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1.
Aging Clin Exp Res ; 32(10): 2115-2131, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32865757

RESUMO

BACKGROUND: In December 2019, a novel human-infecting coronavirus, SARS-CoV-2, had emerged. The WHO has classified the epidemic as a "public health emergency of international concern". A dramatic situation has unfolded with thousands of deaths, occurring mainly in the aged and very ill people. Epidemiological studies suggest that immune system function is impaired in elderly individuals and these subjects often present a deficiency in fat-soluble and hydrosoluble vitamins. METHODS: We searched for reviews describing the characteristics of autoimmune diseases and the available therapeutic protocols for their treatment. We set them as a paradigm with the purpose to uncover common pathogenetic mechanisms between these pathological conditions and SARS-CoV-2 infection. Furthermore, we searched for studies describing the possible efficacy of vitamins A, D, E, and C in improving the immune system function. RESULTS: SARS-CoV-2 infection induces strong immune system dysfunction characterized by the development of an intense proinflammatory response in the host, and the development of a life-threatening condition defined as cytokine release syndrome (CRS). This leads to acute respiratory syndrome (ARDS), mainly in aged people. High mortality and lethality rates have been observed in elderly subjects with CoV-2-related infection. CONCLUSIONS: Vitamins may shift the proinflammatory Th17-mediated immune response arising in autoimmune diseases towards a T-cell regulatory phenotype. This review discusses the possible activity of vitamins A, D, E, and C in restoring normal antiviral immune system function and the potential therapeutic role of these micronutrients as part of a therapeutic strategy against SARS-CoV-2 infection.


Assuntos
Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/dietoterapia , Infecções por Coronavirus/prevenção & controle , Citocinas/imunologia , Pandemias/prevenção & controle , Pneumonia Viral/dietoterapia , Pneumonia Viral/prevenção & controle , Vitaminas/imunologia , Vitaminas/uso terapêutico , Idoso , Ácido Ascórbico/imunologia , Ácido Ascórbico/farmacologia , Ácido Ascórbico/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Humanos , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Vitamina A/imunologia , Vitamina A/farmacologia , Vitamina A/uso terapêutico , Vitamina D/imunologia , Vitamina D/farmacologia , Vitamina D/uso terapêutico , Vitamina E/imunologia , Vitamina E/farmacologia , Vitamina E/uso terapêutico , Vitaminas/farmacologia
2.
Front Immunol ; 11: 2056, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32973814

RESUMO

The pandemic of coronavirus disease 2019 (COVID-19), a disease which causes severe lung injury and multiple organ damage, presents an urgent need for new drugs. The case severity and fatality of COVID-19 are associated with excessive inflammation, namely, a cytokine storm. Metformin, a widely used drug to treat type 2 diabetes (T2D) mellitus and metabolic syndrome, has immunomodulatory activity that reduces the production of proinflammatory cytokines using macrophages and causes the formation of neutrophil extracellular traps (NETs). Metformin also inhibits the cytokine production of pathogenic Th1 and Th17 cells. Importantly, treatment with metformin alleviates various lung injuries in preclinical animal models. In addition, a recent proteomic study revealed that metformin has the potential to directly inhibit SARS-CoV-2 infection. Furthermore, retrospective clinical studies have revealed that metformin treatment reduces the mortality of T2D with COVID-19. Therefore, metformin has the potential to be repurposed to treat patients with COVID-19 at risk of developing severe illness. This review summarizes the immune pathogenesis of SARS-CoV-2 and addresses the effects of metformin on inhibiting cytokine storms and preventing SARS-CoV-2 infection, as well as its side effects.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Lesão Pulmonar/tratamento farmacológico , Metformina/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Animais , Antivirais/efeitos adversos , Antivirais/farmacologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Citocinas/antagonistas & inibidores , Reposicionamento de Medicamentos/métodos , Armadilhas Extracelulares/efeitos dos fármacos , Humanos , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/farmacologia , Inflamação/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Metformina/efeitos adversos , Metformina/farmacologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia
3.
Eur J Endocrinol ; 183(5): R133-R147, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32755992

RESUMO

The SARS-CoV-2 virus responsible for the COVID-19 pandemic has generated an explosion of interest both in the mechanisms of infection leading to dissemination and expression of this disease, and in potential risk factors that may have a mechanistic basis for disease propagation or control. Vitamin D has emerged as a factor that may be involved in these two areas. The focus of this article is to apply our current understanding of vitamin D as a facilitator of immunocompetence both with regard to innate and adaptive immunity and to consider how this may relate to COVID-19 disease. There are also intriguing potential links to vitamin D as a factor in the cytokine storm that portends some of the most serious consequences of SARS-CoV-2 infection, such as the acute respiratory distress syndrome. Moreover, cardiac and coagulopathic features of COVID-19 disease deserve attention as they may also be related to vitamin D. Finally, we review the current clinical data associating vitamin D with SARS-CoV-2 infection, a putative clinical link that at this time must still be considered hypothetical.


