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1.
Methods Mol Biol ; 2442: 533-548, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35320544

RESUMO

Cellular turnover represents a fundamental aspect of immunological homeostasis. While many factors appear to regulate leukocyte removal during inflammatory resolution, recent studies suggest that members of the galectin family play a unique role in orchestrating this process. Unlike cellular removal through apoptotic cell death, several members of the galectin family induce surface expression of phosphatidylserine (PS), a phagocytic marker on cells undergoing apoptosis, in the absence of cell death. However, similar to PS on cells undergoing apoptosis, galectin-induced PS exposure sensitizes cells to phagocytic removal. As galectins appear to prepare cells for phagocytic removal without actually inducing apoptotic cell death, this process has recently been coined preaparesis. Given the unique characteristics of galectin-induced PS exposure in the context of preaparesis, we will examine unique considerations when evaluating the potential impact of different galectin family members on PS exposure and cell viability.


Assuntos
Apoptose , Galectinas , Leucócitos , Fagocitose , Fosfatidilserinas , Apoptose/imunologia , Galectinas/metabolismo , Células HL-60 , Humanos , Leucócitos/imunologia , Fosfatidilserinas/metabolismo
2.
J Immunol ; 208(5): 1214-1223, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35149533

RESUMO

For a long time, how anti-inflammatory factors evolved was largely unknown. In this study, we chose a marine invertebrate, Litopenaeus vannamei, as a model and identified that shrimp mesencephalic astrocyte-derived neurotrophic factor (MANF) was an LPS-induced plasma protein, which exerted its anti-inflammatory roles on shrimp hemocytes by suppressing ERK phosphorylation and Dorsal expression. In addition, we demonstrated that shrimp MANF could be associated with a receptor protein tyrosine phosphatase (RPTP) to mediate negative regulation of ERK activation and Dorsal expression. More interestingly, shrimp RPTP-S overexpression in 293T cells could switch shrimp and human MANF-mediated ERK pathway activation to inhibition. In general, our results indicate that this conserved RPTP is the key component for extracellular MANF-mediated ERK pathway inhibition, which gives a possible explanation about why this neurotropic factor could both protect neuron cells from apoptosis and inhibit immune cell M1 activation in various species.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fatores de Crescimento Neural/metabolismo , Neurônios/fisiologia , Penaeidae/imunologia , Receptores Proteína Tirosina Quinases/metabolismo , Sequência de Aminoácidos , Animais , Apoptose/imunologia , Linhagem Celular , Estresse do Retículo Endoplasmático/fisiologia , Células HEK293 , Humanos , Inflamação/patologia , Lipopolissacarídeos/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Fosforilação/fisiologia , Alinhamento de Sequência
3.
Proc Natl Acad Sci U S A ; 119(4)2022 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-35046017

RESUMO

Alveolar macrophages (AMs) are critical for lung immune defense and homeostasis. They are orchestrators of chronic obstructive pulmonary disease (COPD), with their number significantly increased and functions altered in COPD. However, it is unclear how AM number and function are controlled in a healthy lung and if changes in AMs without environmental assault are sufficient to trigger lung inflammation and COPD. We report here that absence of isthmin 1 (ISM1) in mice (Ism1-/- ) leads to increase in both AM number and functional heterogeneity, with enduring lung inflammation, progressive emphysema, and significant lung function decline, phenotypes similar to human COPD. We reveal that ISM1 is a lung resident anti-inflammatory protein that selectively triggers the apoptosis of AMs that harbor high levels of its receptor cell-surface GRP78 (csGRP78). csGRP78 is present at a heterogeneous level in the AMs of a healthy lung, but csGRP78high AMs are expanded in Ism1-/- mice, cigarette smoke (CS)-induced COPD mice, and human COPD lung, making these cells the prime targets of ISM1-mediated apoptosis. We show that csGRP78high AMs mostly express MMP-12, hence proinflammatory. Intratracheal delivery of recombinant ISM1 (rISM1) depleted csGRP78high AMs in both Ism1-/- and CS-induced COPD mice, blocked emphysema development, and preserved lung function. Consistently, ISM1 expression in human lungs positively correlates with AM apoptosis, suggesting similar function of ISM1-csGRP78 in human lungs. Our findings reveal that AM apoptosis regulation is an important physiological mechanism for maintaining lung homeostasis and demonstrate the potential of pulmonary-delivered rISM1 to target csGRP78 as a therapeutic strategy for COPD.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Pulmão/patologia , Macrófagos Alveolares/metabolismo , Células Epiteliais Alveolares/metabolismo , Animais , Apoptose/imunologia , Líquido da Lavagem Broncoalveolar/imunologia , Modelos Animais de Doenças , /fisiologia , Feminino , Homeostase , Inflamação , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Pulmão/metabolismo , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fagocitose/fisiologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Enfisema Pulmonar/metabolismo , Fumaça/efeitos adversos , Fumar/efeitos adversos , Tabaco/efeitos adversos
4.
Med Oncol ; 39(3): 32, 2022 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-35059896

RESUMO

To investigate the effects of isolated SARS-CoV-2 spike protein on prostate cancer cell survival. The effects of SARS-CoV-2 spike protein on LNCaP prostate cancer cell survival were assessed using clonogenic cell survival assay, quick cell proliferation assay, and caspase-3 activity kits. RT-PCR and immunohistochemistry were performed to investigate underlying molecular mechanisms. SARS-CoV-2 spike protein was found to inhibit prostate cancer cell proliferation as well as promote apoptosis. Further investigation revealed that anti-proliferative effects were associated with downregulation of the pro-proliferative molecule cyclin-dependent kinase 4 (CDK4). The increased rate of apoptosis was associated with the upregulation of pro-apoptotic molecule Fas ligand (FasL). SARS-CoV-2 spike protein inhibits the growth of LNCaP prostate cancer cells in vitro by a two-pronged approach of downregulating the expression of CDK4 and upregulating FasL. The introduction of SARS-CoV-2 spike protein into the body via COVID-19 vaccination may have the potential to inhibit prostate cancer in patients. This potential beneficial association between COVID-19 vaccines and prostate cancer inhibition will require more extensive studies before any conclusions can be drawn about any in vivo effects in a human model.


Assuntos
Vacinas contra COVID-19/imunologia , Proliferação de Células/fisiologia , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/patologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Anticorpos Antivirais/imunologia , Apoptose/imunologia , COVID-19/imunologia , Linhagem Celular Tumoral , Sobrevivência Celular/imunologia , Regulação para Baixo/imunologia , Humanos , Masculino , Regulação para Cima/imunologia , Vacinação/métodos
5.
J Exp Clin Cancer Res ; 41(1): 33, 2022 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-35073964

RESUMO

BACKGROUND: Depletion of certain ribosomal proteins induces p53 activation, which is mediated mainly by ribosomal protein L5 (RPL5) and/or ribosomal protein L11 (RPL11). Therefore, RPL5 and RPL11 may link RPs and p53 activation. Thus, this study aimed to explore whether RPs interact with RPL11 and regulate p53 activation in lung adenocarcinoma (LUAD) cells. METHODS: The endogenous RPL11-binding proteins in A549 cells were pulled down through immunoprecipitation and identified with a proteomics approach. Docking analysis and GST-fusion protein assays were used to analyze the interaction of ribosomal protein S27a (RPS27a) and RPL11. Co-immunoprecipitation and in vitro ubiquitination assays were used to detect the effects of knockdown of RPS27a on the interaction between RPS27a and RPL11, and on p53 accumulation. Cell cycle, apoptosis, cell invasion and migration, cell viability and colony-formation assays were performed in the presence of knockdown of RPS27a. The RPS27a mRNA expression in LUAD was analyzed on the basis of the TCGA dataset, and RPS27a expression was detected through immunohistochemistry in LUAD samples. Finally, RPS27a and p53 expression was analyzed through immunohistochemistry in A549 cell xenografts with knockdown of RPS27a. RESULTS: RPS27a was identified as a novel RPL11 binding protein. GST pull-down assays revealed that RPS27a directly bound RPL11. Knockdown of RPS27a weakened the interaction between RPS27a and RPL11, but enhanced the binding of RPL11 and murine double minute 2 (MDM2), thereby inhibiting the ubiquitination and degradation of p53 by MDM2. Knockdown of RPS27a stabilized p53 in an RPL11-dependent manner and induced cell viability inhibition, cell cycle arrest and apoptosis in a p53-dependent manner in A549 cells. The expression of RPS27a was upregulated in LUAD and correlated with LUAD progression and poorer prognosis. Overexpression of RPS27a correlated with upregulation of p53, MDM2 and RPL11 in LUAD clinical specimens. Knockdown of RPS27a increased p53 activation, thus, suppressing the formation of A549 cell xenografts in nude mice. CONCLUSIONS: RPS27a interacts with RPL11, and RPS27a knockdown enhanced the binding of RPL11 and MDM2, thereby inhibiting MDM2-mediated p53 ubiquitination and degradation; in addition, RPS27a as important roles in LUAD progression and prognosis, and may be a therapeutic target for patients with LUAD.


Assuntos
Adenocarcinoma de Pulmão/genética , Apoptose/imunologia , Ciclo Celular/imunologia , Neoplasias Pulmonares/genética , Proteínas Ribossômicas/metabolismo , Adenocarcinoma de Pulmão/mortalidade , Animais , Proliferação de Células , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Camundongos , Camundongos Nus , Análise de Sobrevida , Transfecção
6.
Viruses ; 14(1)2022 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-35062360

RESUMO

Tripartite motif protein 21 (TRIM21) is an interferon-inducible E3 ligase, containing one RING finger domain, one B-box motif, one coiled-coil domain at the N-terminal, as well as one PRY domain and one SPRY domain at the C-terminal. TRIM21 is expressed in many tissues and plays an important role in systemic autoimmunity. However, TRIM21 plays different roles in different virus infections. In this study, we evaluate the relationship between porcine TRIM21 and PCV2 infection as well as host immune responses. We found that PCV2 infection modulated the expression of porcine TRIM21. TRIM21 can enhance interferons and proinflammatory factors and decrease cellular apoptosis in PCV2-infected cells. These results indicate that porcine TRIM21 plays a critical role in enhancing PCV2 infection, which is a promising target for controlling and developing the treatment of PCV2 infection.


Assuntos
Apoptose/genética , Circovirus/imunologia , Interações entre Hospedeiro e Microrganismos , Imunidade , Doenças dos Suínos/imunologia , Proteínas com Motivo Tripartido/genética , Animais , Apoptose/imunologia , Linhagem Celular , Células HEK293 , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Interferons/imunologia , Suínos , Doenças dos Suínos/virologia , Proteínas com Motivo Tripartido/classificação , Replicação Viral
7.
J Immunol ; 208(3): 732-744, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34996839

RESUMO

Eosinophils are potent innate effector cells associated mainly with type 2 immune responses elicited by helminths and allergens. Their activity needs to be tightly controlled to prevent severe inflammation and tissue damage. Eosinophil degranulation and secretion of inflammatory effector molecules, including cytokines, chemokines, and lipid mediators, can be regulated by activating and inhibitory receptors on the cell surface. In this study, we investigated the modulation of proliferation, apoptosis, gene expression, and cytokine/chemokine secretion from IL-33-activated Mus musculus eosinophils on cross-linking of the transmembrane receptor Sialic acid-binding Ig-like lectin F (Siglec-F). Siglec-F contains an ITIM plus an ITIM-like motif in its intracellular tail and is mainly regarded as an inhibitory and apoptosis-inducing receptor. In vitro costimulation of bone marrow-derived eosinophils with anti-Siglec-F and IL-33 compared with treatment with either alone led to enhanced STAT6 phosphorylation, stronger induction of hypoxia/glycolysis-related proinflammatory genes, and elevated secretion of type 2 cytokines (IL-4, IL-13) and chemokines (CCL3, CCL4) with only minor effects on proliferation and apoptosis. Using a competitive mixed bone marrow chimera approach with wild-type and Siglec-F-deficient eosinophils, we observed no evidence for Siglec-F-regulated inhibition of Aspergillus fumigatus-elicited lung eosinophilia. Truncation of the Siglec-F cytoplasmic tail, but not mutation of the ITIM and ITIM-like motifs, ablated the effect of enhanced cytokine/chemokine secretion. This provides evidence for an ITIM phosphorylation-independent signaling pathway from the cytoplasmic tail of the Siglec-F receptor that enhances effector molecule release from activated eosinophils.


Assuntos
Aspergilose/imunologia , Eosinofilia/imunologia , Eosinófilos/imunologia , Interleucina-33/metabolismo , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/metabolismo , Animais , Apoptose/imunologia , Aspergilose/patologia , Aspergillus fumigatus/imunologia , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Células Cultivadas , Quimiocina CCL3/metabolismo , Quimiocina CCL4/metabolismo , Humanos , Interleucina-13/metabolismo , Interleucina-33/imunologia , Interleucina-4/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Fator de Transcrição STAT6/metabolismo , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/genética
8.
Sci Rep ; 12(1): 1162, 2022 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-35064144

RESUMO

Oral lichen planus (OLP) is a localized autoimmune disease of the oral mucosa, with an incidence of up to 2%. Although corticosteroids are the first-line treatment, they cause several adverse effects. Quercetin, a naturally occurring compound, has fewer side-effects and provides long-term benefits. Besides, it has powerful anti­inflammatory activities. Here, we combined network pharmacology with experimental verification to predict and verify the key targets of quercetin against OLP. First, 66 quercetin-OLP common targets were analyzed from various databases. The protein-protein interaction (PPI) network was constructed. Topology analysis and MCODE cluster analysis of common targets were conducted to identify 12 key targets including TP53, IL-6 and IFN-γ and their connections. Gene functions and key signaling pathways, including reactive oxygen species metabolism, IL-17 pathway and AGE-RAGE pathway, were enriched by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Then, in vitro experiments showed that quercetin interfered with Th1/Th2 balance by acting on IL-6 and IFN-γ to modulate the immune system in treating OLP. Quercetin considerably affected the apoptosis and migration of T lymphocytes in OLP patients. Our study reveals the potential therapeutic targets and signaling pathways of quercetin associated with OLP, and establishes the groundwork for future clinical applications.


Assuntos
Líquen Plano Bucal/tratamento farmacológico , Mucosa Bucal/efeitos dos fármacos , Quercetina/farmacologia , Linfócitos T/efeitos dos fármacos , Adulto , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos , Feminino , Redes Reguladoras de Genes/efeitos dos fármacos , Redes Reguladoras de Genes/imunologia , Voluntários Saudáveis , Humanos , Líquen Plano Bucal/imunologia , Líquen Plano Bucal/patologia , Masculino , Pessoa de Meia-Idade , Mucosa Bucal/imunologia , Mucosa Bucal/patologia , Cultura Primária de Células , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas/efeitos dos fármacos , Mapas de Interação de Proteínas/genética , Mapas de Interação de Proteínas/imunologia , Quercetina/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Linfócitos T/imunologia , Equilíbrio Th1-Th2/efeitos dos fármacos
9.
J Exp Med ; 219(3)2022 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-35019947

RESUMO

T-dependent humoral responses generate long-lived memory B cells and plasma cells (PCs) predominantly through germinal center (GC) reaction. In human and mouse, memory B cells and long-lived PCs are also generated during immune responses to T-independent antigen, including bacterial polysaccharides, although the underlying mechanism for such T-independent humoral memory is not clear. While T-independent antigen can induce GCs, they are transient and thought to be nonproductive. Unexpectedly, by genetic fate-mapping, we find that these GCs actually output memory B cells and PCs. Using a conditional BCL6 deletion approach, we show memory B cells and PCs fail to last when T-independent GCs are precluded, suggesting that the GC experience per se is important for programming longevity of T-independent memory B cells and PCs. Consistent with the fact that infants cannot mount long-lived humoral memory to T-independent antigen, B cells from young animals intrinsically fail to form T-independent GCs. Our results suggest that T-independent GCs support humoral memory, and GC induction may be key to effective vaccines with T-independent antigen.


Assuntos
Antígenos/imunologia , Linfócitos B/imunologia , Centro Germinativo/imunologia , Imunidade Humoral , Memória Imunológica , Linfócitos T/imunologia , Apoptose/genética , Apoptose/imunologia , Linfócitos B/metabolismo , Biomarcadores , Comunicação Celular/imunologia , Centro Germinativo/metabolismo , Imunofenotipagem , Plasmócitos/imunologia , Plasmócitos/metabolismo , Linfócitos T/metabolismo
10.
Nephron ; 146(1): 99-109, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34569551

RESUMO

OBJECTIVE: Myeloid-derived suppressor cells (MDSCs) are heterogeneous cells which can suppress T-cell functionality. Herein, we evaluated the functional importance of MDSCs in the context of kidney ischemia-reperfusion injury (IRI) and explored their ability to regulate innate and adaptive immune cell function in this context. METHODS: The differentiation of MDSCs was induced in vitro by treating cells with GM-CSF and interferon (IFN)-γ. In a murine model of renal IRI, serum creatinine and blood urea nitrogen values were measured to monitor kidney function, while histopathological and immunohistochemical approaches were used to assess kidney injury severity. In addition, flow cytometry was employed to assess the phenotypes and apoptosis of kidney cells in these mice. RESULTS: MDSCs induced by treatment with GM-CSF + IFN-γ could suppress T-cell functionality in vitro. The adoptive transfer of these MDSCs into an IRI mouse model system enhanced kidney damage and impaired renal function following the recruitment of these cells to renal tissues in these mice. Following such adoptive transfer, the relative frequency of MDSCs with a CD11b+Ly6G-Ly6Chigh monocytic-MDSC phenotype decreased, whereas cells with a CD11b+Ly6G+Ly6Clow polymorphonuclear-MDSC phenotype become more prevalent within kidney tissues following IRI. Adoptive transfer also coincided with increased frequencies of macrophages and dendritic cells (DCs) in the kidney tissues. This suggested that M-MDSCs contributed to early-stage renal IRI damage by differentiating into these deleterious cell types. However, MDSC-induced suppression of CD4+ and CD8+ T-cell infiltration was not sufficient to prevent the deterioration of renal function in these mice. CONCLUSIONS: Herein, we successfully developed a protocol wherein MDSCs were differentiated in vitro through combination GM-CSF/IFN-γ treatment. When these MDSCs were subsequently adoptively transferred into a murine model of renal IRI, they aggravated kidney damage, likely owing to the differentiation of M-MDSCs into deleterious macrophages and DCs.


Assuntos
Imunidade Inata , Interferon gama/fisiologia , Rim/irrigação sanguínea , Células Supressoras Mieloides/citologia , Traumatismo por Reperfusão/patologia , Transferência Adotiva , Animais , Apoptose/imunologia , Proliferação de Células , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/terapia , Linfócitos T/imunologia
11.
Immunology ; 165(1): 22-43, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34704249

RESUMO

Neutrophil-centred inflammation and flawed clearance of neutrophils cause and exuberate multiple pathological conditions. These most abundant leukocytes exhibit very high daily turnover in steady-state and stress conditions. Various armours including oxidative burst, NETs and proteases function against pathogens, but also dispose neutrophils to spawn pro-inflammatory responses. Neutrophils undergo death through different pathways upon ageing, infection, executing the intruder's elimination. These include non-lytic apoptosis and other lytic deaths including NETosis, necroptosis and pyroptosis with distinct disintegration of the cellular membrane. This causes release and presence of different intracellular cytotoxic, and tissue-damaging content as cell remnants in the extracellular environment. The apoptotic cells and apoptotic bodies get cleared with non-inflammatory outcomes, while lytic deaths associated remnants including histones and cell-free DNA cause pro-inflammatory responses. Indeed, the enhanced frequencies of neutrophil-associated proteases, cell-free DNA and autoantibodies in diverse pathologies including sepsis, asthma, lupus and rheumatoid arthritis, imply disturbed neutrophil resolution programmes in inflammatory and autoimmune diseases. Thus, the clearance mechanisms of neutrophils and associated remnants are vital for therapeutics. Though studies focused on clearance mechanisms of senescent or apoptotic neutrophils so far generated a good understanding of the same, clearance of neutrophils undergoing distinct lytic deaths, including NETs, are being the subjects of intense investigations. Here, in this review, we are providing the current updates in the clearance mechanisms of apoptotic neutrophils and focusing on not so well-defined recognition, uptake and degradation of neutrophils undergoing lytic death and associated remnants that may provide new therapeutic approaches in inflammation and autoimmunity.


Assuntos
Imunidade , Inflamação/etiologia , Inflamação/metabolismo , Neutrófilos/fisiologia , Animais , Apoptose/imunologia , Biomarcadores , Suscetibilidade a Doenças/imunologia , Armadilhas Extracelulares/imunologia , Regulação da Expressão Gênica , Humanos , Inflamação/patologia , Transdução de Sinais
12.
Inflammation ; 45(1): 387-398, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34536156

RESUMO

Apoptosis is an important cell death mechanism for the resolution of inflammation. Neutrophil spontaneous apoptosis rates were reported to be slightly different in men and women and to be modulated by female sex hormones. The aim of this study was to determine whether different nanoparticles (NPs) will alter the neutrophil and eosinophil apoptotic rates differently in men and women. Using the antiapoptotic cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) and the proapoptotic plant lectin Viscum album agglutinin-I (VAA-I) as controls, we found that these factors respectively delay and induce apoptosis in both neutrophils and eosinophils with apoptotic rates remarkably similar in both sexes. The polyamidoamine (PAMAM) dendrimers of generation 0 (G0) and G3 slightly, but not significantly, accelerate neutrophil apoptosis regardless of sex. Zinc oxide (ZnO), titanium dioxide (TiO2), cerium dioxide (CeO2), and palladium (Pd) but not platinum (Pt) NPs were found to significantly delay neutrophil apoptosis. When results were compared between men and women, only ZnO and Pd NPs were found to significantly delay neutrophil apoptosis in men while ZnO, TiO2, CeO2, and Pt NPs inhibit apoptosis in women neutrophils. In eosinophils, G3, but not G0 NPs, significantly accelerate apoptosis in women. ZnO, Pt, and Pd NPs significantly delay eosinophil apoptosis but only in women. Unlike neutrophils, TiO2 and CeO2 NPs did not significantly delay eosinophil apoptosis. We propose that future studies aiming at determining potential effect NPs on cellular biological processes should incorporate a sex-based analysis based on the differences reported here studying the impact of NPs on human granulocyte apoptosis.


Assuntos
Apoptose/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Eosinófilos/efeitos dos fármacos , Nanopartículas/toxicidade , Neutrófilos/efeitos dos fármacos , Adulto , Apoptose/imunologia , Eosinófilos/imunologia , Eosinófilos/metabolismo , Eosinófilos/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Neutrófilos/metabolismo , Neutrófilos/patologia , Fatores Sexuais
13.
Immunology ; 165(1): 122-140, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34549818

RESUMO

Haemoglobin (Hb) has well-documented inflammatory effects and is normally efficiently scavenged; clearance mechanisms can be overwhelmed during erythrocyte lysis. Whether Hb is preferentially inflammatory in lupus and triggers broad anti-self responses was assessed. Peripheral blood mononuclear cells (PBMCs) derived from SLE patients secreted higher levels of lupus-associated inflammatory cytokines when incubated with human Hb than did PBMCs derived from healthy donors, an effect negated by haptoglobin. Ferric murine Hb triggered the preferential release of lupus-associated cytokines from splenocytes, B cells, CD4 T cells, CD8 T cells and plasmacytoid dendritic cells isolated from ageing, lupus-prone NZM2410 mice, and also had mitogenic effects on B cells. Pull-downs, followed by mass spectrometry, revealed interactions of Hb with several lupus-associated autoantigens; co-incubation of ferric Hb with apoptotic blebs (structures that contain packaged autoantigens) revealed synergies-in terms of cytokine release and autoantibody production in vitro-that were also restricted to the lupus genotype. Murine ferric Hb activated multiple signalling pathways and, in combination with apoptotic blebs, preferentially triggered MAP kinase signalling specifically in splenocytes isolated from lupus-prone mice. Infusion of murine ferric Hb into lupus-prone mice led to enhanced release of lupus-associated cytokines, the generation of a spectrum of autoantibodies and enhanced-onset glomerulosclerosis. Given that the biased recognition of ferric Hb in a lupus milieu, possibly in concert with lupus-associated autoantigens, triggers inflammatory responses and the generation of lupus-associated cytokines, and also stimulates the generation of potentially pathogenic lupus-associated autoantibodies, neutralization of Hb could have beneficial effects.


Assuntos
Autoantígenos/imunologia , Hemoglobinas/metabolismo , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/imunologia , Nefrite Lúpica/etiologia , Nefrite Lúpica/metabolismo , Animais , Apoptose/genética , Apoptose/imunologia , Autoanticorpos/imunologia , Biomarcadores , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Suscetibilidade a Doenças , Humanos , Imidazóis/farmacologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos/imunologia , Nefrite Lúpica/patologia , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos/efeitos dos fármacos , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Camundongos , Ligação Proteica , Transdução de Sinais , Baço/imunologia , Baço/metabolismo
14.
Cell Immunol ; 371: 104452, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34784561

RESUMO

Atopic dermatitis (AD) is a common inflammatory skin disorder that affects children and adults. Despite the pathology of AD involves in immune dysfunction and epidermal barrier function destruction has been found, the mechanism of immune activation and barrier damage remain largely unknown. In the present study, The TNF-α/IFN-γ-stimulated HaCaTs, organotypic AD-like 3D skin equivalents and AD-like mouse model were constructed. The mRNA, histological morphology, protein levels, cytokines were detected by real-time quantitative polymerasechain reaction (RT-qPCR), hematoxylin and eosin (H & E) staining, Immunohistochemistry (IHC), immunoblotting, immunofluorescence (IF) staining, and enzyme linked immunosorbent assay (ELISA), respectively. Cell viability, cell cycle, and apoptosis were respectively calculated using a Methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay and flow cytometry. A dual-luciferase reporter gene system was used to investigate the relationship between miR-1294 and STAT3. Compared with the control group, the expression of miR-1294 decreased in TNF-α/IFN-γ-stimulated HaCaTs (P < 0.001), AD-like skin model, and AD-like mouse model (P < 0.001). Moreover, STAT3 was documented as a direct target of miR-1294. Inflammation (P < 0.05) and epidermal barrier function destruction (P < 0.05) in AD was suppressed by overexpression of miR-1294 but enhanced by STAT3 upregulation and its downstream NF-κB pathway. We also found miR-1294 upregulation inhibited inflammation and epidermal barrier function destruction via targeting STAT3 to suppress NF-κB pathway activation in AD.


Assuntos
Dermatite Atópica/patologia , MicroRNAs/genética , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/metabolismo , Junções Íntimas/fisiologia , Animais , Apoptose/imunologia , Ciclo Celular/fisiologia , Linhagem Celular , Sobrevivência Celular/fisiologia , Dermatite Atópica/genética , Dermatite Atópica/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Células HaCaT , Humanos , Inflamação/imunologia , Interferon gama/metabolismo , Camundongos , Fator de Transcrição STAT3/genética , Pele/imunologia , Pele/patologia , Fator de Necrose Tumoral alfa/metabolismo
15.
Cell Immunol ; 371: 104459, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34847408

RESUMO

Invasive candidiasis is a healthcare-associated fungal infection with a high mortality rate. Neutrophils, the first line of defense during fungal infections, express the immunoregulatory Candida albicans receptors CEACAM1, CEACAM3, and CEACAM6. We analyzed the effects of specific antibodies on C. albicans-induced neutrophil responses. CEACAM6 ligation by 1H7-4B and to some extent CEACAM1 ligation by B3-17, but not CEACAM3 ligation by 308/3-3, resulted in the immediate release of stored CXCL8 and altered transcriptional responses of the C. albicans-stimulated neutrophils. Integrated network analyses and dynamic simulations of signaling cascades predicted alterations in apoptosis and cytokine secretion. We verified that CEACAM6 ligation enhanced Candida-induced neutrophil apoptosis and increased long-term IL-1ß/IL-6 release in responses to C. albicans. CEACAM3 ligation, but not CEACAM1 ligation, increased the long-term release of pro-inflammatory IL-1ß/IL-6. Taken together, we demonstrated for the first time that ligation of CEACAM receptors differentially affects the regulation of C. albicans-induced immune functions in human neutrophils.


Assuntos
Antígenos CD/imunologia , Candida albicans/imunologia , Antígeno Carcinoembrionário/imunologia , Moléculas de Adesão Celular/imunologia , Neutrófilos/imunologia , Anticorpos Monoclonais/imunologia , Apoptose/imunologia , Candidíase Invasiva/mortalidade , Candidíase Invasiva/patologia , Citocinas/imunologia , Feminino , Proteínas Ligadas por GPI/imunologia , Humanos , Imunomodulação/imunologia , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Masculino
17.
Eur J Haematol ; 108(1): 18-27, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34487584

RESUMO

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by a low platelet count and an increased risk of bleeding. In addition to anti-platelet autoantibodies, CD8+ T cells have been implicated as a mechanism of platelet destruction. The current evidence for the existence of platelet-specific CD8+ T cells in ITP is inconclusive. The purpose of this review is to summarize the studies that investigated CD8+ T cells in ITP and to review the methods that have been used to detect autoreactive CD8+ T cells in other autoimmune diseases.


Assuntos
Autoimunidade , Suscetibilidade a Doenças , Púrpura Trombocitopênica Idiopática/etiologia , Linfócitos T/imunologia , Apoptose/genética , Apoptose/imunologia , Autoanticorpos/imunologia , Autoantígenos/imunologia , Biomarcadores , Plaquetas/imunologia , Plaquetas/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Citotoxicidade Imunológica , Gerenciamento Clínico , Suscetibilidade a Doenças/imunologia , Regulação da Expressão Gênica , Genes MHC Classe I , Humanos , Ativação Linfocitária/imunologia , Púrpura Trombocitopênica Idiopática/diagnóstico , Púrpura Trombocitopênica Idiopática/terapia , Linfócitos T/metabolismo
18.
Front Immunol ; 12: 718359, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34867947

RESUMO

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with widespread inflammation, immune dysregulation, and is associated with the generation of destructive anti-DNA autoantibodies. We have shown previously the immune modulatory properties of pCons peptide in the induction of both CD4+ and CD8+ regulatory T cells which can in turn suppress development of the autoimmune disease in (NZB/NZW) F1 (BWF1) mice, an established model of lupus. In the present study, we add novel protein information and further demonstrate the molecular and cellular phenotypes of pCons-induced CD4+ and CD8+ Treg subsets. Flow cytometry analyses revealed that pCons induced CD8+ Treg cells with the following cell surface molecules: CD25highCD28high and low subsets (shown earlier), CD62Lhigh, CD122low, PD1low, CTLA4low, CCR7low and 41BBhigh. Quantitative real-time PCR (qRT-PCR) gene expression analyses revealed that pCons-induced CD8+ Treg cells downregulated the following several genes: Regulator of G protein signaling (RGS2), RGS16, RGS17, BAX, GPT2, PDE3b, GADD45ß and programmed cell death 1 (PD1). Further, we confirmed the down regulation of these genes by Western blot analyses at the protein level. To our translational significance, we showed herein that pCons significantly increased the percentage of CD8+FoxP3+ T cells and further increased the mean fluorescence intensity (MFI) of FoxP3 when healthy peripheral blood mononuclear cells (PBMCs) are treated with pCons (10 µg/ml, for 24-48 hours). In addition, we found that pCons reduced apoptosis in CD4+ and CD8+ T cells and B220+ B cells of BWF1 lupus mice. These data suggest that pCons stimulates cellular, immunological, and molecular changes in regulatory T cells which in turn protect against SLE autoimmunity.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Peptídeos/genética , Peptídeos/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Sequência de Aminoácidos , Animais , Antígenos de Diferenciação de Linfócitos T/genética , Antígenos de Diferenciação de Linfócitos T/metabolismo , Apoptose/genética , Apoptose/imunologia , Modelos Animais de Doenças , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Feminino , Expressão Gênica , Voluntários Saudáveis , Humanos , Tolerância Imunológica/genética , Camundongos , Camundongos Endogâmicos NZB , Pessoa de Meia-Idade , Peptídeos/administração & dosagem , Proteínas RGS/genética , Proteínas RGS/imunologia , Adulto Jovem
19.
Front Immunol ; 12: 740620, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34867962

RESUMO

While the immunomodulatory pathways initiated in immune cells contribute to therapeutic response, their activation in cancer cells play a role in cancer progression. Also, many of the aberrantly expressed immunomodulators on cancer cells are considered as therapeutic targets. Here, we introduce host defense peptide (HDP), a known immuomodulator, as a therapeutic agent to target them. The cationic host defense peptides (HDPs), an integral part of the innate immune system, possess membranolytic activity, which imparts antimicrobial and antitumor efficacy to it. They act as immunomodulators by activating the immune cells. Though their antimicrobial function has been recently reassigned to immunoregulation, their antitumor activity is still attributed to its membranolytic activity. This membrane pore formation ability, which is proportional to the concentration of the peptide, also leads to side effects like hemolysis, limiting their therapeutic application. So, despite the identification of a variety of anticancer HDPs, their clinical utility is limited. Though HDPs are shown to exert the immunomodulatory activity through specific membrane targets on immune cells, their targets on cancer cells are unknown. We show that SSTP1, a novel HDP identified by shotgun cloning, binds to the active IL6/IL6Rα/gp130 complex on cancer cells, rearranging the active site residues. In contrast to the IL6 blockers inhibiting JAK/STAT activity, SSTP1 shifts the proliferative IL6/JAK/STAT signaling to the apoptotic IL6/JNK/AP1 pathway. In IL6Rα-overexpressing cancer cells, SSTP1 induces apoptosis at low concentration through JNK pathway, without causing significant membrane disruption. We highlight the importance of immunomodulatory pathways in cancer apoptosis, apart from its established role in immune cell regulation and cancer cell proliferation. Our study suggests that identification of the membrane targets for the promising anticancer HDPs might lead to the identification of new drugs for targeted therapy.


Assuntos
Proteínas de Anfíbios/imunologia , Peptídeos Catiônicos Antimicrobianos/imunologia , Anuros , Apoptose/imunologia , Interleucina-6/imunologia , Neoplasias/imunologia , Animais , Linhagem Celular Tumoral , Humanos
20.
Front Immunol ; 12: 766757, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34858422

RESUMO

Regulatory T cells (Tregs) are considered important for controlling the onset and development of autoimmune disease. Although studies have shown that miR-21 is expressed at higher levels in Treg cells, it remains largely elusive whether miR-21 regulates the immune-suppressive function of Tregs. In the current study, we generated mice lacking miR-21 specifically in their Tregs and investigated the role of miR-21 in regulating Treg function both in vitro and in vivo. Our study revealed that Tregs lacking miR-21 exhibit normal phenotype and unaltered function in suppressing T cell proliferation and dendritic cell activation in vitro. However, compared with miR-21-sufficient Tregs, they produce significant more IL-17 and IL-10 when under pathogenic Th17-priming condition. Adenoviral delivery of miR-21 into Treg cells is able to reduce the expression of both IL-17 and IL-10. Mechanistic study revealed that miR-21 down-regulates IL-10 expression through direct targeting of IL-10, and suppresses reprogramming of Tregs into IL-17-secreting cells through down-regulating Stat3 activity. However, we detected no significant or marginal difference in the development of various autoimmune diseases between wild type mice and mice with Treg-specific deletion of miR-21. In conclusion, our study demonstrated that miR-21 in Tregs regulates diametrically opposed biological Treg functions and is largely dispensable for the development of autoimmune disease.


Assuntos
Doenças Autoimunes/imunologia , Regulação da Expressão Gênica/imunologia , Ativação Linfocitária/imunologia , MicroRNAs/imunologia , Linfócitos T Reguladores/imunologia , Animais , Apoptose/genética , Apoptose/imunologia , Doenças Autoimunes/genética , Doenças Autoimunes/metabolismo , Proliferação de Células/genética , Interferon gama/genética , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-10/metabolismo , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-17/metabolismo , Ativação Linfocitária/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/genética , Linfócitos T Reguladores/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo
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