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1.
Nanomedicine ; 47: 102614, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36265560

RESUMO

Universal influenza vaccines are urgently needed to prevent recurrent influenza epidemics and inevitable pandemics. We generated double-layered protein nanoparticles incorporating two conserved influenza antigens-nucleoprotein and neuraminidase-through a two-step desolvation-crosslinking method. These protein nanoparticles displayed immunostimulatory properties to antigen-presenting cells by promoting inflammatory cytokine (IL-6 and TNF-α) secretion from JAWS II dendric cells. The nanoparticle immunization induced significant antigen-specific humoral and cellular responses, including antigen-binding and neutralizing antibodies, antibody- and cytokine (IFN-γ and IL-4)-secreting cells, and NP147-155 tetramer-specific cytotoxic T lymphocyte (CTL) responses. Co-administration of monophosphoryl lipid A (MPLA, a toll-like receptor 4 agonist) with the protein nanoparticles further improved immune responses and conferred heterologous and heterosubtypic influenza protection. The MPLA-adjuvanted nanoparticles reduced lung inflammation post-infection. The results demonstrated that the combination of MPLA and conserved protein nanoparticles could be developed into an improved universal influenza vaccine strategy.


Assuntos
Adjuvantes Imunológicos , Infecções por Orthomyxoviridae , Orthomyxoviridae , Citocinas , Neuraminidase , Nucleoproteínas , Animais , Camundongos , Infecções por Orthomyxoviridae/prevenção & controle , Nanopartículas
2.
Proc Natl Acad Sci U S A ; 117(44): 27540-27548, 2020 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-33087566

RESUMO

Enteropathogenic bacterial infections are a global health issue associated with high mortality, particularly in developing countries. Efficient host protection against enteropathogenic bacterial infection is characterized by coordinated responses between immune and nonimmune cells. In response to infection in mice, innate immune cells are activated to produce interleukin (IL)-23 and IL-22, which promote antimicrobial peptide (AMP) production and bacterial clearance. IL-36 cytokines are proinflammatory IL-1 superfamily members, yet their role in enteropathogenic bacterial infection remains poorly defined. Using the enteric mouse pathogen, C.rodentium, we demonstrate that signaling via IL-36 receptor (IL-36R) orchestrates a crucial innate-adaptive immune link to control bacterial infection. IL-36R-deficient mice (Il1rl2-/- ) exhibited significant impairment in expression of IL-22 and AMPs, increased intestinal damage, and failed to contain C. rodentium compared to controls. These defects were associated with failure to induce IL-23 and IL-6, two key IL-22 inducers in the early and late phases of infection, respectively. Treatment of Il1rl2-/- mice with IL-23 during the early phase of C. rodentium infection rescued IL-22 production from group 3 innate lymphoid cells (ILCs), whereas IL-6 administration during the late phase rescued IL-22-mediated production from CD4+ T cell, and both treatments protected Il1rl2-/- mice from uncontained infection. Furthermore, IL-36R-mediated IL-22 production by CD4+ T cells was dependent upon NFκB-p65 and IL-6 expression in dendritic cells (DCs), as well as aryl hydrocarbon receptor (AhR) expression by CD4+ T cells. Collectively, these data demonstrate that the IL-36 signaling pathway integrates innate and adaptive immunity leading to host defense against enteropathogenic bacterial infection.


Assuntos
Imunidade Adaptativa , Citrobacter rodentium/imunologia , Infecções por Enterobacteriaceae/imunologia , Imunidade Inata , Receptores de Interleucina-1/metabolismo , Animais , Citrobacter rodentium/patogenicidade , Modelos Animais de Doenças , Infecções por Enterobacteriaceae/microbiologia , Interleucina-1/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Camundongos , Camundongos Knockout , Receptores de Interleucina-1/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia
3.
Immunology ; 167(1): 64-76, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35689599

RESUMO

In the gut, secretory immunoglobulin A is the predominant humoral response against commensals, although healthy hosts also produce microbiota-specific IgG antibodies. During intestinal inflammation, the content of IgG in the lumen increases along with the proportion of commensal bacteria coated with this antibody, suggesting signalling through the IgG-CD64 axis in the pathogenesis of inflammatory bowel diseases. In this work, we evaluated day by day the frequency of faecal bacteria coated with IgA and IgG during the development of DSS colitis. We studied the phenotype and phagocytic activity of F4/80+ CD64+ colonic macrophages, as well as the production of cytokines and nitric oxide by lamina propria or bone marrow-derived macrophages after stimulation with IgA+ , IgG+ and IgA+ IgG+ bacteria. We found that the percentage of faecal IgA+ IgG+ double-coated bacteria increased rapidly during DSS colitis. Also, analysis of the luminal content of mice with colitis showed a markedly superior ability to coat fresh bacteria. IgA+ IgG+ bacteria were the most potent stimulus for phagocytic activity involving CD64 and Dectin-1 receptors. IgA+ IgG+ bacteria observed during the development of DSS colitis could represent a new marker to monitor permeability and inflammatory progression. The interaction of IgA+ IgG+ bacteria with CD64+ F4/80+ macrophages could be part of the complex cascade of events in colitis. Interestingly, after stimulation, CD64+ colonic macrophages showed features similar to those of restorative macrophages that are relevant for tissue repair and healing.


Assuntos
Colite , Colo , Animais , Bactérias , Colite/induzido quimicamente , Colite/patologia , Colo/patologia , Sulfato de Dextrana , Imunoglobulina A Secretora , Imunoglobulina G , Inflamação/patologia , Macrófagos , Camundongos , Receptores de IgG
4.
Immunology ; 163(2): 145-154, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33501638

RESUMO

Interleukin 36 (IL-36) constitutes a group of cytokines that belong to the IL-1 superfamily. Emerging evidence has suggested a role of IL-36 in the pathogenesis of many inflammatory disorders. Intriguingly, in the gastrointestinal tract, IL-36 has a rather complex function. IL-36 receptor ligands are overexpressed in both animal colitis models and human IBD patients and may play both pathogenic and protective roles, depending on the context. IL-36 cytokines comprise three receptor agonists: IL-36α, IL-36ß and IL-36γ, and two receptor antagonists: IL-36Ra and IL-38. All IL-36 receptor agonists bind to the IL-36R complex and exert pleiotropic effects during inflammatory settings. Here, we first briefly review the processing and secretion of IL-36 cytokines. We then focus on the current understanding of the immunology effects of IL-36 in gut immunity. In addition, we also discuss the ongoing trials that aim to blockage IL-36R signalling for treating chronic intestinal inflammation and present some unexplored questions regarding IL-36 research.


Assuntos
Colite/imunologia , Inflamação/imunologia , Doenças Inflamatórias Intestinais/imunologia , Interleucina-1/metabolismo , Mucosa Intestinal/imunologia , Animais , Modelos Animais de Doenças , Humanos , Interleucinas/metabolismo , Terapia de Alvo Molecular , Receptores de Interleucina-1/metabolismo , Transdução de Sinais
5.
Immunity ; 37(3): 563-73, 2012 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-22981539

RESUMO

Mice lacking junctional adhesion molecule A (JAM-A, encoded by F11r) exhibit enhanced intestinal epithelial permeability, bacterial translocation, and elevated colonic lymphocyte numbers, yet do not develop colitis. To investigate the contribution of adaptive immune compensation in response to increased intestinal epithelial permeability, we examined the susceptibility of F11r(-/-)Rag1(-/-) mice to acute colitis. Although negligible contributions of adaptive immunity in F11r(+/+)Rag1(-/-) mice were observed, F11r(-/-)Rag1(-/-) mice exhibited increased microflora-dependent colitis. Elimination of T cell subsets and cytokine analyses revealed a protective role for TGF-ß-producing CD4(+) T cells in F11r(-/-) mice. Additionally, loss of JAM-A resulted in elevated mucosal and serum IgA that was dependent upon CD4(+) T cells and TGF-ß. Absence of IgA in F11r(+/+)Igha(-/-) mice did not affect disease, whereas F11r(-/-)Igha(-/-) mice displayed markedly increased susceptibility to acute injury-induced colitis. These data establish a role for adaptive immune-mediated protection from acute colitis under conditions of intestinal epithelial barrier compromise.


Assuntos
Imunidade Adaptativa/imunologia , Colite/imunologia , Mucosa Intestinal/imunologia , Intestinos/imunologia , Imunidade Adaptativa/genética , Animais , Translocação Bacteriana/genética , Translocação Bacteriana/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/imunologia , Colite/induzido quimicamente , Colite/genética , Sulfato de Dextrana , Epitélio/imunologia , Epitélio/metabolismo , Feminino , Citometria de Fluxo , Expressão Gênica , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/imunologia , Imunoglobulina A/genética , Imunoglobulina A/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Intestinos/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Permeabilidade , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/imunologia , Fator de Crescimento Transformador beta/metabolismo
6.
Proc Natl Acad Sci U S A ; 115(22): E5076-E5085, 2018 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-29760082

RESUMO

The gut epithelium acts to separate host immune cells from unrestricted interactions with the microbiota and other environmental stimuli. In response to epithelial damage or dysfunction, immune cells are activated to produce interleukin (IL)-22, which is involved in repair and protection of barrier surfaces. However, the specific pathways leading to IL-22 and associated antimicrobial peptide (AMP) production in response to intestinal tissue damage remain incompletely understood. Here, we define a critical IL-36/IL-23/IL-22 cytokine network that is instrumental for AMP production and host defense. Using a murine model of intestinal damage and repair, we show that IL-36γ is a potent inducer of IL-23 both in vitro and in vivo. IL-36γ-induced IL-23 required Notch2-dependent (CD11b+CD103+) dendritic cells (DCs), but not Batf3-dependent (CD11b-CD103+) DCs or CSF1R-dependent macrophages. The intracellular signaling cascade linking IL-36 receptor (IL-36R) to IL-23 production by DCs involved MyD88 and the NF-κB subunits c-Rel and p50. Consistent with in vitro observations, IL-36R- and IL-36γ-deficient mice exhibited dramatically reduced IL-23, IL-22, and AMP levels, and consequently failed to recover from acute intestinal damage. Interestingly, impaired recovery of mice deficient in IL-36R or IL-36γ could be rescued by treatment with exogenous IL-23. This recovery was accompanied by a restoration of IL-22 and AMP expression in the colon. Collectively, these data define a cytokine network involving IL-36γ, IL-23, and IL-22 that is activated in response to intestinal barrier damage and involved in providing critical host defense.


Assuntos
Imunidade Inata/imunologia , Doenças Inflamatórias Intestinais/imunologia , Interleucinas/imunologia , Cicatrização/imunologia , Animais , Doenças Inflamatórias Intestinais/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Camundongos , Camundongos Transgênicos
7.
FASEB J ; 33(3): 3623-3635, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30481488

RESUMO

Autotaxin (ATX or ENPP2) is a secreted lysophospholipase D that produces lysophosphatidic acid (LPA), a pleiotropic lipid mediator acting on specific GPCRs. ATX and LPA have been implicated in key (patho)physiologic processes, including embryonic development, lymphocyte homing, inflammation, and cancer progression. Using LPA receptor knockout mice, we previously uncovered a role for LPA signaling in promoting colitis and colorectal cancer. Here, we examined the role of ATX in experimental colitis through inducible deletion of Enpp2 in adult mice. ATX expression was increased upon induction of colitis, whereas ATX deletion reduced the severity of inflammation in both acute and chronic colitis, accompanied by transient weight loss. ATX expression in lymphocytes was strongly reduced in Rag1-/- and µMT mice, suggesting B cells as a major ATX-producing source, which was validated by immunofluorescence and biochemical analyses. ATX secretion by B cells from control, but not Enpp2 knockout, mice led to ERK activation in colorectal cancer cells and promoted T cell migration. We conclude that ATX deletion suppresses experimental colitis and that B cells are a major source of ATX in the colon. Our study suggests that pharmacological inhibition of ATX could be a therapeutic strategy in colitis.-Lin, S., Haque, A., Raeman, R., Guo, L., He, P., Denning, T. L., El-Rayes, B., Moolenaar, W. H., Yun, C. C. Autotaxin determines colitis severity in mice and is secreted by B cells in the colon.


Assuntos
Linfócitos B/metabolismo , Colite/metabolismo , Colo/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Células HCT116 , Humanos , Inflamação/metabolismo , Linfócitos/metabolismo , Lisofosfolipídeos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Ácidos Lisofosfatídicos/metabolismo , Transdução de Sinais/fisiologia
8.
J Immunol ; 201(2): 573-582, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29848754

RESUMO

Although influenza virus infection remains a concerning disease for public health, the roles of individual cytokines during the immune response to influenza infection are not fully understood. We have identified IL-36γ as a key mediator of immune protection during both high- and low-pathogenesis influenza infection. Il36g mRNA is upregulated in the lung following influenza infection, and mice lacking IL-36γ have greatly increased morbidity and mortality upon infection with either H1N1 or H3N2 influenza. The increased severity of influenza infection in IL-36γ-knockout (KO) mice is associated with increased viral titers, higher levels of proinflammatory cytokines early in infection, and more diffuse pathologic conditions late in the disease course. Interestingly, the increased severity of disease in IL-36γ-KO mice correlates with a rapid loss of alveolar macrophages following infection. We find that the alveolar macrophages from naive IL-36γ-KO mice have higher expression of M2-like surface markers compared with wild-type (WT) mice and show increased apoptosis within 24 h of infection. Finally, transfer of WT alveolar macrophages to IL-36γ-KO mice restores protection against lethal influenza challenge to levels observed in WT mice. Together, these data identify a critical role for IL-36γ in immunity against influenza virus and demonstrate the importance of IL-36γ signaling for alveolar macrophage survival during infection.


Assuntos
Vírus da Influenza A Subtipo H1N1/fisiologia , Vírus da Influenza A Subtipo H3N2/fisiologia , Influenza Humana/imunologia , Interleucina-1/metabolismo , Pulmão/patologia , Macrófagos Alveolares/fisiologia , Infecções por Orthomyxoviridae/imunologia , Transferência Adotiva , Animais , Sobrevivência Celular , Células Cultivadas , Humanos , Interleucina-1/genética , Macrófagos Alveolares/transplante , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Regulação para Cima , Replicação Viral
9.
Nature ; 497(7448): 258-62, 2013 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-23624374

RESUMO

Peripheral mechanisms preventing autoimmunity and maintaining tolerance to commensal microbiota involve CD4(+) Foxp3(+) regulatory T (Treg) cells generated in the thymus or extrathymically by induction of naive CD4(+) Foxp3(-) T cells. Previous studies suggested that the T-cell receptor repertoires of thymic Treg cells and induced Treg cells are biased towards self and non-self antigens, respectively, but their relative contribution in controlling immunopathology, such as colitis and other untoward inflammatory responses triggered by different types of antigens, remains unresolved. The intestine, and especially the colon, is a particularly suitable organ to study this question, given the variety of self-, microbiota- and food-derived antigens to which Treg cells and other T-cell populations are exposed. Intestinal environments can enhance conversion to a regulatory lineage and favour tolerogenic presentation of antigens to naive CD4(+) T cells, suggesting that intestinal homeostasis depends on microbiota-specific induced Treg cells. Here, to identify the origin and antigen-specificity of intestinal Treg cells, we performed single-cell and high-throughput sequencing of the T-cell receptor repertoires of CD4(+) Foxp3(+) and CD4(+) Foxp3(-) T cells, and analysed their reactivity against specific commensal species. We show that thymus-derived Treg cells constitute most Treg cells in all lymphoid and intestinal organs, including the colon, where their repertoire is heavily influenced by the composition of the microbiota. Our results suggest that thymic Treg cells, and not induced Treg cells, dominantly mediate tolerance to antigens produced by intestinal commensals.


Assuntos
Colo/microbiologia , Tolerância Imunológica/imunologia , Simbiose/imunologia , Linfócitos T Reguladores/imunologia , Timo/imunologia , Animais , Antibacterianos/farmacologia , Antígenos de Bactérias/imunologia , Colo/efeitos dos fármacos , Colo/imunologia , Feminino , Fatores de Transcrição Forkhead/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Homeostase/efeitos dos fármacos , Homeostase/imunologia , Tolerância Imunológica/efeitos dos fármacos , Tecido Linfoide/citologia , Tecido Linfoide/imunologia , Masculino , Camundongos , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Análise de Célula Única , Simbiose/efeitos dos fármacos , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo , Timócitos/citologia , Timócitos/efeitos dos fármacos , Timócitos/imunologia , Timócitos/metabolismo , Timo/citologia
10.
Immunology ; 2018 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-29771448

RESUMO

Segmented filamentous bacteria (SFB) are Gram-positive, spore-forming, bacteria that primarily colonize the ileum of the small intestine. Upon direct adherence to intestinal epithelial cells, SFB actively stimulate innate and adaptive immune cell activation. The cardinal features of SFB-induced gut immunity - T helper type 17 (Th17) cell differentiation, IgA production and barrier protection - lead to the containment of SFB and further afford protection against invading pathogens. Th17 cells and interleukin-17A, however, can also reach peripheral sites and exacerbate autoimmunity. In this review, we highlight salient characteristics of SFB-host interactions and detail the cellular and molecular immune mechanisms involved in coordinating these responses.

11.
J Immunol ; 196(1): 34-8, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26590314

RESUMO

IL-1 family members are central mediators of host defense. In this article, we show that the novel IL-1 family member IL-36γ was expressed during experimental colitis and human inflammatory bowel disease. Germ-free mice failed to induce IL-36γ in response to dextran sodium sulfate (DSS)-induced damage, suggesting that gut microbiota are involved in its induction. Surprisingly, IL-36R-deficient (Il1rl2(-/-)) mice exhibited defective recovery following DSS-induced damage and impaired closure of colonic mucosal biopsy wounds, which coincided with impaired neutrophil accumulation in the wound bed. Failure of Il1rl2(-/-) mice to recover from DSS-induced damage was associated with a profound reduction in IL-22 expression, particularly by colonic neutrophils. Defective recovery of Il1rl2(-/-) mice could be rescued by an aryl hydrocarbon receptor agonist, which was sufficient to restore IL-22 expression and promote full recovery from DSS-induced damage. These findings implicate the IL-36/IL-36R axis in the resolution of intestinal mucosal wounds.


