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1.
Nat Immunol ; 17(4): 397-405, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26928339

RESUMEN

The signaling adaptor TRAF3 is a highly versatile regulator of both innate immunity and adaptive immunity, but how its phosphorylation is regulated is still unknown. Here we report that deficiency in or inhibition of the conserved serine-threonine kinase CK1ɛ suppressed the production of type I interferon in response to viral infection. CK1ɛ interacted with and phosphorylated TRAF3 at Ser349, which thereby promoted the Lys63 (K63)-linked ubiquitination of TRAF3 and subsequent recruitment of the kinase TBK1 to TRAF3. Consequently, CK1ɛ-deficient mice were more susceptible to viral infection. Our findings establish CK1ɛ as a regulator of antiviral innate immune responses and indicate a novel mechanism of immunoregulation that involves CK1ɛ-mediated phosphorylation of TRAF3.


Asunto(s)
Caseína Cinasa 1 épsilon/inmunología , Inmunidad Innata/inmunología , Interferón beta/inmunología , Factor 3 Asociado a Receptor de TNF/inmunología , Animales , Caseína Cinasa 1 épsilon/antagonistas & inhibidores , Caseína Cinasa 1 épsilon/genética , Ensayo de Inmunoadsorción Enzimática , Células HEK293 , Células HeLa , Herpes Simple/inmunología , Herpesvirus Humano 1/inmunología , Humanos , Interferón Tipo I/biosíntesis , Interferón Tipo I/inmunología , Interferón beta/biosíntesis , Espectrometría de Masas , Ratones , Ratones Noqueados , Fosforilación , Proteínas Serina-Treonina Quinasas , Reacción en Cadena en Tiempo Real de la Polimerasa , Infecciones por Rhabdoviridae/inmunología , Factor 3 Asociado a Receptor de TNF/genética , Ubiquitinación , Vesiculovirus/inmunología , Fiebre del Nilo Occidental/inmunología , Virus del Nilo Occidental/inmunología
2.
Nature ; 577(7792): 682-688, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31942069

RESUMEN

Mycobacterium tuberculosis is an intracellular pathogen that uses several strategies to interfere with the signalling functions of host immune molecules. Many other bacterial pathogens exploit the host ubiquitination system to promote pathogenesis1,2, but whether this same system modulates the ubiquitination of M. tuberculosis proteins is unknown. Here we report that the host E3 ubiquitin ligase ANAPC2-a core subunit of the anaphase-promoting complex/cyclosome-interacts with the mycobacterial protein Rv0222 and promotes the attachment of lysine-11-linked ubiquitin chains to lysine 76 of Rv0222 in order to suppress the expression of proinflammatory cytokines. Inhibition of ANAPC2 by specific short hairpin RNA abolishes the inhibitory effect of Rv0222 on proinflammatory responses. Moreover, mutation of the ubiquitination site on Rv0222 impairs the inhibition of proinflammatory cytokines by Rv0222 and reduces virulence during infection in mice. Mechanistically, lysine-11-linked ubiquitination of Rv0222 by ANAPC2 facilitates the recruitment of the protein tyrosine phosphatase SHP1 to the adaptor protein TRAF6, preventing the lysine-63-linked ubiquitination and activation of TRAF6. Our findings identify a previously unrecognized mechanism that M. tuberculosis uses to suppress host immunity, and provide insights relevant to the development of effective immunomodulators that target M. tuberculosis.


Asunto(s)
Proteínas Bacterianas/inmunología , Proteínas Bacterianas/metabolismo , Interacciones Huésped-Patógeno/inmunología , Mycobacterium tuberculosis/inmunología , Tuberculosis/inmunología , Ubiquitinación , Ciclosoma-Complejo Promotor de la Anafase/química , Animales , Subunidad Apc2 del Ciclosoma-Complejo Promotor de la Anafase/metabolismo , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Células Cultivadas , Citocinas/antagonistas & inhibidores , Citocinas/inmunología , Citocinas/metabolismo , Femenino , Mediadores de Inflamación/antagonistas & inhibidores , Mediadores de Inflamación/inmunología , Mediadores de Inflamación/metabolismo , Lisina/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/microbiología , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 6/metabolismo , Transducción de Señal , Factor 6 Asociado a Receptor de TNF/antagonistas & inhibidores , Factor 6 Asociado a Receptor de TNF/metabolismo , Factor de Transcripción AP-1/metabolismo , Tuberculosis/microbiología , Virulencia/inmunología
3.
EMBO Rep ; 23(6): e53932, 2022 06 07.
Artículo en Inglés | MEDLINE | ID: mdl-35403787

RESUMEN

Aberrant activation of stimulator of interferon genes (STING) is tightly associated with multiple types of disease, including cancer, infection, and autoimmune diseases. However, the development of STING modulators for the therapy of STING-related diseases is still an unmet clinical need. We employed a high-throughput screening approach based on the interaction of small-molecule chemical compounds with recombinant STING protein to identify functional STING modulators. Intriguingly, the cyclin-dependent protein kinase (CDK) inhibitor Palbociclib was found to directly bind STING and inhibit its activation in both mouse and human cells. Mechanistically, Palbociclib targets Y167 of STING to block its dimerization, its binding with cyclic dinucleotides, and its trafficking. Importantly, Palbociclib alleviates autoimmune disease features induced by dextran sulphate sodium or genetic ablation of three prime repair exonuclease 1 (Trex1) in mice in a STING-dependent manner. Our work identifies Palbociclib as a novel pharmacological inhibitor of STING that abrogates its homodimerization and provides a basis for the fast repurposing of this Food and Drug Administration-approved drug for the therapy of autoinflammatory diseases.