Assuntos
Imunidade Adaptativa/imunologia , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Imunidade Inata/imunologia , Imunocompetência/imunologia , Pulmão/imunologia , Pneumonia Viral/imunologia , Linfócitos T/imunologia , Vitamina D/imunologia , Peptídeos Catiônicos Antimicrobianos/imunologia , Autofagia/imunologia , Betacoronavirus , Defensinas/imunologia , Humanos , Pandemias , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia , Vitamina D/análogos & derivados
4.
Nature ; 585(7823): 102-106, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32848245

RESUMO

Accumulating evidence indicates that gut microorganisms have a pathogenic role in autoimmune diseases, including in multiple sclerosis1. Studies of experimental autoimmune encephalomyelitis (an animal model of multiple sclerosis)2,3, as well as human studies4-6, have implicated gut microorganisms in the development or severity of multiple sclerosis. However, it remains unclear how gut microorganisms act on the inflammation of extra-intestinal tissues such as the spinal cord. Here we show that two distinct signals from gut microorganisms coordinately activate autoreactive T cells in the small intestine that respond specifically to myelin oligodendrocyte glycoprotein (MOG). After induction of experimental autoimmune encephalomyelitis in mice, MOG-specific CD4+ T cells are observed in the small intestine. Experiments using germ-free mice that were monocolonized with microorganisms from the small intestine demonstrated that a newly isolated strain in the family Erysipelotrichaceae acts similarly to an adjuvant to enhance the responses of T helper 17 cells. Shotgun sequencing of the contents of the small intestine revealed a strain of Lactobacillus reuteri that possesses peptides that potentially mimic MOG. Mice that were co-colonized with these two strains showed experimental autoimmune encephalomyelitis symptoms that were more severe than those of germ-free or monocolonized mice. These data suggest that the synergistic effects that result from the presence of these microorganisms should be considered in the pathogenicity of multiple sclerosis, and that further study of these microorganisms may lead to preventive strategies for this disease.


Assuntos
Encefalomielite Autoimune Experimental/microbiologia , Microbioma Gastrointestinal/imunologia , Inflamação/patologia , Medula Espinal/patologia , Linfócitos T/imunologia , Linfócitos T/patologia , Animais , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/prevenção & controle , Feminino , Vida Livre de Germes , Inflamação/imunologia , Intestino Delgado/imunologia , Intestino Delgado/microbiologia , Intestino Delgado/patologia , Lactobacillus reuteri/química , Lactobacillus reuteri/imunologia , Lactobacillus reuteri/patogenicidade , Masculino , Camundongos , Esclerose Múltipla/imunologia , Esclerose Múltipla/microbiologia , Esclerose Múltipla/patologia , Glicoproteína Mielina-Oligodendrócito/química , Glicoproteína Mielina-Oligodendrócito/imunologia , Medula Espinal/imunologia , Células Th17/imunologia , Células Th17/patologia
5.
PLoS Pathog ; 16(8): e1008733, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32817694

RESUMO

Staphylococcus aureus (S. aureus) is one of the most common bacterial infections worldwide, and antibiotic resistant strains such as Methicillin-Resistant S. aureus (MRSA) are a major threat and burden to public health. MRSA not only infects immunocompromised patients but also healthy individuals and has rapidly spread from the healthcare setting to the outside community. However, all vaccines tested in clinical trials to date have failed. Immunocompromised individuals such as patients with HIV or decreased levels of CD4+ T cells are highly susceptible to S. aureus infections, and they are also at increased risk of developing fungal infections. We therefore wondered whether stimulation of antifungal immunity might promote the type of immune responses needed for effective host defense against S. aureus. Here we show that vaccination of mice with a fungal ß-glucan particle (GP) loaded with S. aureus antigens provides protective immunity to S. aureus. We generated glucan particles loaded with the four S. aureus proteins ClfA, IsdA, MntC, and SdrE, creating the 4X-SA-GP vaccine. Vaccination of mice with three doses of 4X-SA-GP promoted protection in a systemic model of S. aureus infection with a significant reduction in the bacterial burden in the spleen and kidneys. 4X-SA-GP vaccination induced antigen-specific Th1 and Th17 CD4+ T cell and antibody responses and provided long-term protection. This work suggests that the GP vaccine system has potential as a novel approach to developing vaccines for S. aureus.


