Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
1.
J Immunol ; 207(1): 234-243, 2021 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-34183366

RESUMEN

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.


Asunto(s)
Macrófagos/inmunología , Receptores Inmunológicos/inmunología , Células TH1/inmunología , Tuberculosis/inmunología , Adulto , Estudios de Cohortes , Femenino , Humanos , Activación de Macrófagos/inmunología , Masculino , Receptores Inmunológicos/genética
2.
J Infect Dis ; 223(5): 854-865, 2021 03 03.
Artículo en Inglés | MEDLINE | ID: mdl-32702113

RESUMEN

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.


Asunto(s)
Córnea , Inflamación , Queratitis , Macrófagos/citología , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/genética , Animales , Polaridad Celular , Córnea/fisiopatología , Progresión de la Enfermedad , Queratitis/tratamiento farmacológico , Queratitis/microbiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Infecciones por Pseudomonas , Pseudomonas aeruginosa , Transducción de Señal
3.
J Immunol ; 203(10): 2614-2620, 2019 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-31578271

RESUMEN

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.


Asunto(s)
Diabetes Mellitus Tipo 2/sangre , Células T Invariantes Asociadas a Mucosa/metabolismo , Receptores OX40/metabolismo , Adulto , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Estudios de Cohortes , Femenino , Humanos , Memoria Inmunológica , Activación de Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Células T Invariantes Asociadas a Mucosa/inmunología , Ligando OX40/farmacología , Fenotipo , Proteínas Recombinantes/farmacología , Transducción de Señal/efectos de los fármacos
4.
Cell Mol Immunol ; 21(7): 674-688, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38740925

RESUMEN

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.


Asunto(s)
Proteína Relacionada con TNFR Inducida por Glucocorticoide , Lisofosfatidilcolinas , Macrófagos , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR , Procesamiento Proteico-Postraduccional , Piroptosis , Sepsis , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Animales , Sepsis/inmunología , Macrófagos/metabolismo , Macrófagos/inmunología , Lisofosfatidilcolinas/metabolismo , Ratones , Proteína Relacionada con TNFR Inducida por Glucocorticoide/metabolismo , Inflamasomas/metabolismo , Masculino , Ratones Noqueados , Humanos , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Sirtuina 2/metabolismo , Sirtuina 2/genética , Acetilación
5.
Immun Inflamm Dis ; 11(3): e802, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36988247

RESUMEN

BACKGROUND: Psoriasis (PsO) is a T-cell-associated inflammatory autoimmune dermatitis. Leucine leucine-37 (LL-37) is upregulated in PsO patients and correlated with the area and severity of PsO. However, the exact relation between LL-37 and T cell-associated inflammation is not well understood. It is very important to clarify the relationship between LL-37 and inflammatory response for clinical diagnosis and treatment of PsO. This study investigated the serum levels of LL-37 and inflammatory cytokines, as well as correlations between them in PsO patients, which aimed to provide new ideas for the diagnosis and treatment of PsO. METHODS: PsO patients (n = 50) and healthy volunteers (n = 33) were recruited in this study. Skin specimens were stained with hematoxylin and eosin (H&E). The serum levels of LL-37, T-helper type 1 (Th1, IFN-γ), T-helper type 17 (Th17, IL-17), T-helper type 22 (Th22, IL-22), and T-helper type 2 cytokines (Th2, IL-4) were assessed by enzyme-linked immunosorbent assay. Some of the patients were re-recruited after treatment to evaluate LL-37 and cytokines levels. RESULTS: Pathological changes were observed in PsO skin lesions. LL-37, IFN-γ, IL-17, and IL-22 serum levels were much higher in PsO patients than those in healthy volunteers (p < .001), and posttreatment reduction was observed in five patients. However, no remarkable difference in IL-4 level (p > .05) was found. LL-37 level was positively correlated with IFN-γ, IL-17, and IL-22 levels (p < .001) in PsO patients. CONCLUSION: LL-37 expression was significantly associated with inflammatory response, which may provide us new ideas for diagnosing and monitoring disease activity of PsO.


Asunto(s)
Citocinas , Psoriasis , Humanos , Citocinas/metabolismo , Interleucina-17 , Leucina , Interleucina-4 , Psoriasis/diagnóstico
6.
J Clin Invest ; 133(6)2023 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-36749634

