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1.
J Innate Immun ; : 1-18, 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36116427

RESUMO

Cathelicidin peptides secreted by leukocytes and epithelial cells are microbicidal but also regulate pathogen sensing via toll-like receptors (TLRs) in the colon by mechanisms that are not fully understood. Herein, analyses with the attaching/effacing pathogen Citrobacter rodentium model of colitis in cathelicidin-deficient (Camp-/-) mice, and colonic epithelia demonstrate that cathelicidins prevent apoptosis by sustaining post-transcriptional synthesis of a TLR adapter, toll-interacting protein (TOLLIP). Cathelicidins induced phosphorylation-activation of epidermal growth factor receptor (EGFR)-kinase, which phosphorylated-inactivated miRNA-activating enzyme Argonaute 2 (AGO2), thus reducing availability of the TOLLIP repressor miRNA-31. Cathelicidins promoted stability of TOLLIP protein via a proteosome-dependent pathway. This cathelicidin-induced TOLLIP upregulation prevented apoptosis in the colonic epithelium by reducing levels of caspase-3 and poly (ADP-ribose) polymerase (PARP)-1 in response to the proinflammatory cytokines, interferon-γ (IFNγ) and tumor necrosis factor-α (TNFα). Further, Camp-/- colonic epithelial cells were more susceptible to apoptosis during C. rodentium infection than wild-type cells. This antiapoptotic effect of cathelicidins, maintaining epithelial TOLLIP protein in the gut, provides insight into cathelicidin's ability to regulate TLR signaling and prevent exacerbated inflammation.

2.
Front Immunol ; 12: 744738, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34691050

RESUMO

The murine interleukin-4 treated macrophage (MIL4) exerts anti-inflammatory and pro-healing effects and has been shown to reduce the severity of chemical-induced colitis. Positing M(IL4) transfer as an anti-inflammatory therapy, the possibility of side-effects must be considered. Consequently, bone marrow-derived M(IL4)s were administered via intraperitoneal injection to mice concomitant with Citrobacter rodentium infection (infections colitis), azoxymethane/dextran sodium sulphate (AOM/DSS) treatment [a model of colorectal cancer (CRC)], or ovalbumin sensitization (airway inflammation). The impact of M(IL4) treatment on C. rodentium infectivity, colon histopathology, tumor number and size and tissue-specific inflammation was examined in these models. The anti-colitic effect of the M(IL4)s were confirmed in the di-nitrobenzene sulphonic acid model of colitis and the lumen-to-blood movement of 4kDa FITC-dextran and bacterial translocation to the spleen and liver was also improved by M(IL4) treatment. Analysis of the other models of disease, that represent comorbidities that can occur in human inflammatory bowel disease (IBD), revealed that M(IL4) treatment did not exaggerate the severity of any of the conditions. Rather, there was reduction in the size (but not number) of polyps in the colon of AOM/DSS-mice and reduced infectivity and inflammation in C. rodentium-infected mice in M(IL4)-treated mice. Thus, while any new therapy can have unforeseen side effects, our data confirm and extend the anti-colitic capacity of murine M(IL4)s and indicate that systemic delivery of one million M(IL4)s did not exaggerate disease in models of colonic or airways inflammation or colonic tumorigenesis.


Assuntos
Colite/patologia , Neoplasias do Colo/patologia , Interleucina-4/imunologia , Macrófagos/transplante , Hipersensibilidade Respiratória/patologia , Animais , Inflamação/patologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL
3.
Gut Microbes ; 12(1): 1785802, 2020 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-32658599