Assuntos
Colite/imunologia , Interleucina-1/biossíntese , Interleucinas/biossíntese , Receptores de Interleucina/imunologia , Cicatrização/imunologia , Animais , Colite/induzido quimicamente , Colite/microbiologia , Colo/imunologia , Colo/lesões , Sulfato de Dextrana , Helicobacter hepaticus/patogenicidade , Humanos , Inflamação/imunologia , Inflamação/patologia , Doenças Inflamatórias Intestinais/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infiltração de Neutrófilos/imunologia , Neutrófilos/imunologia , Neutrófilos/metabolismo , Receptores de Hidrocarboneto Arílico/agonistas , Receptores de Interleucina/genética , Cicatrização/genética , Interleucina 22
12.
J Virol ; 90(15): 6976-6988, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27226368

RESUMO

UNLABELLED: CD4(+) T cells play a central role in orchestrating adaptive immunity. To better understand the roles of CD4(+) T cells in the effects of adjuvants, we investigated the efficacy of a T-dependent influenza virus split vaccine with MF59 or alum in CD4 knockout (CD4KO) and wild-type (WT) mice. CD4(+) T cells were required for the induction of IgG antibody responses to the split vaccine and the effects of alum adjuvant. In contrast, MF59 was found to be highly effective in raising isotype-switched IgG antibodies to a T-dependent influenza virus split vaccine in CD4KO mice or CD4-depleted WT mice equivalent to those in intact WT mice, thus overcoming the deficiency of CD4(+) T cells in helping B cells and inducing immunity against influenza virus. Vaccination with the MF59-adjuvanted influenza virus vaccine was able to induce protective CD8(+) T cells and long-lived antibody-secreting cells in CD4KO mice. The effects of MF59 adjuvant in CD4KO mice might be associated with uric acid, inflammatory cytokines, and the recruitment of multiple immune cells at the injection site, but their cellularity and phenotypes were different from those in WT mice. These findings suggest a new paradigm of CD4-independent adjuvant mechanisms, providing the rationales to improve vaccine efficacy in infants, the elderly, immunocompromised patients, as well as healthy adults. IMPORTANCE: MF59-adjuvanted influenza vaccines were licensed for human vaccination, but the detailed mechanisms are not fully elucidated. CD4(+) T cells are required to induce antibody isotype switching and long-term memory responses. In contrast, we discovered that MF59 was highly effective in inducing isotype-switched IgG antibodies and long-term protective immune responses to a T-dependent influenza vaccine independent of CD4(+) T cells. These findings are highly significant for the following reasons: (i) MF59 can overcome a defect of CD4(+) T cells in inducing protective immunity to vaccination with a T-dependent influenza virus vaccine; (ii) a CD4-independent pathway can be an alternative mechanism for certain adjuvants such as MF59; and (iii) this study has significant implications for improving vaccine efficacies in young children, the elderly, and immunocompromised populations.


Assuntos
Anticorpos/metabolismo , Linfócitos T CD4-Positivos , Imunoglobulina G/imunologia , Isotipos de Imunoglobulinas/imunologia , Vacinas contra Influenza/administração & dosagem , Pneumonia/prevenção & controle , Polissorbatos/administração & dosagem , Esqualeno/administração & dosagem , Linfócitos T/imunologia , Adjuvantes Imunológicos , Animais , Células Produtoras de Anticorpos , Antígenos CD4/fisiologia , Células Cultivadas , Feminino , Imunização/métodos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/complicações , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Pneumonia/etiologia
13.
Am J Pathol ; 185(7): 1809-19, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25976247

RESUMO

The microbiota that populate the mammalian intestine are critical for proper host physiology, yet simultaneously pose a potential danger. Intestinal antigen-presenting cells, namely macrophages and dendritic cells (DCs), are integral components of the mucosal innate immune system that maintain co-existence with the microbiota in face of this constant threat. Intestinal macrophages and DCs integrate signals from the microenvironment to orchestrate innate and adaptive immune responses that ultimately lead to durable tolerance of the microbiota. Tolerance is not a default response, however, because macrophages and DCs remain poised to vigorously respond to pathogens that breach the epithelial barrier. In this review, we summarize the salient features of macrophages and DCs in the healthy and inflamed intestine and discuss how signals from the microbiota can influence their function.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Células Dendríticas/imunologia , Intestinos/imunologia , Macrófagos/imunologia , Microbiota/imunologia , Animais , Distinções e Prêmios , Homeostase/imunologia , Humanos , Tolerância Imunológica/imunologia , Inflamação/imunologia , Intestinos/citologia , Intestinos/microbiologia , Intestinos/patologia , Mamíferos , Patologia , Fenótipo , Sociedades Médicas , Estados Unidos
14.
J Immunol ; 193(1): 431-8, 2014 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-24899505

