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1.
Mol Ther ; 32(5): 1510-1525, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38454605

RESUMO

The acute respiratory virus infection can induce uncontrolled inflammatory responses, such as cytokine storm and viral pneumonia, which are the major causes of death in clinical cases. Cyclophilin A (CypA) is mainly distributed in the cytoplasm of resting cells and released into the extracellular space in response to inflammatory stimuli. Extracellular CypA (eCypA) is upregulated and promotes inflammatory response in severe COVID-19 patients. However, how eCypA promotes virus-induced inflammatory response remains elusive. Here, we observe that eCypA is induced by influenza A and B viruses and SARS-CoV-2 in cells, mice, or patients. Anti-CypA mAb reduces pro-inflammatory cytokines production, leukocytes infiltration, and lung injury in virus-infected mice. Mechanistically, eCypA binding to integrin ß2 triggers integrin activation, thereby facilitating leukocyte trafficking and cytokines production via the focal adhesion kinase (FAK)/GTPase and FAK/ERK/P65 pathways, respectively. These functions are suppressed by the anti-CypA mAb that specifically blocks eCypA-integrin ß2 interaction. Overall, our findings reveal that eCypA-integrin ß2 signaling mediates virus-induced inflammatory response, indicating that eCypA is a potential target for antibody therapy against viral pneumonia.


Assuntos
COVID-19 , Ciclofilina A , Ciclofilina A/metabolismo , Animais , Humanos , Camundongos , COVID-19/metabolismo , COVID-19/virologia , COVID-19/imunologia , Antígenos CD18/metabolismo , SARS-CoV-2 , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Pneumonia Viral/metabolismo , Pneumonia Viral/imunologia , Citocinas/metabolismo , Anticorpos Monoclonais/farmacologia , Transdução de Sinais , Vírus da Influenza A , Modelos Animais de Doenças
2.
J Autoimmun ; 148: 103293, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39096717

RESUMO

Psoriasis is a chronic, proliferative, and inflammatory skin disease closely associated with inflammatory cytokine production. Cyclophilin A (CypA) is an important proinflammatory factor; however, its role in psoriasis remains unclear. The present data indicate that CypA levels are increased in the lesion skin and serum of patients with psoriasis, which is positively correlated with the psoriasis area severity index. Furthermore, extracellular CypA (eCypA) triggered psoriasis-like inflammatory responses in keratinocytes. Moreover, anti-CypA mAb significantly reduced pathological injury, keratinocyte proliferation, cytokine expression in imiquimod-induced mice. Notably, the therapeutic effect of anti-CypA mAb was better than that of the clinically used anti-IL-17A mAb and methotrexate. Mechanistically, eCypA binds to ACE2 and CD147 and is blocked by anti-CypA mAb. eCypA not only induces the dimerization and phosphorylation of ACE2 to trigger the JAK1/STAT3 signaling pathway for cytokine expression but also interacts with CD147 to promote PI3K/AKT/mTOR signaling-mediated keratinocyte proliferation. These findings demonstrate that the binding of eCypA to ACE2 and CD147 cooperatively triggers psoriasis-like inflammation and anti-CypA mAb is a promising candidate for the treatment of psoriasis.


Assuntos
Enzima de Conversão de Angiotensina 2 , Basigina , Ciclofilina A , Queratinócitos , Ligação Proteica , Psoríase , Transdução de Sinais , Basigina/metabolismo , Basigina/imunologia , Ciclofilina A/metabolismo , Humanos , Animais , Psoríase/metabolismo , Psoríase/imunologia , Camundongos , Queratinócitos/metabolismo , Queratinócitos/imunologia , Enzima de Conversão de Angiotensina 2/metabolismo , Inflamação/metabolismo , Inflamação/imunologia , Modelos Animais de Doenças , Masculino , Feminino , Proliferação de Células , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Citocinas/metabolismo
3.
FASEB J ; 35(11): e21958, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34606626