Assuntos
Saccharomyces cerevisiae/imunologia , Infecções Estafilocócicas/imunologia , Vacinas Antiestafilocócicas/imunologia , Staphylococcus aureus/imunologia , Animais , Anticorpos Antibacterianos/imunologia , Coagulase/administração & dosagem , Coagulase/genética , Coagulase/imunologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Saccharomyces cerevisiae/química , Infecções Estafilocócicas/microbiologia , Vacinas Antiestafilocócicas/administração & dosagem , Vacinas Antiestafilocócicas/genética , Staphylococcus aureus/genética , Células Th1/imunologia , Células Th17/imunologia , Vacinação , beta-Glucanas/administração & dosagem , beta-Glucanas/imunologia
6.
Gene ; 757: 144931, 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-32640308

RESUMO

OBJECTIVE: The aim of this study is to investigate the role of close homolog of L1 (CHL1) on inflammatory bowel disease (IBD), and the correlation with the balance of Th17/Treg. METHODS: Dextran sodium sulfate (DSS)-induced IBD mice model was established. CHL1 knockout (KO) mice and CHL1 wild-type (WT) mice were subjected to DSS. CHL1 expression was detected using qRT-PCR. Weight was recorded daily, and disease activity index (DAI) score was assessed. The colon length and histological changes were measured. The number of neutrophils, macrophages and T cells was observed by immunohistochemistry. The expression of inflammatory cytokines and the proportion of Th17/Treg cells were detected by qRT-PCR and flow cytometry. The expression of RORγt, STAT3 and Foxp3 was detected by using immunohistochemistry and Western blot. RESULTS: CHL1 expression was upregulated in DSS-induced IBD mice. DSS-CHLl-KO mice exhibited less weight loss than the DSS-CHLl-WT mice. The DAI score and histological score were decreased in DSS-CHLl-KO mice compared with DSS-CHLl-WT mice, while colon length was increased. Number of neutrophils, macrophages and T cells, and expression of TNF-α, IL-6, IL-17A, IL-21 and IL-23 were decreased in DSS-CHLl-KO mice, while IL-10 expression was increased. Moreover, CHL1-deficient inhibited Th17 cells differentiation and promoted Treg cells differentiation in IBD mice. CHL1-deficient also inhibited the expression of RORγt and STAT3, and promoted the expression of Foxp3 in IBD mice. CONCLUSION: CHL1-deficient reduces the inflammatory response by regulating the balance of Th17/Treg in mice with IBD. CHL1 is expected to be a new target for the treatment of IBD.


Assuntos
Moléculas de Adesão Celular/genética , Doenças Inflamatórias Intestinais/genética , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Animais , Moléculas de Adesão Celular/deficiência , Diferenciação Celular , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Doenças Inflamatórias Intestinais/sangue , Doenças Inflamatórias Intestinais/imunologia , Interleucinas/genética , Interleucinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Linfócitos T Reguladores/citologia , Células Th17/citologia
7.
Nat Commun ; 11(1): 3434, 2020 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-32632085

RESUMO

The immune system of patients infected by SARS-CoV-2 is severely impaired. Detailed investigation of T cells and cytokine production in patients affected by COVID-19 pneumonia are urgently required. Here we show that, compared with healthy controls, COVID-19 patients' T cell compartment displays several alterations involving naïve, central memory, effector memory and terminally differentiated cells, as well as regulatory T cells and PD1+CD57+ exhausted T cells. Significant alterations exist also in several lineage-specifying transcription factors and chemokine receptors. Terminally differentiated T cells from patients proliferate less than those from healthy controls, whereas their mitochondria functionality is similar in CD4+ T cells from both groups. Patients display significant increases of proinflammatory or anti-inflammatory cytokines, including T helper type-1 and type-2 cytokines, chemokines and galectins; their lymphocytes produce more tumor necrosis factor (TNF), interferon-γ, interleukin (IL)-2 and IL-17, with the last observation implying that blocking IL-17 could provide a novel therapeutic strategy for COVID-19.