Asunto(s)
Enfermedades Autoinmunes , Neoplasias , Animales , Enfermedades Autoinmunes/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Neoplasias/metabolismo , Piperazinas/farmacología , Piridinas/farmacología , Piridinas/uso terapéutico
4.
Nature ; 563(7729): 131-136, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30356214

RESUMEN

Accurate repair of DNA double-stranded breaks by homologous recombination preserves genome integrity and inhibits tumorigenesis. Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor that activates innate immunity by initiating the STING-IRF3-type I IFN signalling cascade1,2. Recognition of ruptured micronuclei by cGAS links genome instability to the innate immune response3,4, but the potential involvement of cGAS in DNA repair remains unknown. Here we demonstrate that cGAS inhibits homologous recombination in mouse and human models. DNA damage induces nuclear translocation of cGAS in a manner that is dependent on importin-α, and the phosphorylation of cGAS at tyrosine 215-mediated by B-lymphoid tyrosine kinase-facilitates the cytosolic retention of cGAS. In the nucleus, cGAS is recruited to double-stranded breaks and interacts with PARP1 via poly(ADP-ribose). The cGAS-PARP1 interaction impedes the formation of the PARP1-Timeless complex, and thereby suppresses homologous recombination. We show that knockdown of cGAS suppresses DNA damage and inhibits tumour growth both in vitro and in vivo. We conclude that nuclear cGAS suppresses homologous-recombination-mediated repair and promotes tumour growth, and that cGAS therefore represents a potential target for cancer prevention and therapy.


Asunto(s)
Núcleo Celular/metabolismo , Transformación Celular Neoplásica/patología , Neoplasias/metabolismo , Neoplasias/patología , Nucleotidiltransferasas/metabolismo , Reparación del ADN por Recombinación , Transporte Activo de Núcleo Celular , Adulto , Animales , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Núcleo Celular/enzimología , Roturas del ADN de Doble Cadena , Daño del ADN , Femenino , Células HEK293 , Humanos , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Proteínas de Neoplasias/metabolismo , Neoplasias/genética , Nucleotidiltransferasas/deficiencia , Fosforilación , Ftalazinas/farmacología , Piperazinas/farmacología , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Unión Proteica/efectos de los fármacos , Reparación del ADN por Recombinación/genética , Familia-src Quinasas/metabolismo
5.
Arch Biochem Biophys ; 744: 109673, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37392994

RESUMEN

Inflammatory pathways involving Mesenchymal stromal cells (MSCs) play an important role in Mycobacterium tuberculosis (Mtb) infection. H37Rv (Rv) is a standard virulent strain, however, H37Ra (Ra) is a strain with reduced virulence. Interleukins and chemokines production are known to promote inflammation resistance in mammalian cells and is recently reported to regulate mycobacterial immunopathogenesis via inflammatory responses. MSCs are very important cells during Mtb infection. However, the different expressions of interleukins and chemokines in the process of Mtb-infected MSCs between Ra and Rv remain unclear. We used the techniques of RNA-Seq, qRT-PCR, ELISA, and Western Blotting. We have shown that Rv infection significantly increased mRNA expressions of Mndal, Gdap10, Bmp2, and Lif, thereby increasing more differentiation of MSCs compared with Ra infection in MSCs. Further investigation into the possible mechanisms, we found that Rv infection enhanced more inflammatory response (Mmp10, Mmp3, and Ptgs2) through more activation of the TLR2-MAP3K1-JNK pathway than did Ra infection in MSCs. Further action showed that Rv infection enhanced more Il1α, Il6, Il33, Cxcl2, Ccl3, and Ackr3 production than did Ra infection. Rv infection showed more expressions of Mmp10, Mmp3, Ptgs2, Il1α, Il6, Il33, Cxcl2, Ccl3, and Ackr3 possibly through more active TLR2-MAP3K1-JNK pathway than did Ra infection in MSCs. MSCs may therefore be a new candidate for the prevention and treatment of tuberculosis.


