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1.
J Immunol ; 207(1): 234-243, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34183366

RESUMO

T cell-interacting activating receptor on myeloid cells 1 (TARM-1) is a novel leukocyte receptor expressed in neutrophils and macrophages. It plays an important role in proinflammatory response in acute bacterial infection, but its immunomodulatory effects on chronic Mycobacterium tuberculosis infections remain unclear. TARM-1 expression was significantly upregulated on CD14high monocytes from patients with active pulmonary tuberculosis (TB) as compared that on cells from patients with latent TB or from healthy control subjects. Small interfering RNA knockdown of TARM-1 reduced expression levels of proinflammatory cytokines IL-12, IL-18, IL-1ß, and IL-8 in M. tuberculosis-infected macrophages, as well as that of HLA-DR and costimulatory molecules CD83, CD86, and CD40. Moreover, TARM-1 enhanced phagocytosis and intracellular killing of M. tuberculosis through upregulating reactive oxygen species. In an in vitro monocyte and T cell coculture system, blockade of TARM-1 activity by TARM-1 blocking peptide suppressed CD4+ T cell activation and proliferation. Finally, administration of TARM-1 blocking peptide in a mouse model of M. tuberculosis infection increased bacterial load and lung pathology, which was associated with decreased macrophage activation and IFN-γ production by T cell. Taken together, these results, to our knowledge, demonstrate a novel immune protective role of TARM-1 in M. tuberculosis infection and provide a potential therapeutic target for TB disease.


Assuntos
Macrófagos/imunologia , Receptores Imunológicos/imunologia , Células Th1/imunologia , Tuberculose/imunologia , Adulto , Estudos de Coortes , Feminino , Humanos , Ativação de Macrófagos/imunologia , Masculino , Receptores Imunológicos/genética
2.
J Infect Dis ; 223(5): 854-865, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32702113

RESUMO

BACKGROUND: Signaling lymphocytic activation molecule family-7 (SLAMF7) functions as an immune checkpoint molecule on macrophages in antitumor immunity. However, its role in bacterial infection remains largely unknown. METHODS: Bone marrow-derived macrophages (BMDMs) isolated from wild-type (WT) or SLAMF7 knockout (KO) mice were infected with bacteria or treated with lipopolysaccharide/interferon-γ to investigate the expression and function of SLAMF7 in macrophage polarization. A Pseudomonas aeruginosa keratitis murine model was established to explore the effect of SLAMF7 on P. aeruginosa keratitis using WT vs SLAMF7 KO mice, or recombinant SLAMF7 vs phosphate-buffered saline-treated mice, respectively. RESULTS: SLAMF7 expression was enhanced on M1-polarized or bacterial-infected macrophages, and infiltrating macrophages in P. aeruginosa-infected mouse corneas. SLAMF7 promoted M2 polarization by inducing STAT6 activation. In vivo data showed that SLAMF7 KO aggravated, while treatment with recombinant SLAMF7 alleviated, corneal inflammation and disease severity. In addition, blockage of M2 polarization by Arg-1 inhibitor abrogated the effect of recombinant SLAMF7 in disease progression. CONCLUSIONS: SLAMF7 expression in macrophages was induced upon M1 polarization or bacterial infection and alleviated corneal inflammation and disease progression of P. aeruginosa keratitis by promoting M2 polarization. These findings may provide a potential strategy for the treatment of P. aeruginosa keratitis.


Assuntos
Córnea , Inflamação , Ceratite , Macrófagos/citologia , Família de Moléculas de Sinalização da Ativação Linfocitária/genética , Animais , Polaridade Celular , Córnea/fisiopatologia , Progressão da Doença , Ceratite/tratamento farmacológico , Ceratite/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infecções por Pseudomonas , Pseudomonas aeruginosa , Transdução de Sinais
3.
J Immunol ; 203(10): 2614-2620, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31578271