RESUMO

Cyclophilin A (CypA), a member of the cyclophilin family, plays a vital role in microorganismal infections, inflammatory diseases, and cancers. Interleukin-6 (IL-6) is a pleiotropic cytokine, exerting variety of effects on inflammation, immune response, hematopoiesis, and tumor proliferation. Binding of IL-6 to soluble IL-6 receptor (sIL-6R) induces pro-inflammatory trans-signaling, which has been described to be stronger than anti-inflammatory classic signaling triggered by the binding of IL-6 to membrane-bound IL-6 receptor. Here we found that upon the treatment of IL-6 and sIL-6R, CypA inhibited the ubiquitination-mediated degradation of IL-6 membrane receptor gp130 and enhanced its dimerization, thereby positively regulated the IL-6 trans-signaling and increased the expression of downstream iNOS, IL-6, and CypA. Furthermore, CypA expression could be negatively regulated by suppressor of cytokine signaling 1 (SOCS1). The SH2 and Box domains of SOCS1 interacted with CypA and promoted its K48-linked ubiquitination-mediated degradation, which inhibited the IL-6 trans-signaling pathway. Collectively, our findings reveal an important role of CypA in the positive and negative feedback regulation of the IL-6 trans-signaling pathway.


Assuntos
Ciclofilina A/fisiologia , Interleucina-6/metabolismo , Receptores de Interleucina-6/metabolismo , Proteína 1 Supressora da Sinalização de Citocina/metabolismo , Células A549 , Células HEK293 , Humanos , Transdução de Sinais
4.
Infect Immun ; 88(4)2020 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-31964749

RESUMO

The mechanism underlying the pathogenesis of Nocardia is not fully known. The Nfa34810 protein of Nocardia farcinica has been predicted to be a virulence factor. However, relatively little is known regarding the interaction of Nfa34810 with host cells, specifically invasion and innate immune activation. In this study, we aimed to determine the role of recombinant Nfa34810 during infection. We demonstrated that Nfa34810 is an immunodominant protein located in the cell wall. Nfa34810 protein was able to facilitate the uptake and internalization of latex beads coated with Nfa34810 protein into HeLa cells. Furthermore, the deletion of the nfa34810 gene in N. farcinica attenuated the ability of the bacteria to infect both HeLa and A549 cells. Moreover, stimulation with Nfa34810 triggered macrophages to produce tumor necrosis factor alpha (TNF-α), and it also activated mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) signaling pathways by inducing the phosphorylation of ERK1/2, p38, JNK, p65, and AKT in macrophages. Specific inhibitors of ERK1/2, JNK, and NF-κB significantly reduced the expression of TNF-α, which demonstrated that Nfa34810-mediated TNF-α production was dependent upon the activation of these kinases. We further found that neutralizing antibodies against Toll-like receptor 4 (TLR4) significantly inhibited TNF-α secretion. Taken together, our results indicated that Nfa34810 is a virulence factor of N. farcinica and plays an important role during infection. Nfa34810-induced production of TNF-α in macrophages also involves ERK, JNK, and NF-κB via the TLR4 pathway.


Assuntos
Proteínas de Bactérias/metabolismo , Células Epiteliais/imunologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Nocardia/imunologia , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Células A549 , Células Epiteliais/microbiologia , Células HeLa , Interações Hospedeiro-Patógeno , Humanos , Nocardia/crescimento & desenvolvimento , Fatores de Virulência/metabolismo
5.
J Clin Microbiol ; 57(9)2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31315959

RESUMO

Corynebacterium striatum is an emerging multidrug-resistant (MDR) pathogen that occurs primarily among immunocompromised and chronically ill patients. However, little is known about the genomic diversity of C. striatum, which contributes to its long-term persistence and transmission in hospitals. In this study, a total of 192 C. striatum isolates obtained from 14 September 2017 to 29 March 2018 in a hospital in Beijing, China, were analyzed by antimicrobial susceptibility testing and pulsed-field gel electrophoresis (PFGE). Whole-genome sequencing was conducted on 91 isolates. Nearly all isolates (96.3%, 183/190) were MDR. The highest resistance rate was observed for ciprofloxacin (99.0%, 190/192), followed by cefotaxime (90.6%, 174/192) and erythromycin (89.1%, 171/192). PFGE separated the 192 isolates into 79 pulsotypes, and differences in core genome single-nucleotide polymorphisms (SNPs) partitioned the 91 isolates sequenced into four clades. Isolates of the same pulsotype were identical or nearly identical at the genome level, with some exceptions. Two dominant subclones, clade 3a, and clade 4a, were responsible for the hospital-wide dissemination. Genomic analysis further revealed nine resistance genes mobilized by eight unique cassettes. PFGE and whole-genome sequencing revealed that the C. striatum isolates studied were the result mainly of predominant clones spreading in the hospital. C. striatum isolates in the hospital progressively acquired resistance to antimicrobial agents, demonstrating that isolates of C. striatum may adapt rapidly through the acquisition and accumulation of resistance genes and thus evolve into dominant and persistent clones. These insights will be useful for the prevention of C. striatum infection in hospitals.


