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1.
Nature ; 611(7937): 787-793, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36323781

RESUMO

Emerging studies indicate that cooperation between neurons and immune cells regulates antimicrobial immunity, inflammation and tissue homeostasis. For example, a neuronal rheostat provides excitatory or inhibitory signals that control the functions of tissue-resident group 2 innate lymphoid cells (ILC2s) at mucosal barrier surfaces1-4. ILC2s express NMUR1, a receptor for neuromedin U (NMU), which is a prominent cholinergic neuropeptide that promotes ILC2 responses5-7. However, many functions of ILC2s are shared with adaptive lymphocytes, including the production of type 2 cytokines8,9 and the release of tissue-protective amphiregulin (AREG)10-12. Consequently, there is controversy regarding whether innate lymphoid cells and adaptive lymphocytes perform redundant or non-redundant functions13-15. Here we generate a new genetic tool to target ILC2s for depletion or gene deletion in the presence of an intact adaptive immune system. Transgenic expression of iCre recombinase under the control of the mouse Nmur1 promoter enabled ILC2-specific deletion of AREG. This revealed that ILC2-derived AREG promotes non-redundant functions in the context of antiparasite immunity and tissue protection following intestinal damage and inflammation. Notably, NMU expression levels increased in inflamed intestinal tissues from both mice and humans, and NMU induced AREG production in mouse and human ILC2s. These results indicate that neuropeptide-mediated regulation of non-redundant functions of ILC2s is an evolutionarily conserved mechanism that integrates immunity and tissue protection.


Assuntos
Imunidade Inata , Mucosa Intestinal , Linfócitos , Neuropeptídeos , Animais , Humanos , Camundongos , Citocinas/imunologia , Citocinas/metabolismo , Imunidade Inata/imunologia , Inflamação/imunologia , Inflamação/parasitologia , Inflamação/patologia , Linfócitos/imunologia , Neuropeptídeos/metabolismo , Neuropeptídeos/fisiologia , Anfirregulina , Mucosa Intestinal/imunologia , Mucosa Intestinal/parasitologia , Mucosa Intestinal/patologia
2.
JCI Insight ; 7(19)2022 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-36214222

RESUMO

Intestinal epithelial integrity is commonly disrupted in patients with critical disorders, but the exact underlying mechanisms are unclear. Long noncoding RNAs transcribed from ultraconserved regions (T-UCRs) control different cell functions and are involved in pathologies. Here, we investigated the role of T-UCRs in intestinal epithelial homeostasis and identified T-UCR uc.230 as a major regulator of epithelial renewal, apoptosis, and barrier function. Compared with controls, intestinal mucosal tissues from patients with ulcerative colitis and from mice with colitis or fasted for 48 hours had increased levels of uc.230. Silencing uc.230 inhibited the growth of intestinal epithelial cells (IECs) and organoids and caused epithelial barrier dysfunction. Silencing uc.230 also increased IEC vulnerability to apoptosis, whereas increasing uc.230 levels protected IECs against cell death. In mice with colitis, reduced uc.230 levels enhanced mucosal inflammatory injury and delayed recovery. Mechanistic studies revealed that uc.230 increased CUG-binding protein 1 (CUGBP1) by acting as a natural decoy RNA for miR-503, which interacts with Cugbp1 mRNA and represses its translation. These findings indicate that uc.230 sustains intestinal mucosal homeostasis by promoting epithelial renewal and barrier function and that it protects IECs against apoptosis by serving as a natural sponge for miR-503, thereby preserving CUGBP1 expression.


Assuntos
Proteínas CELF1 , Colite , Homeostase , Mucosa Intestinal , RNA Longo não Codificante , Cicatrização , Animais , Apoptose , Proteínas CELF1/genética , Proteínas CELF1/imunologia , Colite/genética , Colite/imunologia , Homeostase/genética , Homeostase/imunologia , Mucosa Intestinal/imunologia , Camundongos , MicroRNAs/genética , MicroRNAs/imunologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/imunologia , RNA Mensageiro/genética , RNA Mensageiro/imunologia , Cicatrização/genética , Cicatrização/imunologia , Ferimentos e Lesões/genética , Ferimentos e Lesões/imunologia
3.
J Virol ; 96(17): e0070622, 2022 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-36000839

