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1.
Front Immunol ; 12: 648754, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33790913

RESUMO

Background and Aims: Emerging evidence has revealed that innate lymphoid cells (ILCs) play a key role in regulating metabolic disorders. Here, we investigated the role of group 3 ILCs (ILC3s) in the modulation of Non-alcoholic fatty liver disease (NAFLD). Methods: RORγ gfp/gfp (RORgt KI/KI) and Rag2-/- mice with the administration of A213, RORgt antagonist, fed with a high-fat-diet (HFD) for 12 weeks, were used. We performed flow cytometry, real time PCR, and lipidomics analysis of serum and liver, and used RAW264.7 cells and murine primary hepatocytes in vitro. Results: HFD increased ILC3s and M1 macrophages in the liver, and RORgt KI/KI mice deficient in ILC3 showed significant fatty liver, liver fibrosis and significantly increased palmitic acid levels in serum and liver. In addition, administration of A213 to Rag2-/- mice caused significant fatty liver, liver fibrosis, and a significant increase in serum and liver palmitate concentrations, as in RORgt KI/KI mice. Addition of palmitc acid stimulated IL-23 production in cell experiments using RAW264.7. IL-22 produced by ILC3s inhibited the palmitate-induced apoptosis of primary hepatocytes. Conclusions: HFD stimulates IL-23 production by M1 macrophages, thus promoting ILC3 proliferation, whereas IL-22 secreted by ILC3s contributes to the upregulation of hepatic lipid metabolism and has anti-apoptosis activity.


Assuntos
Fígado Gorduroso/imunologia , Imunidade Inata/imunologia , Fígado/imunologia , Linfócitos/imunologia , Macrófagos/imunologia , Animais , Apoptose/imunologia , Células Cultivadas , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Hepatócitos/citologia , Hepatócitos/imunologia , Fígado/metabolismo , Fígado/patologia , Linfócitos/metabolismo , Macrófagos/classificação , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Ácido Palmítico/sangue , Ácido Palmítico/imunologia , Ácido Palmítico/metabolismo , Substâncias Protetoras/metabolismo , Células RAW 264.7
2.
FEBS J ; 288(24): 7043-7059, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33506611

RESUMO

Protein cysteine palmitoylation, or S-palmitoylation, has been known for about 40 years, and thousands of proteins in humans are known to be modified. Because of the large number of proteins modified, the importance and physiological functions of S-palmitoylation are enormous. However, most of the known physiological functions of S-palmitoylation can be broadly classified into two categories, neurological or immunological. This review provides a summary on the function of S-palmitoylation from the immunological perspective. Several important immune signaling pathways are discussed, including STING, NOD1/2, JAK-STAT in cytokine signaling, T-cell receptor signaling, chemotactic GPCR signaling, apoptosis, phagocytosis, and endothelial and epithelial integrity. This review is not meant to be comprehensive, but rather focuses on specific examples to highlight the versatility of palmitoylation in regulating immune signaling, as well as the potential and challenges of targeting palmitoylation to treat immune diseases.


Assuntos
Cisteína/imunologia , Citocinas/imunologia , Inflamação/imunologia , Ácido Palmítico/imunologia , Animais , Humanos , Transdução de Sinais/imunologia
3.
Hum Vaccin Immunother ; 10(11): 3241-50, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25483652

RESUMO

It has been reported that lipopeptides can be used to elicit cytotoxic T lymphocyte (CTL) responses against viral diseases and cancer. In our previous study, we determined that mono-palmitoylated peptides can enhance anti-tumor responses in the absence of adjuvant activity. To investigate whether di-palmitoylated peptides with TLR2 agonist activity are able to induce anti-tumor immunity, we synthesized a di-palmitic acid-conjugated long peptide that contains a murine CTL epitope of HPV E749-57 (Pam2IDG). Pam2IDG stimulated the maturation of bone marrow-derived dendritic cells (BMDCs) through TLR2/6. After immunization, Pam2IDG induced higher levels of T cell responses than those obtained with its non-lipidated counterpart (IDG). In the prophylactic model, Pam2IDG immunization completely inhibited tumor growth, whereas IDG immunization was unable to inhibit tumor growth. However, Pam2IDG immunization could not effectively inhibit the growth of established tumors. Therefore, we further investigated whether the depletion of immunosuppressive factors could improve the therapeutic effects of Pam2IDG. Our data indicate that treatment with Pam2IDG combined with clodronate/liposome delays tumor growth and increases the survival rate. We also observed that the therapeutic effects of Pam2IDG are improved by diminishing the function of tumor-associate macrophages (TAMs) and through the use of an IL10 receptor blocking antibody or a Cyclooxygenase 2 (Cox-2) inhibitor. In conclusion, the depletion of TAMs may enhance the anti-tumor immunity of a TLR2 agonist-conjugated peptide.


Assuntos
Lipopeptídeos/uso terapêutico , Macrófagos/imunologia , Neoplasias/imunologia , Linfócitos T Citotóxicos/imunologia , Receptor 2 Toll-Like/agonistas , Animais , Anticorpos Bloqueadores/imunologia , Anticorpos Bloqueadores/uso terapêutico , Ácido Clodrônico/uso terapêutico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Células Dendríticas/imunologia , Imunização , Imunoterapia , Lipopeptídeos/imunologia , Lipoilação , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/terapia , Ácido Palmítico/química , Ácido Palmítico/imunologia , Proteínas E7 de Papillomavirus/química , Proteínas E7 de Papillomavirus/imunologia , Receptores de Interleucina-10/antagonistas & inibidores , Receptores de Interleucina-10/imunologia , Taxa de Sobrevida , Receptor 2 Toll-Like/imunologia , Receptor 6 Toll-Like/imunologia
4.
J Affect Disord ; 135(1-3): 414-8, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21930301

RESUMO

BACKGROUND: There is evidence that depression is accompanied by oxidative and nitrosative stress (O&NS), as indicated by increased free radical levels, lipid peroxidation, and lowered antioxidant levels. The aims of the present study are to examine whether depression is accompanied by autoimmune responses directed against a) neoepitopes that are formed following O&NS damage; and b) the major anchorage molecules, i.e. palmitic and myristic acids and S-farnesyl-L-cysteine. METHODS: We examined serum IgM antibodies to the conjugated fatty acids, palmitic and myristic acids; acetylcholine; S-farnesyl-L-cysteine; and NO-modified adducts in 26 depressed patients and 17 normal controls. Severity of depression was measured with the Hamilton Depression Rating Scale and severity of fatigue and somatic (F&S) symptoms with the Fibromyalgia and Chronic Fatigue Syndrome (FF) Rating Scale. RESULTS: The prevalences and mean values for the serum IgM levels directed against conjugated palmitic and myristic acids, acetylcholine, S-farnesyl-L-cysteine; and the conjugated NO adducts, NO-tyrosine, NO-phenylalanine, NO-aspartate, NO-histidine, and NO-creatine were significantly higher in depressed patients than in normal controls. The autoimmune responses were significantly related to FF symptoms, such as fatigue and a flu-like malaise, whereas the indicants of nitrosative stress were related to gastro-intestinal and autonomic symptoms. DISCUSSION: Depression is characterized by IgM-related autoimmune responses directed against a) neoepitopes that are normally not detected by the immune system but that due to damage by O&NS have become immunogenic; and b) anchorage epitopes, i.e. palmitic and myristic acids, and S-farnesyl-L-cysteine. These autoimmune responses play a role in the inflammatory and O&NS pathophysiology of depression and may mediate the cellular dysfunctions that contribute to neuroprogression, e.g. aberrations in signal transduction, cellular differentiation and apoptosis.


Assuntos
Autoimunidade/imunologia , Depressão/imunologia , Ácidos Graxos/imunologia , Imunoglobulina M/imunologia , Inflamação/imunologia , Acetilcolina/imunologia , Acetilcolina/metabolismo , Adulto , Idoso , Formação de Anticorpos/imunologia , Estudos de Casos e Controles , Cisteína/análogos & derivados , Cisteína/imunologia , Cisteína/metabolismo , Dano ao DNA , Transtorno Depressivo/complicações , Transtorno Depressivo/imunologia , Epitopos , Fadiga/sangue , Fadiga/complicações , Fadiga/imunologia , Ácidos Graxos/metabolismo , Feminino , Humanos , Imunoglobulina M/sangue , Peroxidação de Lipídeos/imunologia , Masculino , Pessoa de Meia-Idade , Ácido Mirístico/imunologia , Ácido Mirístico/metabolismo , Negociação , Óxido Nítrico , Estresse Oxidativo/imunologia , Estresse Oxidativo/fisiologia , Ácido Palmítico/imunologia , Ácido Palmítico/metabolismo , Índice de Gravidade de Doença
5.
Nat Immunol ; 12(5): 408-15, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21478880