RESUMO

IL-17-expressing CD4+ T lymphocytes (Th17 cells) naturally reside in the intestine where specific cytokines and microbiota, such as segmented filamentous bacteria (SFB), promote their differentiation. Intestinal Th17 cells are thought to initially differentiate in the GALT and/or mesenteric lymph nodes upon Ag encounter and subsequently home to the lamina propria (LP) where they mediate effector functions. However, whether GALT and/or mesenteric lymph nodes are required for intestinal Th17 differentiation as well as how microbiota containing SFB regulate Ag-specific intestinal Th17 cells remain poorly defined. In this study, we observed that naive CD4+ T cells were abundant in the intestinal LP prior to weaning and that the accumulation of Th17 cells in response to microbiota containing SFB occurred in the absence of lymphotoxin-dependent lymphoid structures and the spleen. Furthermore, the differentiation of intestinal Th17 cells in the presence of microbiota containing SFB was dependent on MHC class II expression by CD11c+ cells. Lastly, the differentiation of Ag-specific Th17 cells required both the presence of cognate Ag and microbiota containing SFB. These findings suggest that microbiota containing SFB create an intestinal milieu that may induce Ag-specific Th17 differentiation against food and/or bacterial Ags directly in the intestinal LP.


Assuntos
Bactérias/imunologia , Diferenciação Celular/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Intestinos , Linfonodos/imunologia , Mesentério/imunologia , Células Th17/imunologia , Animais , Antígenos de Bactérias/imunologia , Diferenciação Celular/genética , Antígenos de Histocompatibilidade Classe II/genética , Intestinos/imunologia , Intestinos/microbiologia , Camundongos , Camundongos Knockout , Células Th17/citologia
15.
J Immunol ; 190(5): 2009-16, 2013 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-23359509

RESUMO

The liver has long been described as immunosuppressive, although the mechanisms underlying this phenomenon are incompletely understood. Hepatic stellate cells (HSCs), a population of liver nonparenchymal cells, are potent producers of the regulatory T cell (Treg)-polarizing molecules TGF-ß1 and all-trans retinoic acid, particularly during states of inflammation. HSCs are activated during hepatitis C virus infection and may therefore play a role in the enrichment of Tregs during infection. We hypothesized that Ag presentation in the context of HSC activation will induce naive T cells to differentiate into Foxp3(+) Tregs. To test this hypothesis, we investigated the molecular interactions between murine HSCs, dendritic cells, and naive CD4(+) T cells. We found that HSCs alone do not present Ag to naive CD4(+) T cells, but in the presence of dendritic cells and TGF-ß1, preferentially induce functional Tregs. This Treg induction was associated with retinoid metabolism by HSCs and was dependent on all-trans retinoic acid. Thus, we conclude that HSCs preferentially generate Foxp3(+) Tregs and, therefore, may play a role in the tolerogenic nature of the liver.


Assuntos
Células Dendríticas/imunologia , Fatores de Transcrição Forkhead/imunologia , Células Estreladas do Fígado/imunologia , Fígado/imunologia , Linfócitos T Reguladores/imunologia , Tretinoína/metabolismo , Animais , Apresentação de Antígeno , Comunicação Celular/imunologia , Diferenciação Celular , Células Cultivadas , Técnicas de Cocultura , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Fatores de Transcrição Forkhead/genética , Expressão Gênica , Células Estreladas do Fígado/citologia , Células Estreladas do Fígado/metabolismo , Tolerância Imunológica , Fígado/citologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo , Fator de Crescimento Transformador beta1/imunologia
16.
Am J Physiol Cell Physiol ; 305(1): C1-21, 2013 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-23552284

RESUMO

A complex role has been described for dendritic cells (DCs) in the potentiation and control of vascular inflammation and atherosclerosis. Resident vascular DCs are found in the intima of atherosclerosis-prone vascular regions exposed to disturbed blood flow patterns. Several phenotypically and functionally distinct vascular DC subsets have been described. The functional heterogeneity of these cells and their contributions to vascular homeostasis, inflammation, and atherosclerosis are only recently beginning to emerge. Here, we review the available literature, characterizing the origin and function of known vascular DC subsets and their important role contributing to the balance of immune activation and immune tolerance governing vascular homeostasis under healthy conditions. We then discuss how homeostatic DC functions are disrupted during atherogenesis, leading to atherosclerosis. The effectiveness of DC-based "atherosclerosis vaccine" therapies in the treatment of atherosclerosis is also reviewed. We further provide suggestions for distinguishing DCs from macrophages and discuss important future directions for the field.