RESUMO

Mucosal-associated invariant T (MAIT) cells play a key role in local and systemic immune responses. Studies suggest that type 2 diabetes (T2D) is associated with alterations in the human MAIT cell response. However, the mechanisms that regulate the survival and homeostasis of human MAIT cells are poorly defined. In this study, we demonstrate that the costimulatory TNF superfamily receptor OX40 was highly expressed in MAIT cells of patients with T2D. Compared with OX40-negative MAIT cells, OX40-positive MAIT cells showed a high activation and a memory phenotype. Surprisingly, OX40 expression was negatively correlated with the frequency of MAIT cells in the peripheral blood of T2D patients. Increased cleaved caspase-3 levels were observed in OX40+-expressing MAIT cells in T2D patients. In vitro, activated OX40 signaling by recombinant OX40L protein promoted caspase-3 activation and apoptosis of MAIT cells. Inhibition of caspase-3 restored apoptosis of MAIT cells induced by OX40 signaling. These results identify OX40 as an amplifier of activation-induced cell death of human blood MAIT cells and shed new light on the regulation of MAIT cells in the phase of immune responses in T2D.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Células T Invariantes Associadas à Mucosa/metabolismo , Receptores OX40/metabolismo , Adulto , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Estudos de Coortes , Feminino , Humanos , Memória Imunológica , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Células T Invariantes Associadas à Mucosa/imunologia , Ligante OX40/farmacologia , Fenótipo , Proteínas Recombinantes/farmacologia , Transdução de Sinais/efeitos dos fármacos
4.
Cell Mol Immunol ; 21(7): 674-688, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38740925

RESUMO

The NLRP3 inflammasome functions as an inflammatory driver, but its relationship with lipid metabolic changes in early sepsis remains unclear. Here, we found that GITR expression in monocytes/macrophages was induced by lysophosphatidylcholine (LPC) and was positively correlated with the severity of sepsis. GITR is a costimulatory molecule that is mainly expressed on T cells, but its function in macrophages is largely unknown. Our in vitro data showed that GITR enhanced LPC uptake by macrophages and specifically enhanced NLRP3 inflammasome-mediated macrophage pyroptosis. Furthermore, in vivo studies using either cecal ligation and puncture (CLP) or LPS-induced sepsis models demonstrated that LPC exacerbated sepsis severity/lethality, while conditional knockout of GITR in myeloid cells or NLRP3/caspase-1/IL-1ß deficiency attenuated sepsis severity/lethality. Mechanistically, GITR specifically enhanced inflammasome activation by regulating the posttranslational modification (PTM) of NLRP3. GITR competes with NLRP3 for binding to the E3 ligase MARCH7 and recruits MARCH7 to induce deacetylase SIRT2 degradation, leading to decreasing ubiquitination but increasing acetylation of NLRP3. Overall, these findings revealed a novel role of macrophage-derived GITR in regulating the PTM of NLRP3 and systemic inflammatory injury, suggesting that GITR may be a potential therapeutic target for sepsis and other inflammatory diseases. GITR exacerbates LPC-induced macrophage pyroptosis in sepsis via posttranslational regulation of NLRP3. According to the model, LPC levels increase during the early stage of sepsis, inducing GITR expression on macrophages. GITR not only competes with NLRP3 for binding to the E3 ligase MARCH7 but also recruits MARCH7 to induce the degradation of the deacetylase SIRT2, leading to decreasing ubiquitination but increasing acetylation of NLRP3 and therefore exacerbating LPC-induced NLRP3 inflammasome activation, macrophage pyroptosis and systemic inflammatory injury.


Assuntos
Proteína Relacionada a TNFR Induzida por Glucocorticoide , Lisofosfatidilcolinas , Macrófagos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR , Processamento de Proteína Pós-Traducional , Piroptose , Sepse , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Sepse/imunologia , Macrófagos/metabolismo , Macrófagos/imunologia , Lisofosfatidilcolinas/metabolismo , Camundongos , Proteína Relacionada a TNFR Induzida por Glucocorticoide/metabolismo , Inflamassomos/metabolismo , Masculino , Camundongos Knockout , Humanos , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Sirtuína 2/metabolismo , Sirtuína 2/genética , Acetilação
5.
Sci Rep ; 13(1): 8764, 2023 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-37253756