RESUMO

We hypothesized that the antimicrobial peptide cathelicidin has a physiological role in regulating gut inflammatory homeostasis. We determined that cathelicidin synergizes with LPS to facilitate its internalization and signaling via endosomic TLR4 in colonic epithelium, evoking synthesis of the human neutrophil chemoattractant, CXCL8 (or murine homolog, CXCL1). Interaction of cathelicidin with LPS in the control of CXCL8/CXCL1 synthesis was assessed in human colon epithelial cells, murine colonoids and cathelicidin-null mice (Camp-/- ). Mechanistically, human cathelicidin (LL-37), as an extracellular complex with LPS, interacted with lipid raft-associated GM1 gangliosides to internalize and activate intracellular TLR4. Two signaling pathways converged on CXCL8/CXCL1 production: (1) a p38MAPK-dependent pathway regulated by Src-EGFR kinases; and, (2) a p38MAPK-independent, NF-κB-dependent pathway, regulated by MEK1/2-MAPK. Increased cathelicidin-dependent CXCL8 secretion in the colonic mucosa activated human blood-derived neutrophils. These cathelicidin effects occurred in vitro at concentrations well below those needed for microbicidal function. The important immunomodulatory role of cathelicidins was evident in cathelicidin-null/Camp-/- mice, which had diminished colonic CXCL1 secretion, decreased neutrophil recruitment-activation and reduced bacterial clearance when challenged with the colitis-inducing murine pathogen, Citrobacter rodentium. We conclude that in addition to its known microbicidal action, cathelicidin has a unique pathogen-sensing role, facilitating LPS-mediated intestinal responses, including the production of CXCL8/CXCL1 that would contribute to an integrated tissue response to recruit neutrophils during colitis.


Assuntos
Peptídeos Catiônicos Antimicrobianos/metabolismo , Colo/metabolismo , Interleucina-8/metabolismo , Mucosa Intestinal/metabolismo , Lipopolissacarídeos/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Peptídeos Catiônicos Antimicrobianos/genética , Peptídeos Catiônicos Antimicrobianos/farmacologia , Bactérias/metabolismo , Quimiocina CXCL1/metabolismo , Colite/genética , Colite/imunologia , Colite/metabolismo , Colite/microbiologia , Colo/imunologia , Colo/microbiologia , Células Epiteliais , Gangliosídeo G(M1)/metabolismo , Humanos , Lipopolissacarídeos/farmacologia , Microdomínios da Membrana/efeitos dos fármacos , Microdomínios da Membrana/metabolismo , Camundongos , Subunidade p50 de NF-kappa B/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Transdução de Sinais/efeitos dos fármacos , Catelicidinas
4.
Front Immunol ; 11: 965, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32508838

RESUMO

Host defense peptides, abundantly secreted by colonic epithelial cells and leukocytes, are proposed to be critical components of an innate immune response in the colon against enteropathogenic bacteria, including Shigella spp., Salmonella spp., Clostridium difficile, and attaching and effacing Escherichia coli and Citrobacter rodentium. These short cationic peptides are bactericidal against both Gram-positive and -negative enteric pathogens, but may also exert killing effects on intestinal luminal microbiota. Simultaneously, these peptides modulate numerous cellular responses crucial for gut defenses, including leukocyte chemotaxis and migration, wound healing, cytokine production, cell proliferation, and pathogen sensing. This review discusses recent advances in our understanding of expression, mechanisms of action and microbicidal and immunomodulatory functions of major colonic host defense peptides, namely cathelicidins, ß-defensins, and members of the Regenerating islet-derived protein III (RegIII) and Resistin-like molecule (RELM) families. In a theoretical framework where these peptides work synergistically, aspects of pathogenesis of infectious colitis reviewed herein uncover roles of host defense peptides aimed to promote epithelial defenses and prevent pathogen colonization, mediated through a combination of direct antimicrobial function and fine-tuning of host immune response and inflammation. This interactive host defense peptide network may decode how the intestinal immune system functions to quickly clear infections, restore homeostasis and avoid damaging inflammation associated with pathogen persistence during infectious colitis. This information is of interest in development of host defense peptides (either alone or in combination with reduced doses of antibiotics) as antimicrobial and immunomodulatory therapeutics for controlling infectious colitis.