RESUMO

Rotavirus infects intestinal epithelial cells and is the leading cause of gastroenteritis in infants worldwide. Upon viral infection, intestinal cells produce type I and type III interferons (IFNs) to alert the tissue and promote an antiviral state. These two types of IFN bind to different receptors but induce similar pathways that stimulate the activation of interferon-stimulated genes (ISGs) to combat viral infection. In this work, we studied the spread of a fluorescent wild-type (WT) SA11 rotavirus in human colorectal cancer cells lacking specific interferon receptors and compared it to that of an NSP1 mutant rotavirus that cannot interfere with the host intrinsic innate immune response. We could show that the WT rotavirus efficiently blocks the production of type I IFNs but that type III IFNs are still produced, whereas the NSP1 mutant rotavirus allows the production of both. Interestingly, while both exogenously added type I and type III IFNs could efficiently protect cells against rotavirus infection, endogenous type III IFNs were found to be key to limit infection of human intestinal cells by rotavirus. By using a fluorescent reporter cell line to highlight the cells mounting an antiviral program, we could show that paracrine signaling driven by type III IFNs efficiently controls the spread of both WT and NSP1 mutant rotavirus. Our results strongly suggest that NSP1 efficiently blocks the type I IFN-mediated antiviral response; however, its restriction of the type III IFN-mediated one is not sufficient to prevent type III IFNs from partially inhibiting viral spread in intestinal epithelial cells. Additionally, our findings further highlight the importance of type III IFNs in controlling rotavirus infection, which could be exploited as antiviral therapeutic measures. IMPORTANCE Rotavirus is one of the most common causes of gastroenteritis worldwide. In developing countries, rotavirus infections lead to more than 200,000 deaths in infants and children. The intestinal epithelial cells lining the gastrointestinal tract combat rotavirus infection by two key antiviral compounds known as type I and III interferons. However, rotavirus has developed countermeasures to block the antiviral actions of the interferons. In this work, we evaluated the arms race between rotavirus and type I and III interferons. We determined that although rotavirus could block the induction of type I interferons, it was unable to block type III interferons. The ability of infected cells to produce and release type III interferons leads to the protection of the noninfected neighboring cells and the clearance of rotavirus infection from the epithelium. This suggests that type III interferons are key antiviral agents and could be used to help control rotavirus infections in children.


Assuntos
Células Epiteliais , Interferons , Mucosa Intestinal , Infecções por Rotavirus , Rotavirus , Antivirais/imunologia , Criança , Células Epiteliais/imunologia , Células Epiteliais/virologia , Gastroenterite/virologia , Humanos , Imunidade Inata , Lactente , Interferon Tipo I/antagonistas & inibidores , Interferon Tipo I/imunologia , Interferons/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/virologia , Mutação , Rotavirus/genética , Rotavirus/crescimento & desenvolvimento , Rotavirus/imunologia , Infecções por Rotavirus/imunologia , Infecções por Rotavirus/prevenção & controle , Infecções por Rotavirus/virologia , Proteínas não Estruturais Virais/genética
4.
Science ; 377(6606): 660-666, 2022 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-35926021

RESUMO

The microbiome contributes to the development and maturation of the immune system. In response to commensal bacteria, intestinal CD4+ T lymphocytes differentiate into functional subtypes with regulatory or effector functions. The development of small intestine intraepithelial lymphocytes that coexpress CD4 and CD8αα homodimers (CD4IELs) depends on the microbiota. However, the identity of the microbial antigens recognized by CD4+ T cells that can differentiate into CD4IELs remains unknown. We identified ß-hexosaminidase, a conserved enzyme across commensals of the Bacteroidetes phylum, as a driver of CD4IEL differentiation. In a mouse model of colitis, ß-hexosaminidase-specific lymphocytes protected against intestinal inflammation. Thus, T cells of a single specificity can recognize a variety of abundant commensals and elicit a regulatory immune response at the intestinal mucosa.


Assuntos
Bacteroidetes , Linfócitos T CD4-Positivos , Colite , Mucosa Intestinal , beta-N-Acetil-Hexosaminidases , Animais , Bacteroidetes/enzimologia , Bacteroidetes/imunologia , Linfócitos T CD4-Positivos/imunologia , Antígenos CD8/imunologia , Colite/imunologia , Colite/microbiologia , Modelos Animais de Doenças , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , beta-N-Acetil-Hexosaminidases/imunologia
5.
J Immunol ; 208(10): 2300-2308, 2022 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-35500933

RESUMO

The persistence of a leaky gut in HIV-treated patients leads to chronic inflammation with increased rates of cardiovascular, liver, kidney, and neurological diseases. Tissue regulatory T (tTreg) cells are involved in the maintenance of intestinal homeostasis and wound repair through the IL-33 pathway. In this study, we investigated whether the persistence of gut mucosal injury during HIV infection might be explained in part by a flaw in the mechanisms involved in tissue repair. We observed an increased level of IL-33 in the gut of HIV-infected patients, which is associated with an increased level of fibrosis and a low peripheral reconstitution of CD4+ T cells. Our results showed that intestinal Treg cells from HIV-infected patients were enriched in tTreg cells prone to support tissue repair. However, we observed a functional defect in tTreg cells caused by the lack of amphiregulin secretion, which could contribute to the maintenance of intestinal damage. Our data suggest a mechanism by which the lack of amphiregulin secretion by tTreg may contribute to the lack of repair of the epithelial barrier.