Assuntos
Infecções por Corynebacterium/transmissão , Corynebacterium/classificação , Infecção Hospitalar/transmissão , Transmissão de Doença Infecciosa , Genótipo , Epidemiologia Molecular/métodos , Sequenciamento Completo do Genoma/métodos , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/farmacologia , China/epidemiologia , Corynebacterium/efeitos dos fármacos , Corynebacterium/genética , Corynebacterium/isolamento & purificação , Infecções por Corynebacterium/epidemiologia , Infecção Hospitalar/epidemiologia , Farmacorresistência Bacteriana Múltipla , Eletroforese em Gel de Campo Pulsado , Feminino , Variação Genética , Hospitais , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Estudos Retrospectivos
6.
Microb Pathog ; 137: 103705, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31487535

RESUMO

Nocardia farcinica is the etiological agent of nocardiosis, leading to serious pulmonary or systemic infections. To uncover virulence factors and early diagnostic markers, secreted proteins of N. farcinica IFM 10152 were analyzed using an immunoproteome-based approach. A total of 5 proteins were identified by matrix-assisted laser desorption (MALDI-TOF-MS). Bioinformatic analyses showed that the identified proteins were involved in defense against the host innate immune system and required for pathogenesis. All proteins were expressed in E. coli and antigenicity was analyzed with Western blot. To our knowledge, these proteins with antigenicity were identified for the first time in N. farcinica and they may help elucidate the pathogenesis underlying Nocardia and provide potential future diagnostic markers.


Assuntos
Antígenos de Bactérias/imunologia , Antígenos de Bactérias/isolamento & purificação , Proteínas de Bactérias/imunologia , Proteínas de Bactérias/isolamento & purificação , Nocardia/imunologia , Proteômica , Animais , Antígenos de Bactérias/genética , Proteínas de Bactérias/genética , Escherichia coli/genética , Feminino , Regulação Bacteriana da Expressão Gênica , Imunidade Inata , Camundongos , Camundongos Endogâmicos BALB C , Nocardia/genética , Nocardiose/diagnóstico , Nocardiose/imunologia , Coelhos , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/isolamento & purificação , Fatores de Virulência/genética , Fatores de Virulência/imunologia
7.
iScience ; 26(9): 107535, 2023 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-37636080

RESUMO

Cytokine storms caused by viruses are associated with elevated cytokine levels and uncontrolled inflammatory responses that can lead to acute respiratory distress syndrome. Current antiviral therapies are not sufficient to prevent or treat these complications. Cyclophilin A (CypA) is a key factor that regulates the production of multiple cytokines and could be a potential therapeutic target for cytokine storms. Here, three proteolysis targeting chimeras (PROTACs) targeting CypA were designed. These PROTACs bind to CypA, enhance its ubiquitination, and promote its degradation in both cell lines and mouse organs. During influenza B virus (IBV) infection, PROTAC-mediated CypA depletion reduces P65 phosphorylation and NF-κB-mediated proinflammatory cytokine production in A549 cells. Moreover, Comp-K targeting CypA suppresses excessive secretion of proinflammatory cytokines in bronchoalveolar lavage fluid, reduces lung injury, and enhances survival rates of IBV-infected mice. Collectively, we provide PROTACs targeting CypA, which are potential candidates for the control of cytokine storms.