Assuntos
Betacoronavirus/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Coronavirus/imunologia , Pneumonia Viral/imunologia , Subpopulações de Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Senescência Celular , Infecções por Coronavirus/sangue , Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Humanos , Memória Imunológica , Itália/epidemiologia , Ativação Linfocitária , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/patologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia , Células Th17/imunologia , Células Th17/metabolismo , Células Th17/patologia
8.
J Immunol ; 205(4): 892-898, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32651218

RESUMO

SARS-CoV-2, the virus causing COVID-19, has infected millions and has caused hundreds of thousands of fatalities. Risk factors for critical illness from SARS-CoV-2 infection include male gender, obesity, diabetes, and age >65. The mechanisms underlying the susceptibility to critical illness are poorly understood. Of interest, these comorbidities have previously been associated with increased signaling of Th17 cells. Th17 cells secrete IL-17A and are important for clearing extracellular pathogens, but inappropriate signaling has been linked to acute respiratory distress syndrome. Currently there are few treatment options for SARS-CoV-2 infections. This review describes evidence linking risk factors for critical illness in COVID-19 with increased Th17 cell activation and IL-17 signaling that may lead to increased likelihood for lung injury and respiratory failure. These findings provide a basis for testing the potential use of therapies directed at modulation of Th17 cells and IL-17A signaling in the treatment of COVID-19.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Betacoronavirus/imunologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Interleucina-17/antagonistas & inibidores , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Células Th17/efeitos dos fármacos , Anticorpos Monoclonais Humanizados/efeitos adversos , Comorbidade , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Estado Terminal , Feminino , Humanos , Interleucina-17/metabolismo , Masculino , Pandemias , Pneumonia Viral/virologia , Síndrome do Desconforto Respiratório do Adulto/imunologia , Síndrome do Desconforto Respiratório do Adulto/mortalidade , Síndrome do Desconforto Respiratório do Adulto/virologia , Fatores de Risco , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Células Th17/imunologia
9.
Nat Commun ; 11(1): 3334, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620760

RESUMO

TH17 cells exemplify environmental immune adaptation: they can acquire both a pathogenic and an anti-inflammatory fate. However, it is not known whether the anti-inflammatory fate is merely a vestigial trait, or whether it serves to preserve the integrity of the host tissues. Here we show that the capacity of TH17 cells to acquire an anti-inflammatory fate is necessary to sustain immunological tolerance, yet it impairs immune protection against S. aureus. Additionally, we find that TGF-ß signalling via Smad3/Smad4 is sufficient for the expression of the anti-inflammatory cytokine, IL-10, in TH17 cells. Our data thus indicate a key function of TH17 cell plasticity in maintaining immune homeostasis, and dissect the molecular mechanisms explaining the functional flexibility of TH17 cells with regard to environmental changes.


Assuntos
Homeostase/imunologia , Inflamação/imunologia , Interleucina-10/imunologia , Intestinos/imunologia , Células Th17/imunologia , Animais , Plasticidade Celular/imunologia , Resistência à Doença/genética , Resistência à Doença/imunologia , Células HEK293 , Humanos , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-17/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/imunologia , Staphylococcus aureus/fisiologia , Células Th17/metabolismo , Fator de Crescimento Transformador beta/imunologia , Fator de Crescimento Transformador beta/metabolismo
10.
Proc Natl Acad Sci U S A ; 117(28): 16465-16474, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32601220

RESUMO

Under steady-state conditions, the immune system is poised to sense and respond to the microbiota. As such, immunity to the microbiota, including T cell responses, is expected to precede any inflammatory trigger. How this pool of preformed microbiota-specific T cells contributes to tissue pathologies remains unclear. Here, using an experimental model of psoriasis, we show that recall responses to commensal skin fungi can significantly aggravate tissue inflammation. Enhanced pathology caused by fungi preexposure depends on Th17 responses and neutrophil extracellular traps and recapitulates features of the transcriptional landscape of human lesional psoriatic skin. Together, our results propose that recall responses directed to skin fungi can directly promote skin inflammation and that exploration of tissue inflammation should be assessed in the context of recall responses to the microbiota.


Assuntos
Arthrodermataceae/fisiologia , Microbiota , Psoríase/imunologia , Pele/microbiologia , Animais , Arthrodermataceae/classificação , Arthrodermataceae/genética , Arthrodermataceae/isolamento & purificação , Armadilhas Extracelulares/imunologia , Armadilhas Extracelulares/microbiologia , Feminino , Humanos , Imunidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Psoríase/microbiologia , Psoríase/patologia , Pele/imunologia , Pele/patologia , Simbiose , Células Th17/imunologia
11.
Proc Natl Acad Sci U S A ; 117(32): 19408-19414, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32719138

RESUMO

Untoward effector CD4+ T cell responses are kept in check by immune regulatory mechanisms mediated by CD4+ and CD8+ T cells. CD4+ T helper 17 (Th17) cells, characterized by IL-17 production, play important roles in the pathogenesis of autoimmune diseases (such as arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease, among others) and in the host response to infection and cancer. Here, we demonstrate that human CD4+ T cells cells exposed to a Th17-differentiating milieu are significantly more resistant to immune suppression by CD8+ T cells compared to control Th0 cells. This resistance is mediated, in part, through the action of IL-17A, IL-17F, and IL-17AF heterodimer through their receptors (IL-17RA and IL-17RC) on CD4+ T cells themselves, but not through their action on CD8+ T cells or APC. We further show that IL-17 can directly act on non-Th17 effector CD4+ T cells to induce suppressive resistance, and this resistance can be reversed by blockade of IL-1ß, IL-6, or STAT3. These studies reveal a role for IL-17 cytokines in mediating CD4-intrinsic immune resistance. The pathways induced in this process may serve as a critical target for future investigation and immunotherapeutic intervention.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Tolerância Imunológica/imunologia , Interleucina-17/imunologia , Células Th17/imunologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular , Humanos , Interleucina-17/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia
12.
Mol Immunol ; 125: 32-42, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32629323

RESUMO

Compelling evidence has demonstrated that Th17 cells play an essential role in the pathogenesis of multiple sclerosis (MS). Long noncoding RNAs (lncRNAs) have been confirmed as vital regulators of immune cell differentiation and other functions. However, whether and how lncRNAs influence Th17 cell differentiation and functional behaviors remain largely unclear. Here, we identified that a lncRNA, namely Gm15575, is specifically enriched in Th17 cells and spleen tissues of EAE mice. Functionally, knockdown of Gm15575 in Th17 cells suppressed the secretion of IL17A. Mechanistically, Gm15575 served as a competing endogenous RNA (ceRNA) to block the function of miR-686, positively regulating the expression of CCL7, a pro-inflammatory chemokine with high expression in Th17 cells, and Th17 differentiation. Taken together, our study revealed that Gm15575-miR-686 axis promoted the progression of EAE by regulating Th17 differentiation and expression of CCL7 which elucidated the pathogenesis of autoimmune diseases at genetic level. Gm15575 can be involved in the course of Th17-related autoimmune diseases.


Assuntos
Quimiocina CCL7/biossíntese , Encefalomielite Autoimune Experimental/genética , Regulação da Expressão Gênica/imunologia , MicroRNAs/genética , RNA Longo não Codificante/genética , Células Th17/imunologia , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Quimiocina CCL7/genética , Quimiocina CCL7/imunologia , Encefalomielite Autoimune Experimental/imunologia , Camundongos , MicroRNAs/imunologia , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , RNA Longo não Codificante/imunologia , Regulação para Cima
13.
Mol Immunol ; 125: 162-171, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32688118

RESUMO

BACKGROUND: Baicalin has many biological properties such as anti-oxidation and anti-allergy. The current study aimed to explore the effect of Baicalin on allergic rhinitis (AR) and its potential mechanism of action. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated by density gradient centrifugation. Expression levels of Th17 and Treg cells-related proteins in nasal mucosa and peripheral blood cells were detected by real-time quantitative PCR, flow cytometry and Western blot. The mice were randomly divided into Control, ovalbumin (OVA), l-Baicalin, H-Baicalin, DSGC, 3-MA, and H-Baicalin + Rapa groups. Changes of allergic rhinitis conditions and eosinophil infiltration of the mice were detected and scored by Diff-Quik staining, and histological changes were observed by Hematoxylin & Eosin (H&E) staining and Periodate Schiff (PAS) staining. Serological changes, expression levels of interleukin-17A (IL-17A), interleukin-10 (IL-10), eosinophilic cationic protein (ECP) and anti-OVA-specific antibodies were detected by Enzyme-linked immunosorbent assay (ELISA). RESULTS: Clinical case analysis found that AR patients had a Th17/Treg imbalance and activated autophagy, however, Baicalin restored Th17/Treg cell balance and inhibited autophagy in vitro. in vivo experiments demonstrated that Baicalin inhibited OVA-induced allergic nasal symptoms and the activation of autophagy pathway, which was the same as the regulation of 3-MA, while Rapa could weaken the effects of H-baicalin. Moreover, Baicalin reduced the infiltration of different inflammatory cells of the nasal lavage fluid, prevented the damages to epithelial cells, and improved nasal mucosal thickness and mucus secretion. In addition, Baicalin regulated the balance of mouse anti-OVA-specific antibody levels and expressions of Th17/Treg-associated cytokines. CONCLUSION: Our study revealed that Baicalin can be used to treat AR, and the effect is realized through inhibiting autophagy to regulate Th17/Treg cell differentiation.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Autofagia/efeitos dos fármacos , Flavonoides/farmacologia , Rinite Alérgica/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Animais , Autofagia/imunologia , Humanos , Camundongos , Linfócitos T Reguladores/imunologia , Células Th17/imunologia
14.
Nat Commun ; 11(1): 2856, 2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32503977

RESUMO

Type I interferon (IFN-I) and T helper 17 (TH17) drive pathology in neuromyelitis optica spectrum disorder (NMOSD) and in TH17-induced experimental autoimmune encephalomyelitis (TH17-EAE). This is paradoxical because the prevalent theory is that IFN-I inhibits TH17 function. Here we report that a cascade involving IFN-I, IL-6 and B cells promotes TH17-mediated neuro-autoimmunity. In NMOSD, elevated IFN-I signatures, IL-6 and IL-17 are associated with severe disability. Furthermore, IL-6 and IL-17 levels are lower in patients on anti-CD20 therapy. In mice, IFN-I elevates IL-6 and exacerbates TH17-EAE. Strikingly, IL-6 blockade attenuates disease only in mice treated with IFN-I. By contrast, B-cell-deficiency attenuates TH17-EAE in the presence or absence of IFN-I treatment. Finally, IFN-I stimulates B cells to produce IL-6 to drive pathogenic TH17 differentiation in vitro. Our data thus provide an explanation for the paradox surrounding IFN-I and TH17 in neuro-autoimmunity, and may have utility in predicting therapeutic response in NMOSD.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Interferon Tipo I/imunologia , Neuromielite Óptica/imunologia , Células Th17/imunologia , Adulto , Animais , Autoimunidade , Linfócitos B/imunologia , Linfócitos B/metabolismo , Encefalomielite Autoimune Experimental/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Interleucina-17/imunologia , Interleucina-17/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Neuromielite Óptica/genética , Proteômica
15.
PLoS Negl Trop Dis ; 14(6): e0008386, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32542003

RESUMO

Chromoblastomycosis (CBM) is a chronic worldwide subcutaneous mycosis, caused by several dimorphic, pigmented dematiaceous fungi. It is difficult to treat patients with the disease, mainly because of its recalcitrant nature. The correct activation of host immune response is critical to avoid fungal persistence in the tissue and disease chronification. CD4+ T cells are crucial for the development of protective immunity to F. pedrosoi infection. Here, we investigated T helper cell response dynamics during experimental CBM. Following footpad injection with F. pedrosoi hyphae and conidia, T cells were skewed towards a Th17 and Th1 phenotype. The Th17 population was the main Th cell subset found in the infected area during the early stages of experimental murine CBM, followed by Th1 predominance in the later stages, coinciding with the remission phase of the disease in this experimental model. Depletion of CD25+ cells, which leads to a reduction of Treg cells in the draining lymph node, resulted in decline in fungal burden after 14 days of infection. However, fungal cells were not cleared in the later stages of the disease, prolonging CBM clinical features in those animals. IL-17A and IFN-γ neutralization hindered fungal cell elimination in the course of the disease. Similarly, in dectin-2 KO animals, Th17 contraction in the course of experimental CBM was accompanied by fungal burden decrease in the first 14 days of infection, although it did not affect disease resolution. In this study, we gained insight into T helper subsets' dynamics following footpad injections of F. pedrosoi propagules and uncovered their contribution to disease resolution. The Th17 population proved to be important in eliminating fungal cells in the early stages of infection. The Th1 population, in turn, closely assisted by Treg cells, proved to be relevant not only in the elimination of fungal cells at the beginning of infection but also essential for their complete elimination in later stages of the disease in a mouse experimental model of CBM.


Assuntos
Ascomicetos/imunologia , Cromoblastomicose/imunologia , Lectinas Tipo C/metabolismo , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th17/imunologia , Animais , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Cromoblastomicose/microbiologia , Cromoblastomicose/patologia , Modelos Animais de Doenças , Humanos , Hifas , Interferon gama/metabolismo , Interleucina-17/metabolismo , Lectinas Tipo C/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Esporos Fúngicos
16.
Am J Med Sci ; 360(2): 176-191, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32553747

RESUMO

BACKGROUND: This study aimed to investigate the role of Clostridium butyricum (C. butyricum) in conjunction with the Toll-like receptor2 (TLR2) signaling pathway and T helper 17 (Th17) cells in dextran sodium sulfate (DSS)-induced colitis in mice. METHODS: Forty 8-week-old BALB/c mice were randomly divided into 5 groups of 8 mice for 7 days: control, DSS (5% DSS), DSS+C. butyricum (1 × 109 CFU), DSS+C. butyricum (1 × 108 CFU) and DSS+C. butyricum (1 × 107 CFU) groups. We assessed the disease activity index (DAI) and histological damage scores. The expression levels of TLR2, myeloid differentiation factor 88 (MyD88), nuclear factor kappa-B p65 (NF-κBp65), interleukin (IL) 17 (IL17), IL23 and retineic acid receptor related orphan nuclear receptor gamma t (RORγt) were determined through immunohistochemical staining, western blot and quantitative real-time PCR (qRT-PCR). The expression levels of CD3+CD4+IL17+ cells in peripheral blood were measured by flow cytometry. RESULTS: C. butyricum dose-dependently decreased DAI and histological damage scores in DSS mice and down-regulated the mRNA and protein levels of TLR2, MyD88 and NF-κBp65 in mouse colon tissue (all P < 0.05). In addition, C. butyricum dose-dependently decreased the levels of CD3+CD4+IL17+ cells in peripheral blood and down-regulated the mRNA and protein levels of IL17, IL23 and RORγt in mouse colon tissue (all P < 0.05). Moreover, the effect of C. butyricum on TLR2 was positively correlated with IL17, IL23 and RORγt. CONCLUSIONS: C. butyricum exerts a dose-dependently protective effect on acute intestinal inflammation induced by DSS in mice, by inhibiting the TLR2 signaling pathway, down-regulating the expression of IL23 and RORγt, and inhibiting the secretion of IL17.


Assuntos
Clostridium butyricum , Colite/imunologia , Fator 88 de Diferenciação Mieloide/imunologia , Probióticos , Células Th17/imunologia , Receptor 2 Toll-Like/imunologia , Fator de Transcrição RelA/imunologia , Animais , Peso Corporal , Colite/induzido quimicamente , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Comportamento de Ingestão de Líquido , Comportamento Alimentar , Feminino , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-17/metabolismo , Interleucina-23/genética , Interleucina-23/imunologia , Interleucina-23/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , RNA Mensageiro/metabolismo , Distribuição Aleatória , Transdução de Sinais , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/metabolismo , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo
17.
PLoS One ; 15(6): e0234479, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32542025

RESUMO

There are differences in disease susceptibility to whirling disease (WD) among strains of rainbow trout. The North American strain Trout Lodge (TL) is highly susceptible, whereas the German Hofer (HO) strain is more resistant. The suppressor of cytokine signaling (SOCS) proteins are key in inhibiting cytokine signaling. Their role in modulating the immune response against whirling disease is not completely clear. This study aimed at investigating the transcriptional response of SOCS1 and SOCS3 genes to Myxobolus cerebralis along with that of several upstream regulators and immune response genes. M. cerebralis induced the expression of SOCS1, the IL-6-dependent SOCS3, the anti-inflammatory cytokine IL-10 and the Treg associated transcription factor FOXP3 in TL fish at multiple time points, which likely caused a restricted STAT1 and STAT3 activity affecting the Th17/Treg17 balance. The expression of SOCS1 and the IL-6-dependent SOCS3 was induced constraining the activation of STAT1 and STAT3 in TL fish, thereby causing Th17/Treg17 imbalance and leaving the fish unable to establish a protective immune response against M. cerebralis or control inflammatory reactions increasing susceptibility to WD. Conversely, in HO fish, the expression of SOCS1 and SOCS3 was restrained, whereas the expression of STAT1 and IL-23-mediated STAT3 was induced potentially enabling more controlled immune responses, accelerating parasite clearance and elevating resistance. The induced expression of STAT1 and IL-23-mediated STAT3 likely maintained a successful Th17/Treg17 balance and enabled fish to promote effective immune responses favouring resistance against WD. The results provide insights into the role of SOCS1 and SOCS3 in regulating the activation and magnitude of host immunity in rainbow trout, which may help us understand the mechanisms that underlie the variation in resistance to WD.


Assuntos
Suscetibilidade a Doenças/imunologia , Doenças dos Peixes/imunologia , Myxobolus/imunologia , Oncorhynchus mykiss/imunologia , Doenças Parasitárias em Animais/imunologia , Fator de Transcrição STAT3/imunologia , Proteína 3 Supressora da Sinalização de Citocinas/imunologia , Animais , Oncorhynchus mykiss/parasitologia , Fator de Transcrição STAT1/imunologia , Proteína 1 Supressora da Sinalização de Citocina/imunologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Células Th17/citologia , Células Th17/imunologia
18.
Life Sci ; 254: 117773, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32418896

