biological variables, laboratory tests, and outcome of interest of the study. Results: Data are obtained from the 19 studies identified, which assessed the association between IL-33 and psoriasis. Discussion: It seems to promote the innate-adaptive immune crosstalk: it could induce mast cells and neutrophil response after being released by injured keratinocytes and after stimulation by some cytokines, in particular TNFα, INFγ, and IL-17A. In addition, it seems to be involved from the onset of disease to the development of comorbidities, as psoriatic arthritis. Conclusion: The core of the future research on psoriasis could be to fully understand the role of this complex cytokine, in order also to find a new therapeutic approach.


Assuntos
Imunidade Inata/fisiologia , Interleucina-33/metabolismo , Psoríase/imunologia , Psoríase/metabolismo , Humanos , Células Th1/metabolismo , Células Th17/metabolismo
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