8.
iScience ; 26(12): 108515, 2023 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-38089580

RESUMO

Influenza B circulates annually and causes substantial disease burden in humans. However, little is known about the infection mechanisms of influenza B virus (IBV). Here, we find that the host factor cyclophilin A (CypA) facilitates IBV replication by targeting IBV non-structural protein 1 (BNS1) and nucleoprotein (BNP). CypA promotes OTUD4-mediated K48-linked BNS1 deubiquitination to stabilize BNS1 by upregulating OTUD4 expression. Meanwhile, CypA and the E3 ligase MIB1 competitively interact with BNP to inhibit its proteasomal degradation. Moreover, cyclosporine A treatment or CypA R55A mutation results in an impaired function of CypA in IBV replication. Notably, BNP hijacks CypA into the nucleus to enhance the activity of viral ribonucleoprotein complexes by enhancing the interaction between BNP and IBV polymerase basic protein 1. Taken together, this study unveils the critical role of CypA in facilitating IBV replication, suggesting that CypA is a promising target for anti-IBV drug.

9.
Front Immunol ; 13: 861292, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35693825

RESUMO

Cyclosporine A (CsA) is an immunosuppressive drug that suppresses T cell responses and is broadly used in transplantation. Its immunosuppressive action is closely linked to its binding of cyclophilin A (CypA), which widely distributed in different cell types. CsA also regulates the functions of innate immune cells, but the mechanism remains elusive. Here, we investigate the role of CsA in regulating macrophages polarization in influenza A virus-infected mice and mouse bone marrow-derived macrophages. CsA downregulates pro-inflammatory cytokines expression and upregulates anti-inflammatory cytokines expression. Mechanically, CsA decreases the polarization of macrophages into pro-inflammatory M1 phenotype and increases the polarization of macrophages into anti-inflammatory M2 phenotype. Further studies show that CsA regulates macrophages polarization-associated IFN-γ/STAT1 and IL-4/STAT6 signaling pathways. Meanwhile, all these roles of CsA are eliminated when CypA is absent, suggesting that CsA regulates macrophages polarization and inflammatory responses depend on its binding to CypA. Collectively, these results reveal a crucial mechanism of CsA in attenuating IAV-induced inflammatory responses by a switch in macrophages polarization.


Assuntos
Ciclofilina A , Vírus da Influenza A , Animais , Ciclofilina A/metabolismo , Ciclosporina/farmacologia , Citocinas , Vírus da Influenza A/fisiologia , Macrófagos , Camundongos
10.
Front Microbiol ; 13: 841462, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35283846

RESUMO

Epithelial-mesenchymal transition (EMT) is an important mechanism of lung tissue repair after injury, but excessive EMT may lead to pulmonary fibrosis, respiratory failure, and even death. The EMT triggered by influenza A virus (IAV) and influenza B virus (IBV) is not well understood. We hypothesized that there was difference in EMT induced by different influenza virus strains. Here we discovered that both IAV [A/WSN/1933 (H1N1), WSN] and IBV (B/Yamagata/16/88, Yamagata) infection caused EMT in mouse lung and A549 cells, and more EMT-related genes were detected in mice and cells infected with WSN than those infected with Yamagata. Neuraminidase (NA) of IAV is able to activate latent TGF-ß and the downstream TGF-ß signaling pathway, which play a vital role in EMT. We observed that IAV (WSN) triggered more activated TGF-ß expression and stronger TGF-ß/smad2 signaling pathway than IBV (Yamagata). Most importantly, WSN NA combined more latent TGF-ß than Yamagata NA in A549 cells. Collectively, these data demonstrate that both IAV and IBV induce TGF-ß/smad2 signaling pathway to promote EMT, which might depend on the binding ability of NA to latent TGF-ß.