RESUMO

The overlying strata of the lower coal seam is easy to be collapsed causing the roof caving accident at the end face of the mining working face under repeated mining in close-distance coal seams. In order to predict the roof instability of the end face, the mechanical model of the granular arch structure is established in this study to further analyze its main influencing factors. The results show that the mining height of the working face, the advancing speed, the distance of coal seams, the tip-to-face distance, the strength of the surrounding rock and the support setting the load of the support are the main influencing factors on the roof caving of the end face. Subsequently, the prediction model of roof instability in the end face under repeated mining is constructed through the radial basis function neural network (RBFNN) and the above main influencing factors are regarded as input layer indexes. Meanwhile, the roof subsidence, coal wall deformation and support load are determined as the output layer indexes. The predicted results are closer to the results of sample tests. Finally, the early warning system, including monitoring and early warning, data query, emergency management, user management, and system settings, is designed to monitor roof conditions of the end face and timely warn the roof accidents. The field application proves that the system has good practical value, which is of great significance to intelligent prediction of coal mine stope disaster and prevent the end face roof disaster under repeated mining and. This will promote the safe and efficient construction of coal mine production.

6.
Cornea ; 42(5): 607-614, 2023 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-36729030

RESUMO

PURPOSE: The purpose of this study was to assess the role of leukocyte immunoglobulin-like receptor A5 (LILRA5) in regulating bacterial infection and corneal inflammation. METHODS: The human corneal tissue microarray data set GSE58291 from Gene Expression Omnibus was downloaded. Then, the differentially expressed genes, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, Gene Set Enrichment Analysis, and the immune infiltration analysis were conducted. We constructed the Pseudomonas aeruginosa ( P. aeruginosa ) keratitis mice model using wild-type and LILRA5-deficient mice. The results of the bioinformatics analysis were verified by the cell in vitro and animal in vivo experiments. RESULTS: This study revealed that LILRA5 is substantially expressed in human keratitis and regulates the immune response negatively. Neutrophils were identified as the core fraction of immune cells in keratitis. After P. aeruginosa infection, neutrophils lacking LILRA5 induced elevated levels of proinflammatory cytokines and toll-like receptor 4. LILRA5 deficiency exacerbated the severity of the infection and the production of proinflammatory cytokines in mice. CONCLUSIONS: LILRA5 was discovered as an immunosuppressive regulator in P. aeruginosa keratitis, highlighting its significance in activated immune responses.


Assuntos
Ceratite , Infecções por Pseudomonas , Receptores Imunológicos , Animais , Humanos , Camundongos , Córnea/patologia , Citocinas/metabolismo , Imunoglobulinas/metabolismo , Ceratite/microbiologia , Camundongos Endogâmicos C57BL , Neutrófilos , Pseudomonas aeruginosa , Infecções por Pseudomonas/microbiologia , Receptores Imunológicos/genética
7.
Heliyon ; 9(10): e20806, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37916085

RESUMO

Background: Systemic Lupus Erythematosus (SLE) is a prototypic autoimmune disease, which is accompanied by liver damage. However, it remains unknown whether liver damage is associated with SLE progression. Method: ology: HepG2 and L-02 cells were stimulated with cytokines, and FGL1 mRNA and protein expression levels were determined using Real-time PCR and ELISA, respectively. Regulatory T cells (Treg) isolated from healthy individuals as well as patients with SLE and SLE and liver damage (SLE-LD) were cultured with autologous effector CD4+T cells in the presence of a functional antibody or isotype control. The expression levels of LAG3, CD25, PD-1, CXCR5, ICOS and OX40 were evaluated by flow cytometry. FGL1, IL-10, IL-17a and IL-21 levels in serum or culture supernatants were quantified by ELISA. Results: Patients with SLE-LD exhibits higher disease activity indices and anti-dsDNA antibody levels. Importantly, fibrinogen-like protein 1 (FGL1), a key factor released from the injured liver, is up-regulated in patients with SLE-LD and is associated with disease activity. FGL1 expression is induced by the inflammatory cytokine IL-6 signaling in hepatocytes. Higher expression of the FGL1 receptor lymphocyte activation gene 3 (LAG3) is detected in Treg cells from patients with SLE-LD. The FGL1-LAG3 signaling axis inhibits Treg cell proliferation and impairs the suppressive activity of Treg cells by limiting IL-10 secretion. Furthermore, FGL1-LAG3 signaling promotes the production of pathogenic IL-17a and IL-21 by CD4+T cells by reducing IL-10 level produced by Treg in patients with SLE. Conclusions: The FGL1-LAG3 signal axis is a key mechanism that subverts the suppressive function of Treg cells. This may provide a new therapeutic target for SLE and SLE-induced liver damage.