Asunto(s)
Células Madre Mesenquimatosas , Mycobacterium tuberculosis , Animales , Ratones , Quimiocinas , Ciclooxigenasa 2 , Interleucina-33 , Interleucina-6 , Mamíferos , Metaloproteinasa 10 de la Matriz , Metaloproteinasa 3 de la Matriz , Receptor Toll-Like 2
6.
EMBO Rep ; 22(7): e51678, 2021 07 05.
Artículo en Inglés | MEDLINE | ID: mdl-33987949

RESUMEN

Mycobacterial arabinogalactan (AG) is an essential cell wall component of mycobacteria and a frequent structural and bio-synthetical target for anti-tuberculosis (TB) drug development. Here, we report that mycobacterial AG is recognized by galectin-9 and exacerbates mycobacterial infection. Administration of AG-specific aptamers inhibits cellular infiltration caused by Mycobacterium tuberculosis (Mtb) or Mycobacterium bovis BCG, and moderately increases survival of Mtb-infected mice or Mycobacterium marinum-infected zebrafish. AG interacts with carbohydrate recognition domain (CRD) 2 of galectin-9 with high affinity, and galectin-9 associates with transforming growth factor ß-activated kinase 1 (TAK1) via CRD2 to trigger subsequent activation of extracellular signal-regulated kinase (ERK) as well as induction of the expression of matrix metalloproteinases (MMPs). Moreover, deletion of galectin-9 or inhibition of MMPs blocks AG-induced pathological impairments in the lung, and the AG-galectin-9 axis aggravates the process of Mtb infection in mice. These results demonstrate that AG is an important virulence factor of mycobacteria and galectin-9 is a novel receptor for Mtb and other mycobacteria, paving the way for the development of novel effective TB immune modulators.


Asunto(s)
Mycobacterium tuberculosis , Pez Cebra , Animales , Galactanos , Galectinas/genética , Ratones
7.
Arch Biochem Biophys ; 694: 108612, 2020 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-33007281

RESUMEN

Apoptotic and inflammatory pathways play important roles in Mycobacterium tuberculosis-infected macrophages. Sirt1 is a member of the deacetylase family that is known to promote apoptosis resistance in mammalian cells and was recently reported to regulate mycobacterial immunopathogenesis via inflammatory responses. However, the apoptotic role of Sirt1 in the process of M. tuberculosis infection remains unclear. With the help of mouse peritoneal macrophage samples, we have shown that resveratrol, a Sirt1 activator, inhibited M. tuberculosis-induced apoptosis in peritoneal macrophages. Further, we found that Sirt1 activation prompted M. tuberculosis induced GSK3ß phosphorylation. Further investigation into the possible mechanisms of action showed that Sirt1 directly interacted with GSK3ß and enhanced GSK3ß phosphorylation by promoting its deacetylation. Sirt1 activation inhibited M. tuberculosis growth. Thus, it seemed that Sirt1 acted as a novel regulator of apoptosis signaling in M. tuberculosis infection via its direct effects on GSK3ß. Sirt1 may therefore be a new candidate for the prevention and treatment of tuberculosis.


Asunto(s)
Apoptosis/efectos de los fármacos , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Macrófagos/efectos de los fármacos , Mycobacterium tuberculosis/patogenicidad , Sirtuina 1/metabolismo , Animales , Activadores de Enzimas/farmacología , Femenino , Glucógeno Sintasa Quinasa 3 beta/química , Células HEK293 , Humanos , Macrófagos/metabolismo , Macrófagos/microbiología , Ratones , Mycobacterium tuberculosis/efectos de los fármacos , Fosforilación/efectos de los fármacos , Resveratrol/farmacología , Transducción de Señal/efectos de los fármacos
8.
Brain Behav Immun ; 85: 120-127, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31255682

RESUMEN

Evidence shows that gut microbiota may play important roles in schizophrenia pathogenesis via the "gut-brain" axis, but the mechanisms remain unclear. Here, eighty-four patients with schizophrenia and 84 sex- and age-matched healthy controls were enrolled. Shotgun metagenomic sequencing and 16S rRNA sequencing were performed, and the gut microbiota-associated epitopes (MEs) were predicted, which, together with IgA content, were used to determine the gut microbiota composition associated with gut immune status. Patients with schizophrenia had significantly reduced gut microbiota richnesses compared with those of the healthy controls, and the gut microbiota compositions clearly distinguished the patients with schizophrenia from the healthy controls. Based on two-stage metagenomic-wide association studies, nineteen gut microbiota taxonomies were associated with schizophrenia, and the microbial dysbiosis (MD) index was calculated based on the abundance of differential taxonomies. We found that MD index was positively correlated with MEs diversity and gut IgA levels, and negatively correlated with gut microbiota richness. Glutamate synthase (GOGAT) was more active in the guts of patients with schizophrenia than in those of healthy controls, and high GOGAT activity was associated with altered gut microbiota taxonomies associated with gut IgA levels. Our results may imply a role of the microbiome in the etiology of schizophrenia and contribute to the development of microbiome targeted interventions for schizophrenia.