11.
Cell Rep ; 38(11): 110513, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35294882

RESUMO

The inflammatory response is tightly regulated, but its regulatory principles are still incompletely understood. Cyclophilin A (CypA) has long been considered as a pro-inflammatory factor. Here, we discover how CypA precisely regulates interleukin-1ß (IL-1ß)-mediated inflammatory responses. In lipopolysaccharide-treated mice, CypA deficiency initially inhibits and then promotes lung inflammation, which is closely related to IL-1ß production. Mechanistically, CypA not only facilitates pro-IL-1ß processing by increasing Smurf1-mediated K63-linked ubiquitination in an ATP-dependent manner but also accelerates pro-IL-1ß degradation, depending on Smurf1-mediated K48-linked ubiquitination. Moreover, in IL-1ß-treated mice, CypA exacerbates lung injury by enhancing cytokine production. It also upregulates the ILK/AKT pathway by inhibiting Cyld-mediated K63-linked ILK deubiquitination, which promotes the epithelial-mesenchymal transition (EMT) to facilitate lung repair. Collectively, CypA promotes inflammation activation by increasing IL-1ß production and then promotes inflammation resolution by enhancing redundant pro-IL-1ß degradation and IL-1ß-induced EMT, indicating the complex and delicate regulation of inflammatory response.


Assuntos
Ciclofilina A , Inflamação , Animais , Ciclofilina A/metabolismo , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Ubiquitinação
12.
Cell Rep ; 35(7): 109159, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34010655

RESUMO

During influenza A epidemics, bacterial coinfection is a major cause of increased morbidity and mortality. However, the roles of host factors in regulating influenza A virus (IAV)-triggered bacterial coinfection remain elusive. Cyclophilin A (CypA) is an important regulator of infection and immunity. Here, we show that IAV-induced CypA expression facilitates group A Streptococcus (GAS) coinfection both in vitro and in vivo. Upon IAV infection, CypA interacts with focal adhesion kinase (FAK) and inhibited E3 ligase cCbl-mediated, K48-linked ubiquitination of FAK, which positively regulates integrin α5 expression and actin rearrangement via the FAK/Akt signaling pathway to facilitate GAS colonization and invasion. Notably, CypA deficiency or inhibition by cyclosporine A significantly inhibits IAV-triggered GAS coinfection in mice. Collectively, these findings reveal that CypA is critical for GAS infection, and induction of CypA expression is another way for IAV to promote bacterial coinfection, suggesting that CypA is a promising therapeutic target for the secondary bacterial infection.


Assuntos
Coinfecção/microbiologia , Ciclofilina A/metabolismo , Vírus da Influenza A/patogenicidade , Streptococcus pneumoniae/virologia , Humanos
13.
Artigo em Inglês | MEDLINE | ID: mdl-32117792

RESUMO

Heparin-binding hemagglutinin (HBHA) from mycobacteria is involved in the dissemination of infection and the activation of the host immune response. However, the interaction of Nocardia cyriacigeorgica HBHA with the host cells remains unknown. In the present study, we describe N. cyriacigeorgica HBHA interactions with epithelial cells and organ colonization. We then investigate the mechanisms by which HBHA induces the production of inflammatory cytokines in macrophages. Immunofluorescent microscopy showed that HBHA adhered to A549 cells and HeLa cells and that the C-terminal fragment, which contains a Pro-Ala-Lys-rich domain, was responsible for adhesion. The deletion of the hbha gene in N. cyriacigeorgica mutant strains impaired adhesion to A549 cells and HeLa cells. In addition, the HBHA protein activated the mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signaling pathways and promoted the production of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-10 in macrophages. HBHA-mediated TNF-α production was dependent on the activation of the c-Jun N-terminal kinase (JNK) signal pathways, and the IL-6 and IL-10 production was dependent on the activation of extracellular regulated kinase (ERK) 1/2, MAPK p38 (p38), JNK, and nuclear NF-κB signaling pathways. Additionally, the HBHA-mediated activation of innate immunity was dependent on Toll-like receptor 4 (TLR4). Taken together, these results indicate that N. cyriacigeorgica HBHA not only adheres to epithelial cells and may be involved in organ colonization, but also plays a critical role in the modulation of innate immunity through the MAPK and NF-κB signaling pathways via TLR4.


Assuntos
Proteínas de Bactérias/metabolismo , Citocinas/metabolismo , Lectinas/metabolismo , Nocardiose/imunologia , Nocardiose/microbiologia , Nocardia/fisiologia , Animais , Aderência Bacteriana , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/isolamento & purificação , Linhagem Celular , Humanos , Imunidade Inata , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Lectinas/química , Lectinas/genética , Lectinas/isolamento & purificação , Sistema de Sinalização das MAP Quinases , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Nocardia/genética , Nocardia/crescimento & desenvolvimento , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
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