RESUMO

High-fat diet (HFD) and inflammation are key contributors to insulin resistance and type 2 diabetes (T2D). Interleukin (IL)-1ß plays a role in insulin resistance, yet how IL-1ß is induced by the fatty acids in an HFD, and how this alters insulin signaling, is unclear. We show that the saturated fatty acid palmitate, but not unsaturated oleate, induces the activation of the NLRP3-ASC inflammasome, causing caspase-1, IL-1ß and IL-18 production. This pathway involves mitochondrial reactive oxygen species and the AMP-activated protein kinase and unc-51-like kinase-1 (ULK1) autophagy signaling cascade. Inflammasome activation in hematopoietic cells impairs insulin signaling in several target tissues to reduce glucose tolerance and insulin sensitivity. Furthermore, IL-1ß affects insulin sensitivity through tumor necrosis factor-independent and dependent pathways. These findings provide insights into the association of inflammation, diet and T2D.


Assuntos
Proteínas de Transporte/imunologia , Gorduras na Dieta/imunologia , Inflamassomos/imunologia , Resistência à Insulina/imunologia , Ácido Palmítico/imunologia , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/farmacologia , Animais , Autofagia/imunologia , Caspase 1/imunologia , Ativação Enzimática , Inibidores Enzimáticos/farmacologia , Citometria de Fluxo , Interleucina-1beta/imunologia , Macrófagos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Confocal , Proteína 3 que Contém Domínio de Pirina da Família NLR , Oligopeptídeos/farmacologia , Espécies Reativas de Oxigênio/imunologia , Ribonucleotídeos/farmacologia , Transdução de Sinais
6.
BMC Immunol ; 10: 29, 2009 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-19463182

RESUMO

BACKGROUND: Diabetes is characterized by progressive failure of insulin producing beta cells. It is well known that both saturated fatty acids and various products of immune cells can contribute to the reduction of beta cell viability and functionality during diabetes pathogenesis. However, their joint action on beta cells has not been investigated, so far. Therefore, we explored the possibility that leukocytes and saturated fatty acids cooperate in beta cell destruction. RESULTS: Rat pancreatic islets or insulinoma cells (RIN) were co-cultivated with concanavalin A (ConA)-stimulated rat lymph node cells (LNC), or they were treated with cell-free supernatants (Sn) obtained from ConA-stimulated spleen cells or from activated CD3+ cells, in the absence or presence of palmitic acid (PA). ConA-stimulated LNC or Sn and PA cooperated in inducing caspase-3-dependent RIN cell apoptosis. The observed effect of PA and Sn on RIN cell viability was mediated by p38 mitogen-activated protein kinase (MAPK)-signaling and was achieved through auto-destructive nitric oxide (NO) production. The cooperative effect of Sn was mimicked with the combination of interleukin-1beta, interleukin-2, interleukin-6, interleukin-17, interferon-gamma and tumor necrosis factor-alpha. CONCLUSION: These results imply that stimulated T cells produce cytokines that cooperate with saturated free fatty acids in beta cell destruction during diabetes pathogenesis.