Asunto(s)
Microbioma Gastrointestinal , Esquizofrenia , Disbiosis , Humanos , Inmunidad Mucosa , ARN Ribosómico 16S/genética
9.
Gen Physiol Biophys ; 39(4): 319-330, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32902402

RESUMEN

Aim of this study was to investigate the possible regulatory effect of the programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) signaling pathway on Tregs in ovarian cancer. Immunohistochemistry was used to detect the expression of PD-L1 and PD-1 and the presence of FOXP3+ Tregs in ovarian cancer. Then, ovarian cancer HO8910 cells were subjected to transfection with PD-L1 siRNA in vitro. CCK-8, Transwell and wound healing assays were performed to detect the biological behaviors of ovarian cancer cells. Human T-cells isolated from human peripheral blood were cocultured with HO8910 cells, which were divided into the Control, TGF-ß, and TGF-ß+ anti-PD-L1 groups. The proportion of differentiated Tregs was detected by flow cytometry. Mouse models of ovarian cancer were established, and PD-L1 antibody therapy was administered. Tumor growth and Treg recruitment were observed. PD-L1, PD-1 and FOXP3+ Tregs were found in ovarian cancer tissue. Patients with tumors with an advanced stage and low differentiation and lymph node metastasis had significantly higher levels of PD-1, PD-L1 and FOXP3+ Tregs. After transfection with PD-L1 siRNA, HO8910 cells showed a significant reduction in PD-L1 expression, proliferation, migration and invasion. After T-cells were cocultured with ovarian cancer cells, the TGF-ß+ anti-PD-L1 group showed a substantial decline in the differentiation of T-cells into Tregs compared with the TGF-ß group. Moreover, mice in the anti-PD-L1 group had significantly reduced tumor growth rates, Treg proportions in the tumor microenvironment, and FOXP3 expression.


Asunto(s)
Antígeno B7-H1/fisiología , Neoplasias Ováricas/inmunología , Receptor de Muerte Celular Programada 1/fisiología , Transducción de Señal , Linfocitos T Reguladores/citología , Animales , Células Cultivadas , Femenino , Factores de Transcripción Forkhead , Humanos , Ratones , Microambiente Tumoral
10.
J Infect Dis ; 218(2): 312-323, 2018 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-29228365

RESUMEN

Tuberculosis, caused by Mycobacterium tuberculosis infection, remains a global threat to human health, but knowledge of the molecular mechanisms underlying the pathogenesis of tuberculosis is still limited. Although Notch4, a member of the Notch receptor family, is involved in the initiation of mammary tumors, its function in M. tuberculosis infection remains unclear. In this study, we found that Notch4-deficient mice were more resistant to M. tuberculosis infection, with a much lower bacterial burden and fewer pathological changes in the lungs. Notch4 inhibited M. tuberculosis-induced production of proinflammatory cytokines by interaction with TAK1 and inhibition of its activation. Furthermore, we found that Notch intracellular domain 4 prevented TRAF6 autoubiquitination and suppressed TRAF6-mediated TAK1 polyubiquitination. Finally, Notch inhibitors made mice more resistant to M. tuberculosis infection. These results suggest that Notch4 is a negative regulator of M. tuberculosis-induced inflammatory response, and treatment with a Notch inhibitor could serve as a new therapeutic strategy for tuberculosis.


Asunto(s)
Regulación de la Expresión Génica , Quinasas Quinasa Quinasa PAM/metabolismo , Receptor Notch4/metabolismo , Tuberculosis Pulmonar/patología , Animales , Carga Bacteriana , Citocinas/análisis , Modelos Animales de Enfermedad , Femenino , Células HEK293 , Humanos , Inflamación/patología , Pulmón/microbiología , Pulmón/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Células RAW 264.7 , Receptor Notch4/deficiencia , Factor 6 Asociado a Receptor de TNF/metabolismo , Tuberculosis Pulmonar/microbiología
11.
PLoS Pathog ; 11(1): e1004613, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25615690

RESUMEN

Enterovirus 71 (EV71) is the most virulent pathogen among enteroviruses that cause hand, foot and mouth disease in children but rarely in adults. The mechanisms that determine the age-dependent susceptibility remain largely unclear. Here, we found that the paucity of invariant natural killer T (iNKT) cells together with immaturity of the immune system was related to the susceptibility of neonatal mice to EV71 infection. iNKT cells were crucial antiviral effector cells to protect young mice from EV71 infection before their adaptive immune systems were fully mature. EV71 infection led to activation of iNKT cells depending on signaling through TLR3 but not other TLRs. Surprisingly, iNKT cell activation during EV71 infection required TLR3 signaling in macrophages, but not in dendritic cells (DCs). Mechanistically, interleukin (IL)-12 and endogenous CD1d-restricted antigens were both required for full activation of iNKT cells. Furthermore, CD1d-deficiency led to dramatically increased viral loads in central nervous system and more severe disease in EV71-infected mice. Altogether, our results suggest that iNKT cells may be involved in controlling EV71 infection in children when their adaptive immune systems are not fully developed, and also imply that iNKT cells might be an intervention target for treating EV71-infected patients.