Assuntos
Aterosclerose/imunologia , Células Dendríticas/classificação , Animais , Aterosclerose/patologia , Aterosclerose/terapia , Células Dendríticas/imunologia , Homeostase , Humanos , Imunidade Inata , Inflamação
17.
J Immunol ; 187(2): 733-47, 2011 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-21666057

RESUMO

Although several subsets of intestinal APCs have been described, there has been no systematic evaluation of their phenotypes, functions, and regional localization to date. In this article, we used 10-color flow cytometry to define the major APC subsets in the small and large intestine lamina propria. Lamina propria APCs could be subdivided into CD11c(+)CD11b(-), CD11c(+)CD11b(+), and CD11c(dull)CD11b(+) subsets. CD11c(+)CD11b(-) cells were largely CD103(+)F4/80(-) dendritic cells (DCs), whereas the CD11c(+)CD11b(+) subset comprised CD11c(+)CD11b(+)CD103(+)F4/80(-) DCs and CD11c(+)CD11b(+)CD103(-)F4/80(+) macrophage-like cells. The majority of CD11c(dull)CD11b(+) cells were CD103(-)F4/80(+) macrophages. Although macrophages were more efficient at inducing Foxp3(+) regulatory T (T(reg)) cells than DCs, at higher T cell/APC ratios, all of the DC subsets efficiently induced Foxp3(+) T(reg) cells. In contrast, only CD11c(+)CD11b(+)CD103(+) DCs efficiently induced Th17 cells. Consistent with this, the regional distribution of CD11c(+)CD11b(+)CD103(+) DCs correlated with that of Th17 cells, with duodenum > jejunum > ileum > colon. Conversely, CD11c(+)CD11b(-)CD103(+) DCs, macrophages, and Foxp3(+) T(reg) cells were most abundant in the colon and scarce in the duodenum. Importantly, however, the ability of DC and macrophage subsets to induce Foxp3(+) T(reg) cells versus Th17 cells was strikingly dependent on the source of the mouse strain. Thus, DCs from C57BL/6 mice from Charles River Laboratories (that have segmented filamentous bacteria, which induce robust levels of Th17 cells in situ) were more efficient at inducing Th17 cells and less efficient at inducing Foxp3(+) T(reg) cells than DCs from B6 mice from The Jackson Laboratory. Thus, the functional specializations of APC subsets in the intestine are dependent on the T cell/APC ratio, regional localization, and source of the mouse strain.


Assuntos
Células Apresentadoras de Antígenos/citologia , Células Dendríticas/imunologia , Mucosa Intestinal/anatomia & histologia , Mucosa Intestinal/imunologia , Macrófagos/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Sequência de Aminoácidos , Animais , Células Apresentadoras de Antígenos/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Células Cultivadas , Doença Crônica , Técnicas de Cocultura , Colite/genética , Colite/imunologia , Colite/patologia , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Mucosa Intestinal/metabolismo , Contagem de Linfócitos , Macrófagos/citologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Dados de Sequência Molecular , Especificidade de Órgãos/genética , Especificidade de Órgãos/imunologia , Especificidade da Espécie , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo , Células Th17/citologia , Células Th17/metabolismo
18.
bioRxiv ; 2023 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-37292643

RESUMO

Inflammatory bowel disease (IBD) is a multifactorial, chronic disease that affects approximately 1.5 million people in the United States [1]. It presents with inflammation of the intestine with unknown etiology and its two main forms are Crohn's disease (CD) and ulcerative colitis (UC). Several important factors are implicated in the pathogenesis of IBD, one being dysregulation of the immune system resulting in the accumulation and stimulation of innate and adaptive immune cells and subsequent release of soluble factors, including pro-inflammatory cytokines. One of these cytokines is a member of the IL-36 cytokine family, IL-36γ, which is overexpressed in human IBD and experimental mouse models of colitis. In this study, we explored the role of IL-36γ in promoting CD4 + T cell activation and cytokine secretion. We found that IL-36γ stimulation of naïve CD4 + T cells significantly induced IFNγ expression in vitro and was associated with augmented intestinal inflammation in vivo using naive CD4 + cell transfer model of colitis. Using IFNγ-/- CD4 + cells, we observed a dramatic decrease in the ability of TNFα production and delayed colitis. This data not only suggests that IL-36γ is a master regulator of a pro-inflammatory cytokine network involving IFNγ and TNFα, but also highlights the importance of targeting IL-36γ and IFNγ as therapeutic approaches. Our studies have broad implications in relation to targeting specific cytokines in human IBD.

19.
JCI Insight ; 8(16)2023 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-37463055

RESUMO

Intestinal mucins play an essential role in the defense against bacterial invasion and the maintenance of gut microbiota, which is instrumental in the regulation of host immune systems; hence, its dysregulation is a hallmark of metabolic disease and intestinal inflammation. However, the mechanism by which intestinal mucins control the gut microbiota as well as disease phenotypes remains nebulous. Herein, we report that N-acetylglucosamine (GlcNAc)-6-O sulfation of O-glycans on intestinal mucins performs a protective role against obesity and intestinal inflammation. Chst4-/- mice, lacking GlcNAc-6-O sulfation of the mucin O-glycans, showed significant weight gain and increased susceptibility to dextran sodium sulfate-induced colitis as well as colitis-associated cancer accompanied by significantly reduced immunoglobulin A (IgA) production caused by an impaired T follicular helper cell-mediated IgA response. Interestingly, the protective effects of GlcNAc-6-O sulfation against obesity and intestinal inflammation depend on the gut microbiota, evidenced by the modulation of the gut microbiota by cohousing or microbiota transplantation reversing disease phenotypes and IgA production. Collectively, our findings provide insight into the significance of host glycosylation, more specifically GlcNAc-6-O sulfation on intestinal mucins, in protecting against obesity and intestinal inflammation via regulation of the gut microbiota.


Assuntos
Microbioma Gastrointestinal , Mucinas , Animais , Camundongos , Mucinas/metabolismo , Acetilglucosamina/metabolismo , Polissacarídeos/metabolismo , Inflamação , Obesidade
20.
Gastroenterology ; 141(1): 259-68, 268.e1-8, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21440550

RESUMO

BACKGROUND & AIMS: Dkk1 is a secreted antagonist of the Wnt/ß-catenin signaling pathway. It is induced by inflammatory cytokines during colitis and exacerbates tissue damage by promoting apoptosis of epithelial cells. However, little is known about the physiologic role of Dkk1 in normal intestinal homeostasis and during wound repair following mucosal injury. We investigated whether inhibition of Dkk1 affects the morphology and function of the adult intestine. METHODS: We used doubleridge mice (Dkk1d/d), which have reduced expression of Dkk1, and an inhibitory Dkk1 antibody to modulate Wnt/ß-catenin signaling in the intestine. Intestinal inflammation was induced with dextran sulfate sodium (DSS), followed by a recovery period in which mice were given regular drinking water. Animals were killed before, during, or after DSS administration; epithelial homeostasis and the activity of major signaling pathways were investigated by morphometric analysis, bromo-2'-deoxyuridine incorporation, and immunostaining. RESULTS: Reduced expression of Dkk1 increased proliferation of epithelial cells and lengthened crypts in the large intestine, which was associated with increased transcriptional activity of ß-catenin. Crypt extension was particularly striking when Dkk1 was inhibited during acute colitis. Dkk1d/d mice recovered significantly faster from intestinal inflammation but exhibited crypt architectural irregularities and epithelial hyperproliferation compared with wild-type mice. Survival signaling pathways were concurrently up-regulated in Dkk1d/d mice, including the AKT/ß-catenin, ERK/Elk-1, and c-Jun pathways. CONCLUSIONS: Dkk1, an antagonist of Wnt/ß-catenin signaling, regulates intestinal epithelial homeostasis under physiologic conditions and during inflammation. Depletion of Dkk1 induces a strong proliferative response that promotes wound repair after colitis.


Assuntos
Colite/metabolismo , Colo/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Mucosa Intestinal/metabolismo , Proteínas Wnt/metabolismo , Cicatrização , Doença Aguda , Animais , Anticorpos Monoclonais/administração & dosagem , Azoximetano , Proliferação de Células , Células Cultivadas , Colite/induzido quimicamente , Colite/genética , Colite/patologia , Colo/patologia , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Sulfato de Dextrana , Modelos Animais de Doenças , Regulação para Baixo , Homeostase , Injeções Intraperitoneais , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Mucosa Intestinal/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transdução de Sinais , Fatores de Tempo , Proteínas Wnt/antagonistas & inibidores , beta Catenina/metabolismo
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