RESUMO

The disturbance of the immune homeostasis caused by infection is decisive for multiple organ dysfunction caused by sepsis. Both the th17 cell and the regulatory cell(Tregs) are important components of the immune system and play a crucial role in maintaining immune homeostasis. In this study, we explored the effect of Maresin1, an emerging specific pro-inflammatory mediator, on the balance of Th17/Treg in sepsis, and investigated the underlying mechanism. We used the male C57BL/6 mice to establish the model of sepsis-induced lung injury by cecal ligation and puncture to verify the protective effect of Maresin1. Our study showed that Maresin1 could significantly inhibit the excessive inflammatory response and promote the inflammation regression in the process of sepsis-induced acute lung injury, thereby reducing lung damage and improving lung function. These effects were accompanied with the regulation of Maresin1 on the Th17/Treg balance in the early stages of sepsis. We demonstrated that Maresin1 has a certain effect on increasing the number of Treg and decreasing the number of Th17 cells in the early stages of sepsis, which is consistent with its effect on STAT3/RORγt and STAT5/Foxp3 signal pathways. Our study elucidated for the first time the relationship between Maresin1 and Th17/Treg balance in sepsis-induced acute lung injury.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/imunologia , Ácidos Docosa-Hexaenoicos/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Animais , Citocinas/imunologia , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/imunologia , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Distribuição Aleatória , Fator de Transcrição STAT3/imunologia , Fator de Transcrição STAT5/imunologia , Sepse/tratamento farmacológico , Sepse/imunologia , Transdução de Sinais/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th17/imunologia
19.
Zhongguo Xue Xi Chong Bing Fang Zhi Za Zhi ; 32(2): 203-207, 2020 Apr 26.
Artigo em Chinês | MEDLINE | ID: mdl-32458614

RESUMO

Recently, the incidence of infectious diseases continues to decline in many developed countries; however, the incidence of autoimmune diseases and allergic asthma appears a tendency towards a rise over years. "Hygiene hypothesis" provides new insights into the treatment of autoimmune disorders and allergic diseases based on parasitic infections. Increasing evidence shows that parasitic infections may effectively inhibit the development of diabetes, multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis and allergic asthma. There are complex mechanisms underlying the relationship between parasitic infections and "hygiene hypothesis", among which regulatory T (Treg) cells and Th17 cells are becoming a hot topic of research. This paper reviews the progresses in the research on the relationship between parasitic infections and "hygiene hypothesis", and summarizes the roles of Treg cells and Th17 cells in the interplay between parasitic infections and "hygiene hypothesis".


Assuntos
Hipótese da Higiene , Doenças Parasitárias , Doenças Autoimunes/imunologia , Doenças Autoimunes/parasitologia , Humanos , Higiene , Doenças Parasitárias/imunologia , Células Th17/imunologia
20.
PLoS Pathog ; 16(5): e1008356, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32437421

RESUMO

Tuberculosis (TB) is one of the deadliest diseases, claiming ~2 million deaths annually worldwide. The majority of people in TB endemic regions are vaccinated with Bacillus Calmette Guerin (BCG), which is the only usable vaccine available. BCG is efficacious against meningeal and disseminated TB in children, but protective responses are relatively short-lived and fail to protect against adult pulmonary TB. The longevity of vaccine efficacy critically depends on the magnitude of long-lasting central memory T (TCM) cells, a major source of which is stem cell-like memory T (TSM) cells. These TSM cells exhibit enhanced self-renewal capacity as well as to rapidly respond to antigen and generate protective poly-functional T cells producing IFN-γ, TNF-α, IL-2 and IL-17. It is now evident that T helper Th 1 and Th17 cells are essential for host protection against TB. Recent reports have indicated that Th17 cells preserve the molecular signature for TSM cells, which eventually differentiate into IFN-γ-producing effector cells. BCG is ineffective in inducing Th17 cell responses, which might explain its inadequate vaccine efficacy. Here, we show that revaccination with BCG along with clofazimine treatment promotes TSM differentiation, which continuously restores TCM and T effector memory (TEM) cells and drastically increases vaccine efficacy in BCG-primed animals. Analyses of these TSM cells revealed that they are predominantly precursors to host protective Th1 and Th17 cells. Taken together, these findings revealed that clofazimine treatment at the time of BCG revaccination provides superior host protection against TB by increasing long-lasting TSM cells.


Assuntos
Vacina BCG/imunologia , Vacina BCG/metabolismo , Clofazimina/farmacologia , Memória Imunológica/imunologia , Animais , Vacina BCG/farmacologia , Clofazimina/metabolismo , Quimioterapia Combinada/métodos , Feminino , Imunização Secundária/métodos , Imunogenicidade da Vacina/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mycobacterium bovis/imunologia , Mycobacterium tuberculosis/imunologia , Células-Tronco/imunologia , Células Th1/imunologia , Células Th17/imunologia , Tuberculose/imunologia , Tuberculose Pulmonar/imunologia
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