Assuntos
Peptídeos Catiônicos Antimicrobianos/imunologia , Colite/imunologia , Colo/imunologia , Infecções por Enterobacteriaceae/imunologia , Enterobacteriaceae/imunologia , Imunidade Inata , Animais , Peptídeos Catiônicos Antimicrobianos/metabolismo , Colite/metabolismo , Colite/microbiologia , Colo/metabolismo , Colo/microbiologia , Enterobacteriaceae/patogenicidade , Infecções por Enterobacteriaceae/metabolismo , Infecções por Enterobacteriaceae/microbiologia , Interações Hospedeiro-Patógeno , Humanos , Transdução de Sinais
5.
Cell Tissue Res ; 376(3): 433-442, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30788579

RESUMO

The intestinal mucosa contributes to frontline gut defenses by forming a barrier (physical and biochemical) and preventing the entry of pathogenic microbes. One innate role of the human colonic epithelium is to secrete cathelicidin, a peptide with broad antimicrobial and immunomodulatory functions. In this study, the effect of cathelicidin in the maintenance of epithelial integrity, Toll-like receptor recognition, bacterial invasion and initiation of inflammatory response against Salmonella typhimurium is investigated in cultured human colonic epithelium. We found exogenous human cathelicidin restores the epithelial integrity in S. typhimurium-infected colonic epithelial (T84) cells by mostly post-translational effects associated with reorganization of zonula occludens (ZO)-1 tight junction proteins. Endogenous cathelicidin prevents S. typhimurium internalization as shown in colonic epithelial cells genetically deficient in the only human cathelicidin, LL-37 (shLL-37). Moreover, supplementation of shLL-37 cells with synthetic LL-37 reduces the grade of S. typhimurium internalization in a dose-dependent manner. Mechanistically, shLL-37 cells have lower gene expression of TLR4 and pro-inflammatory cytokine IL-1ß in response to S. typhimurium. Thus, human cathelicidin aids in the early colonic epithelial defenses against enteric S. typhimurium by preventing bacterial invasion and maintaining epithelial barrier integrity, likely to occur due to the production of sensing TLR4 and pro-inflammatory cytokines.


Assuntos
Peptídeos Catiônicos Antimicrobianos/farmacologia , Colo/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Infecções por Salmonella/prevenção & controle , Salmonella typhimurium/efeitos dos fármacos , Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Colo/imunologia , Colo/microbiologia , Células HT29 , Humanos , Interleucina-1beta/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Receptor 4 Toll-Like/imunologia , Proteína da Zônula de Oclusão-1/metabolismo , Catelicidinas
6.
J Virol ; 90(1): 103-16, 2016 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-26468537

RESUMO

UNLABELLED: Interferon-inducible transmembrane proteins (IFITMs) can restrict the entry of a wide range of viruses. IFITM3 localizes to endosomes and can potently restrict the replication of influenza A viruses (IAV) and several other viruses that also enter host cells through the endocytic pathway. Here, we investigate whether IFITMs are involved in protection in ducks, the natural host of influenza virus. We identify and sequence duck IFITM1, IFITM2, IFITM3, and IFITM5. Using quantitative PCR (qPCR), we demonstrate the upregulation of these genes in lung tissue in response to highly pathogenic IAV infection by 400-fold, 30-fold, 30-fold, and 5-fold, respectively. We express each IFITM in chicken DF-1 cells and show duck IFITM1 localizes to the cell surface, while IFITM3 localizes to LAMP1-containing compartments. DF-1 cells stably expressing duck IFITM3 (but not IFITM1 or IFITM2) show increased restriction of replication of H1N1, H6N2, and H11N9 IAV strains but not vesicular stomatitis virus. Although duck and human IFITM3 share only 38% identity, critical residues for viral restriction are conserved. We generate chimeric and mutant IFITM3 proteins and show duck IFITM3 does not require its N-terminal domain for endosomal localization or antiviral function; however, this N-terminal end confers endosomal localization and antiviral function on IFITM1. In contrast to mammalian IFITM3, the conserved YXXθ endocytosis signal sequence in the N-terminal domain of duck IFITM3 is not essential for correct endosomal localization. Despite significant structural and amino acid divergence, presumably due to host-virus coevolution, duck IFITM3 is functional against IAV. IMPORTANCE: Immune IFITM genes are poorly conserved across species, suggesting that selective pressure from host-specific viruses has driven this divergence. We wondered whether coevolution between viruses and their natural host would result in the evasion of IFITM restriction. Ducks are the natural host of avian influenza A viruses and display few or no disease symptoms upon infection with most strains, including highly pathogenic avian influenza. We have characterized the duck IFITM locus and identified IFITM3 as an important restrictor of several influenza A viruses, including avian strains. With only 38% amino acid identity to human IFITM3, duck IFITM3 possesses antiviral function against influenza virus. Thus, despite long coevolution of virus and host effectors in the natural host, influenza virus evasion of IFITM3 restriction in ducks is not apparent.


Assuntos
Interações Hospedeiro-Patógeno , Influenza Aviária/imunologia , Proteínas de Membrana/metabolismo , Orthomyxoviridae/imunologia , Proteínas de Ligação a RNA/metabolismo , Internalização do Vírus , Animais , Linhagem Celular , Galinhas , Patos , Expressão Gênica , Perfilação da Expressão Gênica , Influenza Aviária/patologia , Proteínas de Membrana/genética , Dados de Sequência Molecular , Orthomyxoviridae/fisiologia , Proteínas de Ligação a RNA/genética , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Análise de Sequência de DNA , Homologia de Sequência de Aminoácidos
7.
Dev Comp Immunol ; 41(3): 377-88, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23624185

RESUMO

Birds have a smaller repertoire of immune genes than mammals. In our efforts to study antiviral responses to influenza in avian hosts, we have noted key genes that appear to be missing. As a result, we speculate that birds have impaired detection of viruses and intracellular pathogens. Birds are missing TLR8, a detector for single-stranded RNA. Chickens also lack RIG-I, the intracellular detector for single-stranded viral RNA. Riplet, an activator for RIG-I, is also missing in chickens. IRF3, the nuclear activator of interferon-beta in the RIG-I pathway is missing in birds. Downstream of interferon (IFN) signaling, some of the antiviral effectors are missing, including ISG15, and ISG54 and ISG56 (IFITs). Birds have only three antibody isotypes and IgD is missing. Ducks, but not chickens, make an unusual truncated IgY antibody that is missing the Fc fragment. Chickens have an expanded family of LILR leukocyte receptor genes, called CHIR genes, with hundreds of members, including several that encode IgY Fc receptors. Intriguingly, LILR homologues appear to be missing in ducks, including these IgY Fc receptors. The truncated IgY in ducks, and the duplicated IgY receptor genes in chickens may both have resulted from selective pressure by a pathogen on IgY FcR interactions. Birds have a minimal MHC, and the TAP transport and presentation of peptides on MHC class I is constrained, limiting function. Perhaps removing some constraint, ducks appear to lack tapasin, a chaperone involved in loading peptides on MHC class I. Finally, the absence of lymphotoxin-alpha and beta may account for the observed lack of lymph nodes in birds. As illustrated by these examples, the picture that emerges is some impairment of immune response to viruses in birds, either a cause or consequence of the host-pathogen arms race and long evolutionary relationship of birds and RNA viruses.


Assuntos
Proteínas Aviárias/deficiência , Galinhas/imunologia , Imunidade Inata , Imunoglobulina D/deficiência , Fatores Reguladores de Interferon/deficiência , Receptores Imunológicos/deficiência , Ubiquitina-Proteína Ligases/deficiência , Animais , Proteínas Aviárias/genética , Proteínas Aviárias/imunologia , Infecções Bacterianas/genética , Infecções Bacterianas/imunologia , Infecções Bacterianas/microbiologia , Evolução Biológica , Galinhas/microbiologia , Galinhas/virologia , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno , Imunoglobulina D/genética , Imunoglobulina D/imunologia , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/imunologia , Mamíferos/imunologia , Infecções por Orthomyxoviridae/genética , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Transdução de Sinais , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/imunologia
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