8.
Clin Cardiol ; 46(12): 1481-1487, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37698123

RESUMO

Immune checkpoint inhibitors (ICIs), including antiprogrammed cell-death (PD)-1/anti-PD-ligand (PDL-1) monoclonal antibodies, are effective at improving the prognosis of patients with cancer. Among immune-related adverse events, myocarditis associated with anti-PD-1/anti-PD-L1 antibodies is rare but lacks effective treatment and mortality is very high. In this study, the authors extracted data from the previous 8 years from electronic medical records housed in the hospital information system to identify patients hospitalized with myocarditis putatively caused by anti-PD-1/anti-PD-L1 tumor therapy. Clinical data from these patients are reported. Four patients who developed myocarditis after undergoing treatment with anti-PD-1/anti-PD-L1 antibodies for malignant tumors, all of whom responded favorably to therapy consisting of plasma exchange and glucocorticoids for myocarditis, and all patients improved and were discharged from hospital. Plasma exchange plus systemic glucocorticoids may be effective for treating anti-PD-1/anti-PD-L1 antibody-induced myocarditis in patients with cancer.


Assuntos
Miocardite , Neoplasias , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Glucocorticoides/uso terapêutico , Miocardite/induzido quimicamente , Miocardite/diagnóstico , Miocardite/terapia , Troca Plasmática , Receptor de Morte Celular Programada 1 , Neoplasias/tratamento farmacológico
9.
Int Immunopharmacol ; 108: 108813, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35580452

RESUMO

Immune-checkpoint blockade is widely studied for cancer therapy. Although the co-inhibitory receptor Programmed death-1(PD-1) blockade benefits some non-small cell lung cancer (NSCLC) patients, a large portion of NSCLC patients still fail to respond to this immunotherapy, and the underlying mechanism is unclear. Thus, a synergistic therapy to enhance the effect of PD-1 is urgently needed to improve the poor outcome of NSCLC patients. Here, we demonstrated that effector memory T cells were increased and T cell response became stronger in PD-1 immunotherapy responders (n = 20) but not in non-responders (n = 10). The expression of co-stimulatory receptor OX40 was upregulated on T cells following PD-1 immunotherapy and was positively associated with the percentage of PD-1+T cells and the responsiveness of T cells. Combination treatment of antagonistic anti-PD-1 and agonistic anti-OX40 antibodies (Abs) promoted the proliferation and cytokines production of T cells from PBMCs of non-responders ex vivo. Consistently, anti-PD-1 and anti-OX40 therapy synergistically augmented T cell response in an in vivo mouse lung cancer model. Our study confirmed the antitumor effects of anti-PD-1/OX40 combination in lung cancer patients as well as in the murine lung cancer model, and the results provide a rationale for clinical trials evaluating the therapeutic effect of this combination of antibodies for NSCLC immunotherapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Anticorpos/uso terapêutico , Antígeno B7-H1 , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Imunidade , Imunoterapia/métodos , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Receptor de Morte Celular Programada 1
10.
Front Immunol ; 12: 580989, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34177879