RESUMEN

Uncontrolled inflammation occurred in sepsis results in multiple organ injuries and shock, which contributes to the death of patients with sepsis. However, the regulatory mechanisms that restrict excessive inflammation are still elusive. Here, we identified an Ig-like receptor called signaling lymphocyte activation molecular family 7 (SLAMF7) as a key suppressor of inflammation during sepsis. We found that the expression of SLAMF7 on monocytes/macrophages was significantly elevated in patients with sepsis and in septic mice. SLAMF7 attenuated TLR-dependent MAPK and NF-κB signaling activation in macrophages by cooperating with Src homology 2-containing inositol-5'­phosphatase 1 (SHIP1). Furthermore, SLAMF7 interacted with SHIP1 and TNF receptor-associated factor 6 (TRAF6) to inhibit K63 ubiquitination of TRAF6. In addition, we found that tyrosine phosphorylation sites within the intracellular domain of SLAMF7 and the phosphatase domain of SHIP1 were indispensable for the interaction between SLAMF7, SHIP1, and TRAF6 and SLAMF7-mediated modulation of cytokine production. Finally, we demonstrated that SLAMF7 protected against lethal sepsis and endotoxemia by downregulating macrophage proinflammatory cytokines and suppressing inflammation-induced organ damage. Taken together, our findings reveal a negative regulatory role of SLAMF7 in polymicrobial sepsis, thus providing sights into the treatment of sepsis.


Asunto(s)
Sepsis , Factor 6 Asociado a Receptor de TNF , Animales , Ratones , Inflamación/metabolismo , Macrófagos/metabolismo , FN-kappa B/metabolismo , Monoéster Fosfórico Hidrolasas/genética , Monoéster Fosfórico Hidrolasas/metabolismo , Sepsis/genética , Sepsis/metabolismo , Factor 6 Asociado a Receptor de TNF/genética
7.
Immunobiology ; 228(3): 152391, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-37167681

RESUMEN

The application of programmed cell death protein 1 (PD-1) antibodies has brought great benefits to non-small cell lung cancer (NSCLC) patients. Nevertheless, not all patients respond to anti-PD-1 immunotherapy. This study aimed to find response markers to predict efficacy of anti-PD-1 immunotherapy in NSCLC patients. 80 patients with NSCLC who would accept anti-PD-1 immunotherapy were recruited, and peripheral blood was obtained before and after treatment. Flow cytometry was used to detect proportions of circulating cell subsets and expression of co-stimulatory molecules, co-inhibitory molecules and cytokines in T cells from pre- and post-treatment patients. Results showed that proportions of CD4+ and CD8+ T cells, NK, γδT and mucosal-associated invariant T (MAIT) cells were higher and regulatory T cells (Tregs) were lower in responders (n = 50) after treatment but no obvious difference was found in non-responders (n = 30). After treatment, responders showed an increase in the frequency of co-stimulatory and co-inhibitory molecules, as well as the production of cytokines in T cells. This study indicates that monitoring the alterations of immune markers in circulating cells from NSCLC patients may be helpful to discriminate responders and non-responders, which provides a potential novel way to assess efficacy of anti-PD-1 immunotherapy.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Linfocitos T CD8-positivos , Inmunoterapia/métodos , Citocinas
8.
Int Immunopharmacol ; 108: 108813, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-35580452

RESUMEN

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.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Animales , Anticuerpos/uso terapéutico , Antígeno B7-H1 , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Inmunidad , Inmunoterapia/métodos , Neoplasias Pulmonares/tratamiento farmacológico , Ratones , Receptor de Muerte Celular Programada 1
9.
Artículo en Inglés | MEDLINE | ID: mdl-32974219

RESUMEN

CD103 is considered as a surface marker for the resident immune cells. However, little is known about the intrinsic function of CD103 in infection and inflammation. In this study, we found that CD103 was highly expressed in CD4+T cells of the gastric mucosa from patients with H. pylori-positive gastritis. Mucosal resident CD103+CD4+T cells exhibited an increase in the CD45RO+CCR7- effector memory phenotype and high expression of the chemokine receptors CXCR3 and CCR9 compared with those in CD103-CD4+T cells. An In vitro coculture study demonstrated that H. pylori-specific antigen CagA/VacA-primed dendritic cells (DCs) induced proliferation and IFN-γ, TNF as well as IL-17 production by CD103+CD4+T cells from patients with H. pylori-positive gastritis, while blocking CD103 with a neutralizing antibody reduced proliferation and IFN-γ, TNF, and IL-17 production by CD103+CD4+T cells cocultured with DCs. Moreover, immunoprecipitation revealed that CD103 interacted with TCR α/ß and CD3ζ, and activation of CD103 enhanced the phosphorylation of ZAP70 induced by the TCR signal. Finally, increased T-bet and Blimp1 levels were also observed in CD103+CD4+T cells, and activating CD103 increased T-bet and Blimp1 expression in CD4+T cells. Our results explored the intrinsic function of CD103 in gastric T cells from patients with H. pylori-positive gastritis, which may provide a therapeutic target for the treatment of gastritis.


Asunto(s)
Gastritis , Infecciones por Helicobacter , Helicobacter pylori , Linfocitos T CD4-Positivos , Mucosa Gástrica , Humanos , Linfocitos T
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA