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1.
J Biol Chem ; 300(7): 107422, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38815866

RESUMO

Infiltration of monocyte-derived cells to sites of infection and injury is greater in males than in females, due in part, to increased chemotaxis, the process of directed cell movement toward a chemical signal. The mechanisms governing sexual dimorphism in chemotaxis are not known. We hypothesized a role for the store-operated calcium entry (SOCE) pathway in regulating chemotaxis by modulating leading and trailing edge membrane dynamics. We measured the chemotactic response of bone marrow-derived macrophages migrating toward complement component 5a (C5a). Chemotactic ability was dependent on sex and inflammatory phenotype (M0, M1, and M2), and correlated with SOCE. Notably, females exhibited a significantly lower magnitude of SOCE than males. When we knocked out the SOCE gene, stromal interaction molecule 1 (STIM1), it eliminated SOCE and equalized chemotaxis across both sexes. Analysis of membrane dynamics at the leading and trailing edges showed that STIM1 influences chemotaxis by facilitating retraction of the trailing edge. Using BTP2 to pharmacologically inhibit SOCE mirrored the effects of STIM1 knockout, demonstrating a central role of STIM/Orai-mediated calcium signaling. Importantly, by monitoring the recruitment of adoptively transferred monocytes in an in vivo model of peritonitis, we show that increased infiltration of male monocytes during infection is dependent on STIM1. These data support a model in which STIM1-dependent SOCE is necessary and sufficient for mediating the sex difference in monocyte recruitment and macrophage chemotactic ability by regulating trailing edge dynamics.


Assuntos
Cálcio , Quimiotaxia , Macrófagos , Camundongos Knockout , Monócitos , Molécula 1 de Interação Estromal , Molécula 1 de Interação Estromal/metabolismo , Molécula 1 de Interação Estromal/genética , Animais , Feminino , Masculino , Macrófagos/metabolismo , Monócitos/metabolismo , Camundongos , Cálcio/metabolismo , Sinalização do Cálcio , Caracteres Sexuais , Camundongos Endogâmicos C57BL
2.
Mil Med Res ; 10(1): 11, 2023 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-36882803

RESUMO

Gulf War Illness (GWI) encompass a spectrum of maladies specific to troops deployed during the Persian Gulf War (1990-1991). There are several hypothesized factors believed to contribute to GWI, including (but not limited to) exposures to chemical agents and a foreign environment (e.g., dust, pollens, insects, and microbes). Moreover, the inherent stress associated with deployment and combat has been associated with GWI. While the etiology of GWI remains uncertain, several studies have provided strong evidence that chemical exposures, especially neurotoxicants, may be underlying factors for the development of GWI. This mini style perspective article will focus on some of the major evidence linking chemical exposures to GWI development and persistence decades after exposure.


Assuntos
Guerra do Golfo , Veteranos , Humanos
3.
Vaccines (Basel) ; 10(2)2022 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-35214706

RESUMO

"Bugs as drugs" in medicine encompasses the use of microbes to enhance the efficacy of vaccination, such as the delivery of vaccines by Leishmania-the protozoan etiological agent of leishmaniasis. This novel approach is appraised in light of the successful development of vaccines for Covid-19. All relevant aspects of this pandemic are summarized to provide the necessary framework in contrast to leishmaniasis. The presentation is in a side-by-side matching format with particular emphasis on vaccines. The comparative approach makes it possible to highlight the timeframe of the vaccine workflows condensed by the caveats of pandemic urgency and, at the same time, provides the background of Leishmania behind its use as a vaccine carrier. Previous studies in support of the latter are summarized as follows. Leishmaniasis confers life-long immunity on patients after cure, suggesting the effective vaccination is achievable with whole-cell Leishmania. A new strategy was developed to inactivate these cells in vitro, rendering them non-viable, hence non-disease causing, albeit retaining their immunogenicity and adjuvanticity. This was achieved by installing a dual suicidal mechanism in Leishmania for singlet oxygen (1O2)-initiated inactivation. In vitro cultured Leishmania were genetically engineered for cytosolic accumulation of UV-sensitive uroporphyrin I and further loaded endosomally with a red light-sensitive cationic phthalocyanine. Exposing these doubly dye-loaded Leishmania to light triggers intracellular production of highly reactive but extremely short-lived 1O2, resulting in their rapid and complete inactivation. Immunization of susceptible animals with such inactivated Leishmania elicited immunity to protect them against experimental leishmaniasis. Significantly, the inactivated Leishmania was shown to effectively deliver transgenically add-on ovalbumin (OVA) to antigen-presenting cells (APC), wherein OVA epitopes were processed appropriately for presentation with MHC molecules to activate epitope-specific CD8+ T cells. Application of this approach to deliver cancer vaccine candidates, e.g., enolase-1, was shown to suppress tumor development in mouse models. A similar approach is predicted to elicit lasting immunity against infectious diseases, including complementation of the spike protein-based vaccines in use for COVID-19. This pandemic is devastating, but brings to light the necessity of considering many facets of the disease in developing vaccination programs. Closer collaboration is essential among those in diverse disciplinary areas to provide the roadmap toward greater success in the future. Highlighted herein are several specific issues of vaccinology and new approaches worthy of consideration due to the pandemic.

4.
Immune Netw ; 21(5): e35, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34796039

RESUMO

Gulf War Veterans' Illnesses (GWI) encompasses a broad range of unexplained symptomology specific to Veterans of the Persian Gulf War. Gastrointestinal (GI) distress is prominent in veterans with GWI and often presents as irritable bowel syndrome (IBS). Neurotoxins, including organophosphorus pesticides and sarin gas, are believed to have contributed to the development of GWI, at least in a subset of Veterans. However, the effects of such agents have not been extensively studied for their potential impact to GI disorders and immunological stability. Here we utilized an established murine model of GWI to investigate deleterious effects of diisopropyl fluorophosphate (DFP) exposure on the mucosal epithelium in vivo and in vitro. In vivo, acute DFP exposure negatively impacts the mucosal epithelium by reducing tight junction proteins and antimicrobial peptides as well as altering intestinal microbiome composition. Furthermore, DFP treatment reduced the expression of IL-17 in the colonic epithelium. Conversely, both IL-17 and IL-17C treatment could combat the negative effects of DFP and other cholinesterase inhibitors in murine intestinal organoid cells. Our findings demonstrate that acute exposure to DFP can result in rapid deterioration of mechanisms protecting the GI tract from disease. These results are relevant to suspected GWI exposures and could help explain the propensity for GI disorders in GWI Veterans.

5.
Immune Netw ; 21(3): e18, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34277108

RESUMO

TLR signaling is critical for broad scale immune recognition of pathogens and/or danger molecules. TLRs are particularly important for the activation and the maturation of cells comprising the innate immune response. In recent years it has become apparent that several different TLRs regulate the function of lymphocytes as well, albeit to a lesser degree compared to innate immunity. TLR2 heterodimerizes with either TLR1 or TLR6 to broadly recognize bacterial lipopeptides as well as several danger-associated molecular patterns. In general, TLR2 signaling promotes immune cell activation leading to tissue inflammation, which is advantageous for combating an infection. Conversely, inappropriate or dysfunctional TLR2 signaling leading to an overactive inflammatory response could be detrimental during sterile inflammation and autoimmune disease. This review will highlight and discuss recent research advances linking TLR2 engagement to autoimmune inflammation.

6.
Cell Rep ; 35(13): 109303, 2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34192530

RESUMO

Pathogenic Th17 cells drive inflammation in autoimmune disease, yet the molecular programming underlying Th17 cell pathogenicity remains insufficiently understood. Activation of Toll-like receptor 2 (TLR2) increases Th17 cell inflammatory potential, but little is known regarding the mechanistic outcomes of TLR2 signaling in Th17 cells. Here, we demonstrate that TLR2 is comparable to IL-23 in inducing pathogenicity and increasing the migratory capacity of Th17 cells. We perform RNA sequencing of Th17 cells stimulated though the TLR2 pathway and find differential expression of several genes linked with the Th17 genetic program as well as genes not previously associated with pathogenic Th17 cells, including Ipcef1. Enforced expression of Ipcef1 in Th17 cells abolishes the TLR2-dependent increases in migratory capacity and severely impairs the ability of Th17 cells to induce experimental autoimmune encephalomyelitis. This study establishes the importance of the TLR2 signaling pathway in inducing Th17 cell pathogenicity and driving autoimmune inflammation.


Assuntos
Proteínas de Transporte , Movimento Celular , Células Th17 , Receptor 2 Toll-Like , Animais , Masculino , Proteínas de Transporte/metabolismo , Diferenciação Celular/genética , Proliferação de Células , Sistema Nervoso Central/patologia , Regulação para Baixo/genética , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Interleucina-1beta , Interleucina-23 , Camundongos Endogâmicos C57BL , Transdução de Sinais , Células Th17/citologia , Células Th17/imunologia , Receptor 2 Toll-Like/metabolismo , Transcrição Gênica
7.
Front Immunol ; 10: 1911, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456807

RESUMO

Proper orchestration of T lymphocyte development is critical, as T cells underlie nearly all responses of the adaptive immune system. Developing thymocytes differentiate in response to environmental cues carried from cell surface receptors to the nucleus, shaping a distinct transcriptional program that defines their developmental outcome. Our recent work has identified a previously undescribed role for the vacuolar ATPase (V-ATPase) in facilitating the development of murine thymocytes progressing toward the CD4+ and CD8+ αß T cell lineages. Vav1Cre recombinase-mediated deletion of the a2 isoform of the V-ATPase (a2V) in mouse hematopoietic cells leads to a specific and profound loss of peripheral CD4+ and CD8+ αß T cells. Utilizing T cell-restricted LckCre and CD4Cre strains, we further traced this deficiency to the thymus and found that a2V plays a cell-intrinsic role throughout intrathymic development. Loss of a2V manifests as a partial obstruction in the double negative stage of T cell development, and later, a near complete failure of positive selection. These data deepen our understanding of the biological mechanisms that orchestrate T cell development and lend credence to the recent focus on V-ATPase as a potential chemotherapeutic target to combat proliferative potential in T cell lymphoblastic leukemias and autoimmune disease.


Assuntos
Linfopoese , Linfócitos T/fisiologia , Timócitos/fisiologia , Timo/citologia , Timo/enzimologia , ATPases Vacuolares Próton-Translocadoras/fisiologia , Animais , Linfócitos T CD4-Positivos/fisiologia , Linfócitos T CD8-Positivos/fisiologia , Feminino , Deleção de Genes , Leucopenia/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor Notch1/metabolismo , Transdução de Sinais , Timo/imunologia , ATPases Vacuolares Próton-Translocadoras/deficiência , ATPases Vacuolares Próton-Translocadoras/genética
8.
Cell Rep ; 23(8): 2318-2329, 2018 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-29791844

RESUMO

T helper 17 (Th17) cell development is programmed by the orphan nuclear receptor RORγt, but the underlying mechanism is not well understood. Nuclear receptor-mediated transcriptional activation depends on coactivators. Here, we show that steroid receptor coactivator-3 (SRC-3) critically regulates Th17 cell differentiation. Reduced incidence of experimental autoimmune encephalitis (EAE) associated with decreased Th17 cell generation in vivo was observed in mice with SRC-3 deletion specifically in T cells. In vitro, SRC-3 deficiency did not affect TGF-ß/IL-6-induced Th17 cell generation but severely impaired pathogenic Th17 differentiation induced by IL-1/IL-6/IL-23. Microarray analysis revealed that SRC-3 not only regulates IL-17A but also IL-1R1 expression. SRC-3 bound to Il17a and Il1r1 loci in a RORγt-dependent manner and was required for recruitment of the p300 acetyltransferase. Thus, SRC-3 is critical for RORγt-dependent gene expression in Th17 cell-driven autoimmune diseases.


Assuntos
Diferenciação Celular , Coativador 3 de Receptor Nuclear/metabolismo , Células Th17/citologia , Células Th17/imunologia , Animais , Polaridade Celular , Cromatina/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Loci Gênicos , Células HEK293 , Humanos , Interleucinas/metabolismo , Camundongos Transgênicos , Coativador 3 de Receptor Nuclear/deficiência , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Ligação Proteica , Receptores de Interleucina-1/metabolismo
9.
J Leukoc Biol ; 102(5): 1229-1235, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28848043

RESUMO

T cell activation and effector function is characterized by changes in metabolism. Altered metabolism is common to almost all types of activated T cells, but fatty acid synthesis seems to especially drive the formation of Th17 cells. Indeed, research has demonstrated that inhibition of early fatty acid synthesis through targeting of acetyl-CoA carboxylase (ACC1) can inhibit Th17 cell formation and instead promote the generation of regulatory T cells. Fatty acid synthase (FASN) is downstream of ACC, and previous studies have shown that FASN activity influences both cancer and inflammation. However, it remains to be determined whether FASN is a viable target for inhibiting Th17 cell function. Here, we demonstrate that FASN is a critical metabolic control for the generation of inflammatory subsets of Th17 cells. Conversely, inhibiting FASN function promotes IFN-γ production by Th1 and Th1-like Th17 cells. In vivo, inhibition of FASN, specifically in Th17 cells, leads to reduction of experimental autoimmune encephalomyelitis disease. These studies demonstrate the necessity of FASN in the autoimmune inflammatory function of Th17 cells.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Ácido Graxo Sintase Tipo I/imunologia , Interferon gama/imunologia , Interleucina-17/imunologia , Células Th17/imunologia , 4-Butirolactona/análogos & derivados , 4-Butirolactona/farmacologia , Animais , Diferenciação Celular , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/genética , Inibidores Enzimáticos/farmacologia , Ácido Graxo Sintase Tipo I/antagonistas & inibidores , Ácido Graxo Sintase Tipo I/genética , Regulação da Expressão Gênica , Humanos , Interferon gama/genética , Interleucina-17/genética , Interleucina-23/genética , Interleucina-23/imunologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Peptídeos , Cultura Primária de Células , Transdução de Sinais , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/patologia , Células Th17/efeitos dos fármacos , Células Th17/patologia , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/imunologia
10.
Neoplasia ; 19(3): 237-249, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28254151

RESUMO

Wilms' tumors (WT), which accountfor 6% of all childhood cancers, arise from dysregulated differentiation of nephrogenic progenitor cells from embryonic kidneys. Though there is an improvement in the prognosis of WT, still 10% of patients with WT die due to recurrence. Thus more effective treatment approaches are necessary. We previously characterized the inflammatory microenvironment in human WT and observed the robust expression of COX-2. The aim of this study was to extend our studies to analyze the role of COX-2 pathway components in WT progression using a mouse model of WT. Herein, COX-2 pathway components such as COX-2, HIF1-α, p-ERK1/2, and p-STAT3 were upregulated in mouse and human tumor tissues. In our RPPA analysis, COX-2 was up-regulated in M15 cells after Wt1 gene was knocked down. Flow cytometry analysis showed the increased infiltration of immune suppressive inflammatory cells such as pDC's and Treg cells in tumors. The chemotactic chemokines responsible for the infiltration of these cells were also induced in CCR5 and CXCR4 dependent manner respectively. The immunosuppressive cytokines IL-10, TGF-ß, and TNF-α were also up-regulated. Furthermore, more pronounced Th2 and Treg induced cytokine response was observed than Th1 response in tumors. Basing on all these evidences it is speculated that COX-2 pathway may be a beneficial target for the treatment of WT. It may be most effective as an adjuvant therapy together with other inhibitors. Thus, our current study provides a good rationale for initiating animal studies to confirm the efficacy of COX-2 inhibitors in decreasing tumor cell growth in vivo.


Assuntos
Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/metabolismo , Ciclo-Oxigenase 2/metabolismo , Tolerância Imunológica , Transdução de Sinais , Microambiente Tumoral/imunologia , Tumor de Wilms/imunologia , Tumor de Wilms/metabolismo , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Análise por Conglomerados , Citocinas/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Perfilação da Expressão Gênica , Humanos , Mediadores da Inflamação/metabolismo , Fator de Crescimento Insulin-Like II/genética , Fator de Crescimento Insulin-Like II/metabolismo , Camundongos , Camundongos Knockout , Modelos Biológicos , Mutação , Fenótipo , Microambiente Tumoral/genética , Proteínas WT1/metabolismo , Tumor de Wilms/genética , Tumor de Wilms/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Methods Mol Biol ; 1390: 215-27, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26803632

RESUMO

Toll-like receptor (TLR) signaling represents an evolutionary-conserved mechanism allowing for the rapid detection of broad molecular patterns that are common to different groups of pathogens. TLRs are traditionally associated with cells of the innate immune response where ligation of a TLR alone can lead to cellular activation and the initialization of an immune response. Cells of adaptive immunity, namely different classes of T and B lymphocytes, are also known to express a variety of TLRs. Conversely, the functional and signaling outcomes of TLRs are decidedly different in cells of the adaptive immune response. T lymphocytes generally have substantially lower TLR expression compared to innate cells, suggesting that TLRs function in a highly specialized capacity in this cell type. Certain TLRs act in a co-stimulatory capacity on T cells, amplifying activation only in the presence of simultaneous T-cell receptor engagement. However, the full array of TLR signaling events and outcomes in T lymphocytes remains poorly understood. Here, we describe a few methods for investigating the general function of TLRs on T lymphocytes in vitro and in vivo with an emphasis on the study of CD4(+) T cells. Most of these procedures can be adapted for the study of TLR signaling on other classes of lymphocytes as well.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Inflamação/metabolismo , Receptores Toll-Like/metabolismo , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular , Sobrevivência Celular , Regulação da Expressão Gênica , Imunofenotipagem , Inflamação/genética , Inflamação/imunologia , Ativação Linfocitária , Camundongos , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Receptores Toll-Like/genética
12.
J Vis Exp ; (98)2015 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-25938923

RESUMO

Antigen inexperienced (naïve) CD4(+) T cells undergo expansion and differentiation to effector subsets at the time of T cell receptor (TCR) recognition of cognate antigen presented on MHC class II. The cytokine signals present in the environment at the time of TCR activation are a major factor in determining the effector fate of a naïve CD4(+) T cell. Although the cytokine environment during naïve T cell activation may be complex and involve both redundant and opposing signals in vivo, the addition of various cytokine combinations during naive CD4(+) T cell activation in vitro can readily promote the establishment of effector T helper lineages with hallmark cytokine and transcription factor expression. Such differentiation experiments are commonly used as a first step for the evaluation of targets believed to promote or inhibit the development of certain CD4(+) T helper subsets. The addition of mediators, such as signaling agonists, antagonists, or other cytokines, during the differentiation process can also be used to study the influence of a particular target on T cell differentiation. Here, we describe a basic protocol for the isolation of naïve T cells from mouse and the subsequent steps necessary for polarizing naïve cells to various T helper effector lineages in vitro.


Assuntos
Linfócitos T CD4-Positivos/citologia , Subpopulações de Linfócitos T/citologia , Animais , Apresentação de Antígeno , Antígenos/imunologia , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/imunologia , Citocinas/imunologia , Feminino , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Antígenos de Linfócitos T/imunologia , Subpopulações de Linfócitos T/imunologia
13.
J Biol Chem ; 290(24): 14875-83, 2015 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-25922079

RESUMO

Obesity and metabolic disorders such as insulin resistance and type 2 diabetes have become a major threat to public health globally. The mechanisms that lead to insulin resistance in type 2 diabetes have not been well understood. In this study, we show that mice deficient in MAPK phosphatase 5 (MKP5) develop insulin resistance spontaneously at an early stage of life and glucose intolerance at a later age. Increased macrophage infiltration in white adipose tissue of young MKP5-deficient mice correlates with the development of insulin resistance. Glucose intolerance in MKP5-deficient mice is accompanied by significantly increased visceral adipose weight, reduced AKT activation, enhanced p38 activity, and increased inflammation in visceral adipose tissue when compared with wild-type (WT) mice. Deficiency of MKP5 resulted in increased inflammatory activation in macrophages. These findings thus demonstrate that MKP5 critically controls inflammation in white adipose tissue and the development of metabolic disorders.


Assuntos
Tecido Adiposo/patologia , Inflamação/enzimologia , Resistência à Insulina , Fosfatases da Proteína Quinase Ativada por Mitógeno/metabolismo , Tecido Adiposo/enzimologia , Animais , Glucose/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfatases da Proteína Quinase Ativada por Mitógeno/genética
14.
Immunity ; 42(4): 692-703, 2015 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-25888259

RESUMO

The interleukin-17 (IL-17) family of cytokines has emerged as a critical player in inflammatory diseases. Among them, IL-25 has been shown to be important in allergic inflammation and protection against parasitic infection. Here we have demonstrated that IL-17B, a poorly understood cytokine, functions to inhibit IL-25-driven inflammation. IL-17B and IL-25, both binding to the interleukin-17 receptor B (IL-17RB), were upregulated in their expression after acute colonic inflammation. Individual inhibition of these cytokines revealed opposing functions in colon inflammation: IL-25 was pathogenic but IL-17B was protective. Similarly opposing phenotypes were observed in Citrobacter rodentium infection and allergic asthma. Moreover, IL-25 was found to promote IL-6 production from colon epithelial cells, which was inhibited by IL-17B. Therefore, our data demonstrate that IL-17B is an anti-inflammatory cytokine in the IL-17 family.


Assuntos
Asma/imunologia , Colite/imunologia , Disbiose/imunologia , Infecções por Enterobacteriaceae/imunologia , Interleucina-17/imunologia , Interleucinas/imunologia , Mucosa Intestinal/imunologia , Animais , Antibacterianos , Asma/induzido quimicamente , Asma/genética , Asma/patologia , Linhagem Celular , Citrobacter rodentium/imunologia , Colite/induzido quimicamente , Colite/genética , Colite/patologia , Disbiose/induzido quimicamente , Disbiose/genética , Disbiose/patologia , Infecções por Enterobacteriaceae/genética , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/patologia , Células Epiteliais/imunologia , Células Epiteliais/patologia , Regulação da Expressão Gênica , Interleucina-17/deficiência , Interleucina-17/genética , Interleucina-6/genética , Interleucina-6/imunologia , Interleucinas/deficiência , Interleucinas/genética , Mucosa Intestinal/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ovalbumina , Ligação Proteica , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/imunologia , Transdução de Sinais , Dodecilsulfato de Sódio
15.
PLoS Pathog ; 11(3): e1004706, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25768794

RESUMO

The role of IL-1ß and IL-18 during lung infection with the gram-negative bacterium Francisella tularensis LVS has not been characterized in detail. Here, using a mouse model of pneumonic tularemia, we show that both cytokines are protective, but through different mechanisms. Il-18-/- mice quickly succumb to the infection and showed higher bacterial burden in organs and lower level of IFNγ in BALF and serum compared to wild type C57BL/6J mice. Administration of IFNγ rescued the survival of Il-18-/- mice, suggesting that their decreased resistance to tularemia is due to inability to produce IFNγ. In contrast, mice lacking IL-1 receptor or IL-1ß, but not IL-1α, appeared to control the infection in its early stages, but eventually succumbed. IFNγ administration had no effect on Il-1r1-/- mice survival. Rather, Il-1r1-/- mice were found to have significantly reduced titer of Ft LPS-specific IgM. The anti-Ft LPS IgM was generated in a IL-1ß-, TLR2-, and ASC-dependent fashion, promoted bacteria agglutination and phagocytosis, and was protective in passive immunization experiments. B1a B cells produced the anti-Ft LPS IgM and these cells were significantly decreased in the spleen and peritoneal cavity of infected Il-1b-/- mice, compared to C57BL/6J mice. Collectively, our results show that IL-1ß and IL-18 activate non-redundant protective responses against tularemia and identify an essential role for IL-1ß in the rapid generation of pathogen-specific IgM by B1a B cells.


Assuntos
Anticorpos Antibacterianos/imunologia , Subpopulações de Linfócitos B/imunologia , Imunoglobulina M/imunologia , Interleucina-1beta/imunologia , Tularemia/imunologia , Animais , Western Blotting , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Lipopolissacarídeos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infecções Respiratórias/imunologia
16.
Cell Rep ; 10(10): 1722-1734, 2015 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-25772359

RESUMO

The type I interferon system is essential for antiviral immune response and is a primary target of viral immune evasion strategies. Here, we show that virus infection induces the expression of MAPK phosphatase 5 (MKP5), a dual-specificity phosphatase (DUSP), in host cells. Mice deficient in MKP5 were resistant to H1N1 influenza infection, which is associated with increased IRF3 activation and type I interferon expression in comparison with WT mice. Increased type I interferon responses were also observed in MKP5-deficient cells and animals upon other RNA virus infection, including vesicular stomatitis virus and sendai virus. These observations were attributed to the ability of MKP5 to interact with and dephosphorylate IRF3. Our study reveals a critical function of a DUSP in negative regulation of IRF3 activity and demonstrates a mechanism by which influenza and other RNA viruses inhibit type I interferon response in the host through MKP5.

17.
J Immunol ; 194(7): 3088-95, 2015 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-25716993

RESUMO

Members of the MAPK phosphatase (MKP) protein family play critical roles in immune responses through differential regulation of MAPK activation. In this study, we show that MKP7, also known as dual-specificity phosphatase 16, was required for CD4(+) T cell responses in vivo. Mkp7(-/-) CD4(+) T cells exhibited enhanced ERK and JNK activation, and produced increased amount of IL-2 compared with Mkp7(+/+) cells upon activation. Mkp7(-/-) CD4(+) T cells were selectively defective in Th17 differentiation in vitro, which was rescued by blocking IL-2 or inhibition of ERK activation. Furthermore, mice carrying Mkp7(-/-) T cells were deficient in generation of Th17 and T follicular helper cells in vivo, and were resistant to autoimmune experimental encephalomyelitis. Our results thus demonstrate an essential role of MKP7 in effector T cell function.


Assuntos
Diferenciação Celular/genética , Fosfatases de Especificidade Dupla/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação da Expressão Gênica , Interleucina-2/genética , Fosfatases da Proteína Quinase Ativada por Mitógeno/genética , Linfócitos T/citologia , Linfócitos T/metabolismo , Animais , Autoimunidade/genética , Autoimunidade/imunologia , Fosfatases de Especificidade Dupla/deficiência , Fosfatases de Especificidade Dupla/metabolismo , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Genes Letais , Interleucina-2/metabolismo , Ativação Linfocitária/imunologia , Camundongos , Camundongos Transgênicos , Fosfatases da Proteína Quinase Ativada por Mitógeno/deficiência , Fosfatases da Proteína Quinase Ativada por Mitógeno/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T/imunologia , Células Th17/citologia , Células Th17/imunologia , Células Th17/metabolismo
19.
Immunity ; 40(1): 153-65, 2014 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-24412615