RESUMO

The coronavirus disease 2019 (COVID-19) emerged around December 2019 and have become a global epidemic disease currently. Specific antibodies against SAS-COV-2 could be detected in COVID-19 patients' serum or plasma, but the clinical values of these antibodies as well as the effects of clinical drugs on humoral responses have not been fully demonstrated. In this study, 112 plasma samples were collected from 36 patients diagnosed with laboratory-confirmed COVID-19 in the Fifth Affiliated Hospital of Sun Yat-sen University. The IgG and IgM antibodies against receptor binding domain (RBD) and spike protein subunit 1 (S1) of SAS-COV-2 were detected by ELISA. We found that COVID-19 patients generated specific antibodies against SARS-CoV-2 after infection, and the levels of anti-RBD IgG within 2 to 3 weeks from onset were negatively associated with the time of positive-to-negative conversion of SARS-CoV-2 nucleic acid. Patients with severe symptoms had higher levels of anti-RBD IgG in 2 to 3 weeks from onset. The use of chloroquine did not significantly influence the patients' antibody titer but reduced C-reaction protein (CRP) level. Using anti-viral drugs (lopinavir/ritonavir or arbidol) reduced antibody titer and peripheral lymphocyte count. While glucocorticoid therapy developed lower levels of peripheral lymphocyte count and higher levels of CRP, lactate dehydrogenase (LDH), α-Hydroxybutyrate dehydrogenase(α-HBDH), total bilirubin (TBIL), direct bilirubin (DBIL). From these results, we suggested that the anti-RBD IgG may provide an early protection of host humoral responses against SAS-COV-2 infection within 2 to 3 weeks from onset, and clinical treatment with different drugs displayed distinct roles in humoral and inflammatory responses.


Assuntos
COVID-19/imunologia , Indóis/uso terapêutico , Lopinavir/uso terapêutico , Ritonavir/uso terapêutico , SARS-CoV-2/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/sangue , Formação de Anticorpos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Glicoproteína da Espícula de Coronavírus/imunologia , Tratamento Farmacológico da COVID-19
11.
Trials ; 21(1): 622, 2020 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-32641091

RESUMO

BACKGROUND: The outbreak of COVID-19 (caused by SARS-Cov-2) is very serious, and no effective antiviral treatment has yet been confirmed. The adage "old drug, new trick" in this context may suggest the important therapeutic potential of existing drugs. We found that the lopinavir/ritonavir treatment recommended in the fifth edition of the Treatment Plan of China can only help to improve a minority of throat-swab nucleic-acid results (3/15) in hospitals. Our previous use of chloroquine to treat patients with COVID-19 infection showed an improvement in more throat-swab nucleic-acid results (5/10) than the use of lopinavir/ritonavir. METHODS/DESIGN: This is a prospective, open-label, randomized controlled, multicenter clinical study. The study consists of three phases: a screening period, a treatment period of no more than 10 days, and a follow-up period for each participant. Participants with COVID-19 infection who are eligible for selection for the study will be randomly allocated to the trial group or the control group. The control group will be given lopinavir/ritonavir treatment for no more than 10 days. The trial group will be given chloroquine phosphate treatment for no more than 10 days. The primary outcome is the clinical recovery time at no more than 28 days after the completion of therapy and follow-up. The secondary outcomes include the rate of treatment success after the completion of therapy and follow-up, the time of treatment success after no more than 28 days, the rate of serious adverse events during the completion of therapy and follow-up, and the time to return to normal temperature (calculated from the onset of illness) during the completion of therapy and follow-up. Comparisons will be performed using two-sided tests with a statistical significance level of 5%. DISCUSSION: This experiment should reveal the efficacy and safety of using chloroquine versus lopinavir/ritonavir for patients with mild/general COVID-19 infection. If the new treatment including chloroquine shows a higher rate of throat-swab SARS-CoV-2 real-time fluorescent reverse transcription polymerase chain reaction (RT-PCR) negativity and is safe, it could be tested as a future COVID-19 treatment. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ID: ChiCTR2000029741 . Registered on 11 February 2020.


Assuntos
Betacoronavirus , Cloroquina/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Lopinavir/administração & dosagem , Pneumonia Viral/tratamento farmacológico , Ritonavir/administração & dosagem , COVID-19 , Cloroquina/efeitos adversos , Quimioterapia Combinada , Humanos , Lopinavir/efeitos adversos , Pandemias , Estudos Prospectivos , Ritonavir/efeitos adversos , SARS-CoV-2 , Tratamento Farmacológico da COVID-19
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