Assuntos
Apoptose/imunologia , Comunicação Celular , Células Secretoras de Insulina/imunologia , Insulinoma/imunologia , Ácido Palmítico/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Caspase 3/metabolismo , Linhagem Celular Tumoral , Técnicas de Cocultura , Citocinas/imunologia , Citocinas/metabolismo , Células Secretoras de Insulina/patologia , Insulinoma/patologia , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Ácido Palmítico/imunologia , Ratos , Transdução de Sinais , Linfócitos T/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
7.
Infect Immun ; 75(5): 2253-9, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17325056

RESUMO

Genomic analysis of Mycoplasma pneumoniae revealed the existence of a large number of putative lipoprotein genes compared with the numbers in other bacteria. However, the pathogenic roles of M. pneumoniae lipoproteins are still obscure. In this study, we synthesized a lipopeptide (designated M. pneumoniae paralogous lipoprotein 1 [MPPL-1]) in which an S-dipalmitoylglyceryl cysteine was coupled to a peptide with a consensus sequence of a putative paralogous lipoprotein group characteristic of M. pneumoniae. The cytokine-inducing activity of MPPL-1 in human monocytic cells was much weaker (approximately 700-fold weaker) than that of the known mycoplasmal S-dipalmitoylated lipopeptide FSL-1 or MALP-2. MPPL-1 required Toll-like receptor (TLR2) to activate NF-kappaB-dependent gene transcription in HEK293 cells, although a 1,000-fold-larger amount of MPPL-1 was needed to exert activity similar to that of FSL-1 in the cells. TLR2-mediated recognition of MPPL-1 was synergistically upregulated by TLR6 but not by TLR1 or TLR10, although the activity was still weak. In addition, MPPL-1 did not antagonize FSL-1 recognition in human monocytic cells and TLR2/TLR6-expressing HEK293 cells. Thus, these results suggest that there is preferential selective recognition of diacylated lipopeptides due to the magnitude of an affinity with TLR2 and TLR6 and the roles of increased paralogous lipoprotein genes of M. pneumoniae in evasion of TLR2 recognition.


Assuntos
Lipoproteínas , Mycoplasma pneumoniae/química , Ácido Palmítico , Sequência de Aminoácidos , Linhagem Celular , Citocinas/metabolismo , Diglicerídeos/imunologia , Regulação da Expressão Gênica , Humanos , Lipopeptídeos , Lipoproteínas/síntese química , Lipoproteínas/química , Lipoproteínas/imunologia , Ativação de Macrófagos , Dados de Sequência Molecular , Monócitos/imunologia , Mycoplasma pneumoniae/imunologia , Oligopeptídeos/imunologia , Ácido Palmítico/síntese química , Ácido Palmítico/química , Ácido Palmítico/imunologia , Receptor 2 Toll-Like/metabolismo , Receptores Toll-Like/metabolismo
8.
J Immunol Methods ; 234(1-2): 23-34, 2000 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-10669766

RESUMO

The reactivities of two panels of anti-HAV human sera from geographically distinct areas (Chile and Spain) to synthetic peptides from the VP1, VP2 and VP3 hepatitis A virus capsid proteins were examined by an enzyme-linked immunosorbent assay (ELISA) procedure. Two and four branched multiple antigenic peptides (MAPs) and palmitoylated peptides were compared with free synthetic sequences for the detection of IgM anti-HAV antibodies in the two panels of human sera. Our results showed that acute hepatitis A patient sera recognized preferentially homogeneous two branched MAPs and palmitic acid conjugated peptides. The palmitoyl-derived VP3(110-121) peptide and the corresponding dimeric MAP were the most sensitive and appropriate for serological studies of HAV-infected patients by ELISA, sensitivity and specificity being higher than 90% and 95%, respectively. These peptide-based tests open up new avenues in the development of peptide-based immunosorbent assays for the detection of acute HAV disease.


Assuntos
Antígenos Virais/imunologia , Capsídeo/imunologia , Hepatite A/diagnóstico , Fragmentos de Peptídeos/imunologia , Proteínas Estruturais Virais/imunologia , Doença Aguda , Capsídeo/síntese química , Proteínas do Capsídeo , Ensaio de Imunoadsorção Enzimática/métodos , Epitopos de Linfócito B/imunologia , Hepatite A/sangue , Hepatite A/imunologia , Anticorpos Anti-Hepatite A , Antígenos da Hepatite A , Anticorpos Anti-Hepatite/sangue , Anticorpos Anti-Hepatite/imunologia , Humanos , Testes Imunológicos/métodos , Ácido Palmítico/imunologia , Fragmentos de Peptídeos/síntese química , Peptídeos/síntese química , Peptídeos/imunologia , Kit de Reagentes para Diagnóstico , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Proteínas Estruturais Virais/síntese química
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