Asunto(s)
Enterovirus Humano A/inmunología , Infecciones por Enterovirus/inmunología , Inmunidad Celular , Macrófagos/inmunología , Células T Asesinas Naturales/inmunología , Receptor Toll-Like 3/fisiología , Animales , Células Cultivadas , Infecciones por Enterovirus/genética , Humanos , Inmunidad Celular/genética , Activación de Linfocitos/genética , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Ratones Noqueados , Células T Asesinas Naturales/metabolismo , Transducción de Señal/inmunología
12.
Nat Microbiol ; 9(7): 1856-1872, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38806671

RESUMEN

Adaptation to hypoxia is a major challenge for the survival of Mycobacterium tuberculosis (Mtb) in vivo. Interferon (IFN)-γ-producing CD8+ T cells contribute to control of Mtb infection, in part by promoting antimicrobial activities of macrophages. Whether Mtb counters these responses, particularly during hypoxic conditions, remains unknown. Using metabolomic, proteomic and genetic approaches, here we show that Mtb induced Rv0884c (SerC), an Mtb phosphoserine aminotransferase, to produce D-serine. This activity increased Mtb pathogenesis in mice but did not directly affect intramacrophage Mtb survival. Instead, D-serine inhibited IFN-γ production by CD8+ T cells, which indirectly reduced the ability of macrophages to restrict Mtb upon co-culture. Mechanistically, D-serine interacted with WDR24 and inhibited mTORC1 activation in CD8+ T cells. This decreased T-bet expression and reduced IFN-γ production by CD8+ T cells. Our findings suggest an Mtb evasion mechanism where pathogen metabolic adaptation to hypoxia leads to amino acid-dependent suppression of adaptive anti-TB immunity.


Asunto(s)
Linfocitos T CD8-positivos , Interferón gamma , Macrófagos , Mycobacterium tuberculosis , Serina , Tuberculosis , Animales , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Mycobacterium tuberculosis/inmunología , Ratones , Serina/metabolismo , Interferón gamma/metabolismo , Interferón gamma/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/microbiología , Tuberculosis/inmunología , Tuberculosis/microbiología , Ratones Endogámicos C57BL , Transaminasas/metabolismo , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Hipoxia/inmunología , Hipoxia/metabolismo , Femenino , Interacciones Huésped-Patógeno/inmunología
13.
Nat Commun ; 15(1): 4216, 2024 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-38760394

RESUMEN

Antimicrobial peptides (AMPs), ancient scavengers of bacteria, are very poorly induced in macrophages infected by Mycobacterium tuberculosis (M. tuberculosis), but the underlying mechanism remains unknown. Here, we report that L-alanine interacts with PRSS1 and unfreezes the inhibitory effect of PRSS1 on the activation of NF-κB pathway to induce the expression of AMPs, but mycobacterial alanine dehydrogenase (Ald) Rv2780 hydrolyzes L-alanine and reduces the level of L-alanine in macrophages, thereby suppressing the expression of AMPs to facilitate survival of mycobacteria. Mechanistically, PRSS1 associates with TAK1 and disruptes the formation of TAK1/TAB1 complex to inhibit TAK1-mediated activation of NF-κB pathway, but interaction of L-alanine with PRSS1, disables PRSS1-mediated impairment on TAK1/TAB1 complex formation, thereby triggering the activation of NF-κB pathway to induce expression of AMPs. Moreover, deletion of antimicrobial peptide gene ß-defensin 4 (Defb4) impairs the virulence by Rv2780 during infection in mice. Both L-alanine and the Rv2780 inhibitor, GWP-042, exhibits excellent inhibitory activity against M. tuberculosis infection in vivo. Our findings identify a previously unrecognized mechanism that M. tuberculosis uses its own alanine dehydrogenase to suppress host immunity, and provide insights relevant to the development of effective immunomodulators that target M. tuberculosis.


Asunto(s)
Alanina , Péptidos Antimicrobianos , Macrófagos , Mycobacterium tuberculosis , FN-kappa B , Tuberculosis , Mycobacterium tuberculosis/patogenicidad , Mycobacterium tuberculosis/metabolismo , Animales , Ratones , FN-kappa B/metabolismo , Humanos , Macrófagos/microbiología , Macrófagos/metabolismo , Macrófagos/inmunología , Alanina/metabolismo , Péptidos Antimicrobianos/metabolismo , Péptidos Antimicrobianos/genética , Tuberculosis/microbiología , Tuberculosis/inmunología , Alanina-Deshidrogenasa/metabolismo , Alanina-Deshidrogenasa/genética , Quinasas Quinasa Quinasa PAM/metabolismo , Quinasas Quinasa Quinasa PAM/genética , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Transducción de Señal , Ratones Endogámicos C57BL , Células RAW 264.7 , Femenino
14.
World J Biol Psychiatry ; 24(4): 321-329, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-35950568