Assuntos
Anfirregulina , Infecções por HIV , Linfócitos T Reguladores , Anfirregulina/imunologia , Linfócitos T CD4-Positivos/imunologia , Gastroenteropatias/imunologia , Gastroenteropatias/virologia , Infecções por HIV/imunologia , Humanos , Inflamação/imunologia , Interleucina-33/imunologia , Mucosa Intestinal/imunologia , Linfócitos T Reguladores/imunologia
6.
Immunity ; 55(4): 623-638.e5, 2022 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-35385697

RESUMO

The epithelium is an integral component of mucosal barrier and host immunity. Following helminth infection, the intestinal epithelial cells secrete "alarmin" cytokines, such as interleukin-25 (IL-25) and IL-33, to initiate the type 2 immune responses for helminth expulsion and tolerance. However, it is unknown how helminth infection and the resulting cytokine milieu drive epithelial remodeling and orchestrate alarmin secretion. Here, we report that epithelial O-linked N-Acetylglucosamine (O-GlcNAc) protein modification was induced upon helminth infections. By modifying and activating the transcription factor STAT6, O-GlcNAc transferase promoted the transcription of lineage-defining Pou2f3 in tuft cell differentiation and IL-25 production. Meanwhile, STAT6 O-GlcNAcylation activated the expression of Gsdmc family genes. The membrane pore formed by GSDMC facilitated the unconventional secretion of IL-33. GSDMC-mediated IL-33 secretion was indispensable for effective anti-helminth immunity and contributed to induced intestinal inflammation. Protein O-GlcNAcylation can be harnessed for future treatment of type 2 inflammation-associated human diseases.


Assuntos
Alarminas , Mucosa Intestinal , Acilação , Alarminas/imunologia , Anti-Helmínticos/imunologia , Biomarcadores Tumorais , Citocinas , Proteínas de Ligação a DNA , Helmintíase/imunologia , Humanos , Hiperplasia , Inflamação , Interleucina-33 , Mucosa Intestinal/imunologia , Mebendazol , N-Acetilglucosaminiltransferases/imunologia , Proteínas Citotóxicas Formadoras de Poros , Fator de Transcrição STAT6/imunologia
7.
Front Immunol ; 13: 838328, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35251032

RESUMO

Confirmed SARS-coronavirus-2 infection with gastrointestinal symptoms and changes in microbiota associated with coronavirus disease 2019 (COVID-19) severity have been previously reported, but the disease impact on the architecture and cellularity of ileal Peyer's patches (PP) remains unknown. Here we analysed post-mortem tissues from throughout the gastrointestinal (GI) tract of patients who died with COVID-19. When virus was detected by PCR in the GI tract, immunohistochemistry identified virus in epithelium and lamina propria macrophages, but not in lymphoid tissues. Immunohistochemistry and imaging mass cytometry (IMC) analysis of ileal PP revealed depletion of germinal centres (GC), disruption of B cell/T cell zonation and decreased potential B and T cell interaction and lower nuclear density in COVID-19 patients. This occurred independent of the local viral levels. The changes in PP demonstrate that the ability to mount an intestinal immune response is compromised in severe COVID-19, which could contribute to observed dysbiosis.


Assuntos
Atrofia/imunologia , COVID-19/imunologia , Centro Germinativo/imunologia , Mucosa Intestinal/imunologia , Nódulos Linfáticos Agregados/imunologia , Linfócitos B/imunologia , Humanos , Tecido Linfoide/imunologia , Macrófagos/imunologia , SARS-CoV-2/imunologia , Linfócitos T/imunologia
8.
Front Immunol ; 13: 837443, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35281065