RESUMO

Patients with systemic autoimmune diseases show increased incidence of atherosclerosis. However, the contribution of proatherogenic factors to autoimmunity remains unclear. We found that atherogenic mice (herein referred to as LDb mice) exhibited increased serum interleukin-17, which was associated with increased numbers of T helper 17 (Th17) cells in secondary lymphoid organs. The environment within LDb mice was substantially favorable for Th17 cell polarization of autoreactive T cells during homeostatic proliferation, which was considerably inhibited by antibodies directed against oxidized low-density lipoprotein (oxLDL). Moreover, the uptake of oxLDL induced dendritic-cell-mediated Th17 cell polarization by triggering IL-6 production in a process dependent on TLR4, CD36, and MyD88. Furthermore, self-reactive CD4(+) T cells that expanded in the presence of oxLDL induced more profound experimental autoimmune encephalomyelitis. These findings demonstrate that proatherogenic factors promote the polarization and inflammatory function of autoimmune Th17 cells, which could be critical for the pathogenesis of atherosclerosis and other related autoimmune diseases.


Assuntos
Aterosclerose/imunologia , Células Dendríticas/imunologia , Encefalomielite Autoimune Experimental/imunologia , Interleucina-17/metabolismo , Células Th17/imunologia , Transferência Adotiva , Animais , Anticorpos Bloqueadores/metabolismo , Aterosclerose/genética , Autoimunidade , Antígenos CD36/metabolismo , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Interleucina-6/metabolismo , Lipoproteínas LDL/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/metabolismo , Receptor 4 Toll-Like/metabolismo
20.
PLoS Pathog ; 9(9): e1003628, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24068935

RESUMO

Although the protective functions by T helper 17 (Th17) cytokines against extracellular bacterial and fungal infection have been well documented, their importance against intracellular bacterial infection remains unclear. Here, we investigated the contribution of Th17 responses to host defense against intracellular bacteria Listeria monocytogenes and found that Th17 cell generation was suppressed in this model. Unexpectedly, mice lacking both p35 and EBI3 cleared L. monocytogenes as efficiently as wild-type mice, whereas p35-deficient mice failed to do so. Furthermore, both innate cells and pathogen-specific T cells from double-deficient mice produced significantly higher IL-17 and IL-22 compared to wild-type mice. The bacterial burden in the liver of double-deficient mice treated with anti-IL-17 was significantly increased compared to those receiving a control Ab. Transfer of Th17 cells specific for listeriolysin O as well as administration of IL-17 and IL-22 significantly suppressed bacterial growth in p35-deficient mice, indicating the critical contribution of Th17 responses to host defense against the intracellular pathogen in the absence of IL-12 and proper Th1 responses. Our findings unveil a novel immune evasion mechanism whereby the intracellular bacteria exploit IL-27EBI3 to suppress Th17-mediated protective immunity.


Assuntos
Regulação para Baixo , Imunidade Celular , Subunidade p35 da Interleucina-12/metabolismo , Listeria monocytogenes/imunologia , Listeriose/imunologia , Receptores de Citocinas/metabolismo , Células Th17/imunologia , Animais , Carga Bacteriana , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/microbiologia , Linfócitos T CD8-Positivos/patologia , Linfócitos T CD8-Positivos/transplante , Células Cultivadas , Regulação da Expressão Gênica , Evasão da Resposta Imune , Imunidade Inata , Subunidade p35 da Interleucina-12/genética , Interleucina-17/genética , Interleucina-17/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Listeria monocytogenes/crescimento & desenvolvimento , Listeria monocytogenes/isolamento & purificação , Listeriose/microbiologia , Listeriose/patologia , Listeriose/terapia , Fígado/imunologia , Fígado/microbiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Antígenos de Histocompatibilidade Menor , Receptores de Citocinas/genética , Baço/imunologia , Baço/metabolismo , Baço/microbiologia , Baço/patologia , Células Th17/metabolismo , Células Th17/microbiologia , Células Th17/patologia , Interleucina 22
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