RESUMEN

OBJECTIVE: P-type atypical lymphocytes may play important roles in the aetiology and therapy of schizophrenia. However, there is merely a direct immunological characterisation of it. The aim of this study is to explore the surface antigens of these cells and their comparative ultrastructure in schizophrenia. METHODS: We recruited 25 age-and gender-matched patients with unmedicated schizophrenia, other mental diseases and healthy individuals. Peripheral venous blood was smeared and stained. CD4+, CD8+ and CD19+ cell surface antigen- positive lymphocytes were purified using magnetic beads and prepared for light microscopy and electron microscopy. RESULTS: The percentages of P-type atypical lymphocytes (34.53% ± 9.92%) were significantly higher (p < 0.0001) in schizophrenia than that of other mental diseases (9.79% ± 3.45%). These cells could present CD4+, CD8+ and CD19+ surface antigens. Their relative ultrastructure differed from that of normal lymphocytes, especially in mitochondria, which showed abundant, aggregated and quite irregular mitochondria; for example, slight dilation of the foci, swelling, degeneration, and even cavity. CONCLUSIONS: P-type atypical lymphocytes could be found among CD4+, CD8+, and CD19 + lymphocytes with schizophrenia. Their abnormal ultrastructure of mitochondria implied that energy metabolism might play an important role in the aetiology of schizophrenia.


Asunto(s)
Esquizofrenia , Humanos , Antígenos de Superficie , Linfocitos , Antígenos CD19 , Mitocondrias
15.
Int Immunopharmacol ; 124(Pt B): 111058, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37844466

RESUMEN

Mycobacterium tuberculosis (M.tb), the most successful pathogen responsible for approximately 1.6 million deaths in 2021, employs various strategies to evade host antibacterial defenses, including mechanisms to counteract nitric oxide (NO) and certain cytokines. While Amyloid ß (A4) precursor-like protein 2 (Aplp2) has been implicated in various physiological and pathological processes, its role in tuberculosis (TB) pathogenesis remains largely uncharted. This study unveils a significant reduction in Aplp2 levels in TB patients, M.tb-infected macrophages, and mice. Intriguingly, Aplp2 mutation or knockdown results in diminished macrophage-mediated killing of M.tb, accompanied by decreased inducible nitric oxide synthase (iNOS) expression and reduced cytokine production, notably interleukin-1ß (Il-1ß). Notably, Aplp2 mutant mice exhibit heightened susceptibility to mycobacterial infection, evident through aggravated histopathological damage and increased lung bacterial loads, in contrast to Mycobacterium bovis BCG-infected wild-type (WT) mice. Mechanistically, the cleaved product of APLP2, AICD2, generated by γ-secretase, translocates to the nucleus, where it interacts with p65, culminating in enhanced the nuclear factor κB (NF-κB) transcriptional activity. This interaction triggers the upregulation of Il-1ß and iNOS expression. Collectively, our findings illuminate Aplp2's pivotal role in safeguarding against mycobacterial infections by promoting M.tb clearance through NO- or IL-1ß-mediated bactericidal effects. Therefore, we unveil a novel immune evasion strategy employed by M.tb, which could potentially serve as a target for innovative TB interventions.


Asunto(s)
Mycobacterium tuberculosis , Tuberculosis , Humanos , Animales , Ratones , Péptidos beta-Amiloides/metabolismo , Macrófagos , FN-kappa B/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo
16.
Cell Rep ; 42(3): 112275, 2023 03 28.
Artículo en Inglés | MEDLINE | ID: mdl-36943864

RESUMEN

Enhancing chemosensitivity is one of the largest unmet medical needs in cancer therapy. Cyclic GMP-AMP synthase (cGAS) connects genome instability caused by platinum-based chemotherapeutics to type I interferon (IFN) response. Here, by using a high-throughput small-molecule microarray-based screening of cGAS interacting compounds, we identify brivanib, known as a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor, as a cGAS modulator. Brivanib markedly enhances cGAS-mediated type I IFN response in tumor cells treated with platinum. Mechanistically, brivanib directly targets cGAS and enhances its DNA binding affinity. Importantly, brivanib synergizes with cisplatin in tumor control by boosting CD8+ T cell response in a tumor-intrinsic cGAS-dependent manner, which is further validated by a patient-derived tumor-like cell clusters model. Taken together, our findings identify cGAS as an unprecedented target of brivanib and provide a rationale for the combination of brivanib with platinum-based chemotherapeutics in cancer treatment.