RESUMO

An ideal protective vaccine against SARS-CoV-2 should not only be effective in preventing disease, but also in preventing virus transmission. It should also be well accepted by the population and have a simple logistic chain. To fulfill these criteria, we developed a thermostable, orally administered vaccine that can induce a robust mucosal neutralizing immune response. We used our platform based on retrovirus-derived enveloped virus-like particles (eVLPs) harnessed with variable surface proteins (VSPs) from the intestinal parasite Giardia lamblia, affording them resistance to degradation and the triggering of robust mucosal cellular and antibody immune responses after oral administration. We made eVLPs expressing various forms of the SARS-CoV-2 Spike protein (S), with or without membrane protein (M) expression. We found that prime-boost administration of VSP-decorated eVLPs expressing a pre-fusion stabilized form of S and M triggers robust mucosal responses against SARS-CoV-2 in mice and hamsters, which translate into complete protection from a viral challenge. Moreover, they dramatically boosted the IgA mucosal response of intramuscularly injected vaccines. We conclude that our thermostable orally administered eVLP vaccine could be a valuable addition to the current arsenal against SARS-CoV-2, in a stand-alone prime-boost vaccination strategy or as a boost for existing vaccines.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/imunologia , Proteínas M de Coronavírus/imunologia , Giardia lamblia/imunologia , Mucosa Intestinal/imunologia , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/imunologia , Animais , Antígenos de Protozoários/imunologia , Cricetinae , Humanos , Imunidade , Imunização Secundária , Imunoglobulina A/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Temperatura , Potência de Vacina , Vacinas de Partículas Semelhantes a Vírus
9.
J Virol ; 96(7): e0020222, 2022 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-35297667

RESUMO

In the United States, most new cases of human immunodeficiency virus (HIV) belong to the at-risk group of gay and bisexual men. Developing therapies to reverse viral latency and prevent spread is paramount for the HIV cure agenda. In gay and bisexual men, a major, yet poorly characterized, route of HIV entry is via transport across the colonic epithelial barrier. While colonic tears and paracellular transport contribute to infection, we hypothesize that HIV entry through the colonic mucosa proceeds via a process known as transcytosis, involving (i) virion binding to the apical surface of the colonic epithelium, (ii) viral endocytosis, (iii) transport of virions across the cell, and (iv) HIV release from the basolateral membrane. Using Caco-2 colonic epithelial cells plated as a polarized monolayer in transwells, we characterized the mechanism of HIV transport. After exposing the monolayer to HIV apically, reverse transcription quantitative PCR (RT-qPCR) of the viral genome present in the basolateral chamber revealed that transport is dose dependent, cooperative, and inefficient, with released virus first detectable at 12 h. Inefficiency may be associated with >50% decline in detectable intracellular virus that correlates temporally with increased association of the virion with lysosomal-associated membrane protein 1 (LAMP-1+) endosomes. Microscopy revealed green fluorescent protein (GFP)-labeled HIV within the confines of the epithelial monolayer, with no virus detectable between cells, suggesting that viral transport is transcellular. Treatment of the monolayer with endocytosis inhibitors, cholesterol reducing agents, and small interfering RNA (siRNA) to caveolin showed that viral endocytosis is mediated by caveolin-coated endosomes contained in lipid rafts. These results indicate that HIV transport across the intestinal epithelial barrier via transcytosis is a viable mechanism for viral spread and a potential therapeutic target. IMPORTANCE Despite the success of combination antiretroviral therapy in suppressing HIV replication and the emergence and effectiveness of PrEP-based prevention strategies, in 2018, 37,968 people in the United States received a new HIV diagnosis, accompanied by 15,820 deaths. While the annual number of new diagnoses decreased 7% from 2014 to 2018, 14% of people with HIV did not know they were infected. Gay and bisexual men accounted for 69% of all HIV diagnoses and 83% of diagnoses among males. Due to the scope of the HIV epidemic, determining and understanding precise routes of infection and the mechanisms of viral spread are paramount to ending the epidemic. Since transcellular transport of HIV across an intact colonic epithelial barrier is poorly understood, our overall goal is to characterize the molecular events involved in HIV transcytosis across the intestinal epithelial cell.


Assuntos
Colo , Endocitose , Infecções por HIV , HIV , Mucosa Intestinal , Células CACO-2 , Caveolinas/metabolismo , Colo/imunologia , Colo/virologia , Endossomos/metabolismo , HIV/metabolismo , Infecções por HIV/metabolismo , Infecções por HIV/prevenção & controle , Infecções por HIV/transmissão , Humanos , Mucosa Intestinal/imunologia , Mucosa Intestinal/virologia , Masculino
10.
Front Immunol ; 13: 822754, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35154141

RESUMO

Wild pigs usually showed high tolerance and resistance to several diseases in the wild environment, suggesting that the gut bacteria of wild pigs could be a good source for discovering potential probiotic strains. In our study, wild pig feces were sequenced and showed a higher relative abundance of the genus Lactobacillus (43.61% vs. 2.01%) than that in the domestic pig. A total of 11 lactic acid bacteria (LAB) strains including two L. rhamnosus, six L. mucosae, one L. fermentum, one L. delbrueckii, and one Enterococcus faecalis species were isolated. To investigate the synergistic effects of mixed probiotics strains, the mixture of 11 LAB strains from an intestinal ecology system was orally administrated in mice for 3 weeks, then the mice were challenged with Escherichia coli ATCC 25922 (2 × 109 CFU) and euthanized after challenge. Mice administrated with LAB strains showed higher (p < 0.05) LAB counts in feces and ileum. Moreover, alterations of specific bacterial genera occurred, including the higher (p < 0.05) relative abundance of Butyricicoccus and Clostridium IV and the lower (p < 0.05) abundance of Enterorhabdus in mice fed with mixed LAB strains. Mice challenged with Escherichia coli showed vacuolization of the liver, lower GSH in serum, and lower villus to the crypt proportion and Claudin-3 level in the gut. In contrast, administration of mixed LAB strains attenuated inflammation of the liver and gut, especially the lowered IL-6 and IL-1ß levels (p < 0.05) in the gut. Our study highlighted the importance of gut bacterial diversity and the immunomodulation effects of LAB strains mixture from wild pig in gut health.


Assuntos
Infecções por Escherichia coli/terapia , Enteropatias/terapia , Lactobacillales/fisiologia , Probióticos/farmacologia , Animais , Escherichia coli/efeitos dos fármacos , Infecções por Escherichia coli/imunologia , Infecções por Escherichia coli/metabolismo , Infecções por Escherichia coli/microbiologia , Fezes/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Imunidade/efeitos dos fármacos , Enteropatias/imunologia , Enteropatias/metabolismo , Enteropatias/microbiologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Lactobacillales/isolamento & purificação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Probióticos/uso terapêutico , Sus scrofa
11.
Elife ; 112022 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-35137688

RESUMO

Interferon-lambda (IFN-λ) protects intestinal epithelial cells (IECs) from enteric viruses by inducing expression of antiviral IFN-stimulated genes (ISGs). Here, we find that bacterial microbiota stimulate a homeostatic ISG signature in the intestine of specific pathogen-free mice. This homeostatic ISG expression is restricted to IECs, depends on IEC-intrinsic expression of IFN-λ receptor (Ifnlr1), and is associated with IFN-λ production by leukocytes. Strikingly, imaging of these homeostatic ISGs reveals localization to pockets of the epithelium and concentration in mature IECs. Correspondingly, a minority of mature IECs express these ISGs in public single-cell RNA sequencing datasets from mice and humans. Furthermore, we assessed the ability of orally administered bacterial components to restore localized ISGs in mice lacking bacterial microbiota. Lastly, we find that IECs lacking Ifnlr1 are hyper-susceptible to initiation of murine rotavirus infection. These observations indicate that bacterial microbiota stimulate ISGs in localized regions of the intestinal epithelium at homeostasis, thereby preemptively activating antiviral defenses in vulnerable IECs to improve host defense against enteric viruses.


Assuntos
Enterovirus/fisiologia , Microbioma Gastrointestinal/fisiologia , Mucosa Intestinal/imunologia , Receptores de Interferon/genética , Animais , Fenômenos Fisiológicos Bacterianos , Feminino , Homeostase , Masculino , Camundongos , Receptores de Interferon/metabolismo
12.
Int J Mol Sci ; 23(4)2022 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-35216425

RESUMO

Bacteria and viruses are both important pathogens causing intestinal infections, and studies on their pathogenic mechanisms tend to focus on one pathogen alone. However, bacterial and viral co-infections occur frequently in clinical settings, and infection by one pathogen can affect the severity of infection by another pathogen, either directly or indirectly. The presence of synergistic or antagonistic effects of two pathogens in co-infection can affect disease progression to varying degrees. The triad of bacterial-viral-gut interactions involves multiple aspects of inflammatory and immune signaling, neuroimmunity, nutritional immunity, and the gut microbiome. In this review, we discussed the different scenarios triggered by different orders of bacterial and viral infections in the gut and summarized the possible mechanisms of synergy or antagonism involved in their co-infection. We also explored the regulatory mechanisms of bacterial-viral co-infection at the host intestinal immune interface from multiple perspectives.


Assuntos
Infecções Bacterianas/imunologia , Coinfecção/imunologia , Imunidade nas Mucosas/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Viroses/imunologia , Animais , Coinfecção/microbiologia , Coinfecção/virologia , Humanos , Mucosa Intestinal/virologia
13.
Nat Commun ; 13(1): 874, 2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-35169117

RESUMO

IL-18 is emerging as an IL-22-induced and epithelium-derived cytokine which contributes to host defence against intestinal infection and inflammation. In contrast to its known role in Goblet cells, regulation of barrier function at the molecular level by IL-18 is much less explored. Here we show that IL-18 is a bona fide IL-22-regulated gate keeper for intestinal epithelial barrier. IL-22 promotes crypt immunity both via induction of phospho-Stat3 binding to the Il-18 gene promoter and via Il-18 independent mechanisms. In organoid culture, while IL-22 primarily increases organoid size and inhibits expression of stem cell genes, IL-18 preferentially promotes organoid budding and induces signature genes of Lgr5+ stem cells via Akt-Tcf4 signalling. During adherent-invasive E. coli (AIEC) infection, systemic administration of IL-18 corrects compromised T-cell IFNγ production and restores Lysozyme+ Paneth cells in Il-22-/- mice, but IL-22 administration fails to restore these parameters in Il-18-/- mice, thereby placing IL-22-Stat3 signalling upstream of the IL-18-mediated barrier defence function. IL-18 in return regulates Stat3-mediated anti-microbial response in Paneth cells, Akt-Tcf4-triggered expansion of Lgr5+ stem cells to facilitate tissue repair, and AIEC clearance by promoting IFNγ+ T cells.


Assuntos
Infecções por Escherichia coli/imunologia , Imunidade nas Mucosas/imunologia , Interleucina-18/imunologia , Interleucinas/imunologia , Mucosa Intestinal/imunologia , Animais , Doença de Crohn/microbiologia , Doença de Crohn/patologia , Disbiose/microbiologia , Escherichia coli/imunologia , Interferon gama/imunologia , Interleucina-18/genética , Mucosa Intestinal/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Muramidase/metabolismo , Organoides , Celulas de Paneth/imunologia , Regiões Promotoras Genéticas/genética , Fator de Transcrição STAT3/metabolismo , Junções Íntimas/imunologia
14.
Nat Immunol ; 23(2): 251-261, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35102343

RESUMO

Tumor necrosis factor (TNF) drives chronic inflammation and cell death in the intestine, and blocking TNF is a therapeutic approach in inflammatory bowel disease (IBD). Despite this knowledge, the pathways that protect the intestine from TNF are incompletely understood. Here we demonstrate that group 3 innate lymphoid cells (ILC3s) protect the intestinal epithelium from TNF-induced cell death. This occurs independent of interleukin-22 (IL-22), and we identify that ILC3s are a dominant source of heparin-binding epidermal growth factor-like growth factor (HB-EGF). ILC3s produce HB-EGF in response to prostaglandin E2 (PGE2) and engagement of the EP2 receptor. Mice lacking ILC3-derived HB-EGF exhibit increased susceptibility to TNF-mediated epithelial cell death and experimental intestinal inflammation. Finally, human ILC3s produce HB-EGF and are reduced from the inflamed intestine. These results define an essential role for ILC3-derived HB-EGF in protecting the intestine from TNF and indicate that disruption of this pathway contributes to IBD.


Assuntos
Fator de Crescimento Semelhante a EGF de Ligação à Heparina/imunologia , Imunidade Inata/imunologia , Inflamação/imunologia , Intestinos/imunologia , Linfócitos/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Células Epiteliais/imunologia , Mucosa Intestinal/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/imunologia
15.
Front Immunol ; 13: 768076, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35185874

RESUMO

The gastrointestinal tract represents one of the largest body surfaces that is exposed to the outside world. It is the only mucosal surface that is required to simultaneously recognize and defend against pathogens, while allowing nutrients containing foreign antigens to be tolerated and absorbed. It differentiates between these foreign substances through a complex system of pattern recognition receptors expressed on the surface of the intestinal epithelial cells as well as the underlying immune cells. These immune cells actively sample and evaluate microbes and other particles that pass through the lumen of the gut. This local sensing system is part of a broader distributed signaling system that is connected to the rest of the body through the enteric nervous system, the immune system, and the metabolic system. While local tissue homeostasis is maintained by commensal bacteria that colonize the gut, colonization itself may not be required for the activation of distributed signaling networks that can result in modulation of peripheral inflammation. Herein, we describe the ability of a gut-restricted strain of commensal bacteria to drive systemic anti-inflammatory effects in a manner that does not rely upon its ability to colonize the gastrointestinal tract or alter the mucosal microbiome. Orally administered EDP1867, a gamma-irradiated strain of Veillonella parvula, rapidly transits through the murine gut without colonization or alteration of the background microbiome flora. In murine models of inflammatory disease including delayed-type hypersensitivity (DTH), atopic dermatitis, psoriasis, and experimental autoimmune encephalomyelitis (EAE), treatment with EDP1867 resulted in significant reduction in inflammation and immunopathology. Ex vivo cytokine analyses revealed that EDP1867 treatment diminished production of pro-inflammatory cytokines involved in inflammatory cascades. Furthermore, blockade of lymphocyte migration to the gut-associated lymphoid tissues impaired the ability of EDP1867 to resolve peripheral inflammation, supporting the hypothesis that circulating immune cells are responsible for promulgating the signals from the gut to peripheral tissues. Finally, we show that adoptively transferred T cells from EDP1867-treated mice inhibit inflammation induced in recipient mice. These results demonstrate that an orally-delivered, non-viable strain of commensal bacteria can mediate potent anti-inflammatory effects in peripheral tissues through transient occupancy of the gastrointestinal tract, and support the development of non-living bacterial strains for therapeutic applications.


Assuntos
Antibacterianos/farmacologia , Bactérias/imunologia , Citocinas/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Inflamação/imunologia , Animais , Bactérias/efeitos dos fármacos , Bactérias/crescimento & desenvolvimento , Células Epiteliais/efeitos dos fármacos , Feminino , Humanos , Imunidade nas Mucosas , Inflamação/etiologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Simbiose , Linfócitos T/metabolismo
16.
Front Immunol ; 13: 812899, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35185906

RESUMO

Organized intestinal mucosal immune response appears to be restricted to tetrapods. In teleost fish, there is no evidence for the existence of a particular intestinal region that facilitates the interaction of antigen-presenting cells (APCs) and T cells, such as secondary lymphoid organs. Indeed, despite their importance in the defense against pathogens, the location and manner of APC-T cell interaction within the fish gut is unknown. Here, using non-invasive live imaging of newly developed transgenic reporter lines, we addressed the spatial organization and behavior of APCs and T cells in the intestine of medaka fish both during homeostasis and inflammation. We report that Ccr9a+ T cells are recruited to a band in the lamina propria next to the muscularis mucosa in which Ccl25-expressing cells are present. Ccr9a+ T cells contact APCs for several minutes, in a process mediated by connexin 43. This type of interaction was observed in homeostasis and inflammation, with the interaction being longer and more frequent during inflammation. Thus, our results demonstrate that the mucosal immune response in the intestine of medaka is organized and endowed with a specific region with specialized microenvironment and function.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Mucosa Intestinal/imunologia , Linfócitos T/imunologia , Animais , Quimiocinas CC/metabolismo , Oryzias/imunologia , Receptores CCR/metabolismo
17.
Int J Mol Sci ; 23(3)2022 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-35163417

RESUMO

Some say that all diseases begin in the gut. Interestingly, this concept is actually quite old, since it is attributed to the Ancient Greek physician Hippocrates, who proposed the hypothesis nearly 2500 years ago. The continuous breakthroughs in modern medicine have transformed our classic understanding of the gastrointestinal tract (GIT) and human health. Although the gut microbiota (GMB) has proven to be a core component of human health under standard metabolic conditions, there is now also a strong link connecting the composition and function of the GMB to the development of numerous diseases, especially the ones of musculoskeletal nature. The symbiotic microbes that reside in the gastrointestinal tract are very sensitive to biochemical stimuli and may respond in many different ways depending on the nature of these biological signals. Certain variables such as nutrition and physical modulation can either enhance or disrupt the equilibrium between the various species of gut microbes. In fact, fat-rich diets can cause dysbiosis, which decreases the number of protective bacteria and compromises the integrity of the epithelial barrier in the GIT. Overgrowth of pathogenic microbes then release higher quantities of toxic metabolites into the circulatory system, especially the pro-inflammatory cytokines detected in osteoarthritis (OA), thereby promoting inflammation and the initiation of many disease processes throughout the body. Although many studies link OA with GMB perturbations, further research is still needed.


Assuntos
Disbiose , Microbioma Gastrointestinal/imunologia , Mucosa Intestinal , Osteoartrite , Animais , Disbiose/imunologia , Disbiose/microbiologia , Humanos , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Osteoartrite/etiologia , Osteoartrite/imunologia , Osteoartrite/microbiologia
18.
Science ; 375(6583): 859-863, 2022 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-35201883

RESUMO

Group 3 innate lymphoid cells (ILC3s) are innate immune effectors that contribute to host defense. Whether ILC3 functions are stably modified after pathogen encounter is unknown. Here, we assess the impact of a time-restricted enterobacterial challenge to long-term ILC3 activation in mice. We found that intestinal ILC3s persist for months in an activated state after exposure to Citrobacter rodentium. Upon rechallenge, these "trained" ILC3s proliferate, display enhanced interleukin-22 (IL-22) responses, and have a superior capacity to control infection compared with naïve ILC3s. Metabolic changes occur in C. rodentium-exposed ILC3s, but only trained ILC3s have an enhanced proliferative capacity that contributes to increased IL-22 production. Accordingly, a limited encounter with a pathogen can promote durable phenotypic and functional changes in intestinal ILC3s that contribute to long-term mucosal defense.


Assuntos
Citrobacter rodentium/imunologia , Infecções por Enterobacteriaceae/imunologia , Imunidade nas Mucosas , Mucosa Intestinal/imunologia , Ativação Linfocitária , Linfócitos/imunologia , Imunidade Adaptativa , Animais , Proliferação de Células , Feminino , Imunidade Inata , Memória Imunológica , Interleucinas/metabolismo , Intestinos/imunologia , Listeria monocytogenes , Listeriose/imunologia , Linfócitos/metabolismo , Masculino , Redes e Vias Metabólicas , Camundongos , Camundongos Endogâmicos C57BL , Consumo de Oxigênio , RNA-Seq , Reinfecção/imunologia
19.
J Exp Med ; 219(2)2022 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-35024767

RESUMO

Gut innate lymphoid cells (ILCs) show remarkable phenotypic diversity, yet microenvironmental factors that drive this plasticity are incompletely understood. The balance between NKp46+, IL-22-producing, group 3 ILCs (ILC3s) and interferon (IFN)-γ-producing group 1 ILCs (ILC1s) contributes to gut homeostasis. The gut mucosa is characterized by physiological hypoxia, and adaptation to low oxygen is mediated by hypoxia-inducible transcription factors (HIFs). However, the impact of HIFs on ILC phenotype and gut homeostasis is not well understood. Mice lacking the HIF-1α isoform in NKp46+ ILCs show a decrease in IFN-γ-expressing, T-bet+, NKp46+ ILC1s and a concomitant increase in IL-22-expressing, RORγt+, NKp46+ ILC3s in the gut mucosa. Single-cell RNA sequencing revealed HIF-1α as a driver of ILC phenotypes, where HIF-1α promotes the ILC1 phenotype by direct up-regulation of T-bet. Loss of HIF-1α in NKp46+ cells prevents ILC3-to-ILC1 conversion, increases the expression of IL-22-inducible genes, and confers protection against intestinal damage. Taken together, our results suggest that HIF-1α shapes the ILC phenotype in the gut.


Assuntos
Antígenos Ly/metabolismo , Plasticidade Celular/imunologia , Trato Gastrointestinal/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Imunidade Inata , Linfócitos Intraepiteliais/imunologia , Linfócitos Intraepiteliais/metabolismo , Receptor 1 Desencadeador da Citotoxicidade Natural/metabolismo , Animais , Biomarcadores , Suscetibilidade a Doenças , Expressão Gênica , Perfilação da Expressão Gênica , Homeostase , Imunidade nas Mucosas , Imunofenotipagem , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Subpopulações de Linfócitos , Camundongos , Camundongos Knockout , Microbiota , Análise de Célula Única
20.
J Immunol ; 208(3): 745-752, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-35031577

RESUMO

Cystic fibrosis (CF) is an inherited life-threatening disease accompanied by repeated lung infections and multiorgan inflammation that affects tens of thousands of people worldwide. The causative gene, cystic fibrosis transmembrane conductance regulator (CFTR), is mutated in CF patients. CFTR functions in epithelial cells have traditionally been thought to cause the disease symptoms. Recent work has shown an additional defect: monocytes from CF patients show a deficiency in integrin activation and adhesion. Because monocytes play critical roles in controlling infections, defective monocyte function may contribute to CF progression. In this study, we demonstrate that monocytes from CFTRΔF508 mice (CF mice) show defective adhesion under flow. Transplanting CF mice with wild-type (WT) bone marrow after sublethal irradiation replaced most (60-80%) CF monocytes with WT monocytes, significantly improved survival, and reduced inflammation. WT/CF mixed bone marrow chimeras directly demonstrated defective CF monocyte recruitment to the bronchoalveolar lavage and the intestinal lamina propria in vivo. WT mice reconstituted with CF bone marrow also show lethality, suggesting that the CF defect in monocytes is not only necessary but also sufficient to cause disease. We also show that monocyte-specific knockout of CFTR retards weight gains and exacerbates dextran sulfate sodium-induced colitis. Our findings show that providing WT monocytes by bone marrow transfer rescues mortality in CF mice, suggesting that similar approaches may mitigate disease in CF patients.


Assuntos
Adesão Celular/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/terapia , Monócitos/imunologia , Monócitos/transplante , Animais , Transplante de Medula Óssea , Líquido da Lavagem Broncoalveolar/citologia , Colite/patologia , Fibrose Cística/patologia , Integrinas/metabolismo , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Camundongos , Camundongos Endogâmicos C57BL
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