Asunto(s)
Alanina , Antineoplásicos , Neoplasias , Nucleotidiltransferasas , Triazinas , Humanos , Ensayos Analíticos de Alto Rendimiento , Alanina/análogos & derivados , Nucleotidiltransferasas/metabolismo , Interferones/inmunología , Cisplatino/administración & dosificación , Antineoplásicos/administración & dosificación , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Células Tumorales Cultivadas/efectos de los fármacos , Neoplasias/tratamiento farmacológico
17.
J Immunol ; 185(12): 7435-42, 2010 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-21068409

RESUMEN

MAPK phosphatase-1 (MKP-1) is an archetypical member of the dual-specificity phosphatase family that deactivates MAPKs. Induction of MKP-1 has been implicated in attenuating the LPS- or peptidoglycan-induced biosynthesis of proinflammatory cytokines, but the role of noncoding RNA in the expression of the MKP-1 is still poorly understood. In this study, we show that MKP-1 is a direct target of microRNA-101 (miR-101). Transfection of miR-101 attenuates induction of MKP-1 by LPS as well as prolonged activation of p38 and JNK/stress-activated protein kinase, whereas inhibition of miR-101 enhances the expression of MKP-1 and shortens p38 and JNK activation. We also found that expression of miR-101 is induced by multiple TLR ligands, including LPS, peptidoglycan, or polyinosinic-polycytidylic acid, and that inhibition of PI3K/Akt by LY294002 or Akt RNA interference blocks the induction of miR-101 by LPS in RAW264.7 macrophage cells. Moreover, treatment of cells with dexamethasone, a widely used anti-inflammatory agent, markedly inhibits miR-101 expression and enhances the expression of MKP-1 in LPS-stimulated macrophages. Together, these results indicate that miR-101 regulates the innate immune responses of macrophages to LPS through targeting MKP-1.


Asunto(s)
Fosfatasa 1 de Especificidad Dual/inmunología , Inmunidad Innata/fisiología , Macrófagos/inmunología , MicroARNs/inmunología , Animales , Antiinflamatorios/farmacología , Línea Celular , Dexametasona/farmacología , Fosfatasa 1 de Especificidad Dual/biosíntesis , Activación Enzimática/efectos de los fármacos , Activación Enzimática/inmunología , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Inmunidad Innata/efectos de los fármacos , Lipopolisacáridos/farmacología , MAP Quinasa Quinasa 4/inmunología , MAP Quinasa Quinasa 4/metabolismo , Macrófagos/metabolismo , Ratones , MicroARNs/biosíntesis , Receptores Toll-Like/agonistas , Receptores Toll-Like/inmunología , Receptores Toll-Like/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/inmunología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
18.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 34(1): 75-79, 2022 Jan.
Artículo en Zh | MEDLINE | ID: mdl-35307065

RESUMEN

OBJECTIVE: To explore the association between levels of thyroid-stimulating hormone (TSH) on admission and prognosis of patients admitted to intensive care unit (ICU). METHODS: The data were collected from patients who were admitted to the ICU of the Beth Israel Deaconess Medical Center in the United States from 2001 to 2012 with available TSH test records within 24 hours after the ICU admission via the Medical Information Mart for Intensive Care-III v1.4 (MIMIC-III v1.4). Information including gender, age, ethnicity, type of admission, mechanical ventilation (MV) or renal replacement therapy (RRT) received on admission, comorbidities, and TSH test records within 24 hours after the ICU admission were collected. The sequential organ failure assessment (SOFA) score, simplified acute physiology score II (SAPS II) and the comorbidities index Elixhauser (SID30) score were calculated according to the parameters. The primary outcome was hospital mortality. Differences in baseline characteristics and prognosis were examined between patients with normal TSH levels and abnormal TSH levels which was determined according to a dichotomous variable provided by the data. Multivariable Logistic regression was used to analyze the association between TSH levels and prognosis after adjusting for confounding factors. A sensitivity analysis was conducted which categorized the study population as three groups (i.e., decreased, normal, and elevated TSH levels) using the range of 0.30-3.00 mU/L as the normal range of TSH. RESULTS: A total of 3 425 ICU patients were enrolled in the study, of which 2 692 (78.60%) were with normal TSH and 733 (21.40%) were with abnormal TSH. There was no statistically significant difference in gender, age, ethnicity, type of admission and the ratio of MV between the normal TSH and abnormal TSH groups. Compared with normal TSH group, the patients in abnormal TSH had a higher SOFA, SAPS II and SID30 scores as well as the ratio of RRT [SOFA score: 4 (2, 7) vs. 4 (2, 6), SAPS II score: 38.02±13.76 vs. 36.53±13.75, SID30 score: 11 (4, 22) vs. 11 (0, 20), RRT ratio: 5.32% (39/733) vs. 3.49% (94/2 692), all P < 0.05]. The hospital mortality of patients in normal TSH was significantly higher than that of those in abnormal TSH [9.82% (72/733) vs. 5.94% (160/2 692), P < 0.01]. After adjusting for confounding factors, abnormal TSH was significantly associated with hospital mortality [odds ratio (OR) = 1.71, 95% confidence interval (95%CI) was 1.24-2.35, P = 0.001]. In the sensitivity analysis in which the range of 0.30-3.00 mU/L was used as the normal range of TSH, compared with normal TSH, decreased TSH (OR = 2.36, 95%CI was 1.40-3.97, P = 0.001) and elevated TSH (OR = 1.44, 95%CI was 1.05-1.98, P = 0.023) were both significantly associated with increased hospital mortality. CONCLUSIONS: An abnormal level of TSH within 24 hours after admitted to ICU is an independent risk factor for hospital mortality among ICU patients.


Asunto(s)
Unidades de Cuidados Intensivos , Tirotropina , Mortalidad Hospitalaria , Humanos , Puntuaciones en la Disfunción de Órganos , Pronóstico
19.
Chemosphere ; 291(Pt 2): 132940, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-34798113

RESUMEN

Environmental pollution with plastics including polyethylene terephthalate (PET) has become a severe global problem, especially microplastic pollution, which is acknowledged as an emerging global pollutant. Biodegradation as a feasible and promising method has been studied, while colonization as the initiating step of the degradation process has seldom been studied. Here in this paper, we explored for the first time the key role of ultraviolet (UV) irradiation and nonionic surfactant polysorbate 80 (Tween-80, 0.2% V/V) in the proliferation and colonization of three functional bacteria (Pseudomonas putida, Pseudomonas sp. and Paracoccus sp.) on amorphous PET (APET). We found that 25 days of UV irradiation can trigger photolytic degradation process (appear the stretching vibration of associating carboxyl end group and the in-plane bending vibration of -OH) and introduce oxygen-containing functional groups on the surface of APET, even though the hydrophobicity of APET was scarcely changed. With regard to Tween-80, it can be utilized by these bacteria strains as carbon source to promote the proliferation, and it can also improve the cell surface hydrophobicity to stimulate the bacterial colonization during the first ten days of the experiment. When UV-irradiation and Tween-80 were provided together, the former factor can provide the target sites for functional bacteria to colonize, and the later factor can provide more candidates waiting to colonize by stimulating proliferation. As a result, an even better proliferation and colonization result can be achieved through the synergistic effect between the two factors. To some extent, the exposure between potential degrading bacteria and substrates to be degraded can be increased, which will create conditions for degrading. Generally, this research can provide certain theoretical basis and technical guidance for the remediation of plastic-polluted soil and the ocean.


Asunto(s)
Plásticos , Tereftalatos Polietilenos , Bacterias , Biodegradación Ambiental , Proliferación Celular , Polietileno , Polisorbatos , Tensoactivos
20.
Mol Med Rep ; 25(5)2022 May.
Artículo en Inglés | MEDLINE | ID: mdl-35244189

RESUMEN

Acute kidney injury (AKI) is the most common and serious complication of sepsis, and it is also the main cause of mortality in patients with sepsis. The G protein­coupled receptor 55 (GPR55) inhibitor CID16020046 was found to suppress the inflammatory response in sepsis models in mice. The aim of the present study was to investigate the effect of CID16020046 on AKI in sepsis mouse models and elucidate the possible underlying mechanisms. A sepsis model in mice was established by cecal ligation/perforation (CLP). The expression levels of GPR55 in the serum of patients with sepsis and the renal tissues of septic mice were determined via reverse transcription­quantitative PCR and western blot analyses, respectively. The pathological injury of renal tissue was evaluated using H&E and periodic acid­Schiff staining. ELISA was performed to detect the levels of renal injury­related factors, including blood urea nitrogen (BUN), creatinine (Cre), kidney injury molecule 1 (KIM1) and neutrophil gelatinase­associated lipocalin (NGAL) in septic mice. Moreover, the levels of pro­inflammatory cytokines (TNF­α, IL­6 and IL­1ß) were detected via ELISA and western blotting. Apoptosis was determined using TUNEL staining and western blotting. The expression levels of Rho­associated protein kinase (ROCK) pathway­related proteins (Ras homolog family member A, ROCK1 and ROCK2) was measured via western blotting. Finally, H&E staining was used to evaluate the effect of CID16020046 on various organs in mice. Compared with the control subjects, the expression level of GPR55 in the serum of patients with sepsis was significantly increased. Compared with the sham group, CID16020046 (20 mg/kg) significantly decreased the levels of BUN and Cre in the serum, as well as the contents of KIM1 and NGAL in the urine. Furthermore, CID16020046 significantly decreased the contents of TNF­α, IL­6 and IL­1ß in the serum and renal tissue of septic mice, and reduced cell apoptosis. In addition, CID16020046 effectively suppressed the expression levels of ROCK pathway­related proteins, and H&E staining revealed that CID16020046 (20 mg/kg) had no toxic effect on the heart, liver, spleen or lung in normal mice. In conclusion, CID16020046 may prove useful for the development of drugs for the treatment of sepsis­induced AKI.


Asunto(s)
Lesión Renal Aguda , Sepsis , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/etiología , Animales , Compuestos de Azabiciclo/uso terapéutico , Benzoatos , Modelos Animales de Enfermedad , Humanos , Riñón/patología , Ratones , Receptores de Cannabinoides/uso terapéutico , Sepsis/complicaciones , Sepsis/tratamiento farmacológico , Sepsis/metabolismo , Quinasas Asociadas a rho
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