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1.
Signal Transduct Target Ther ; 6(1): 328, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471088

RESUMO

Understanding the pathological features of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in an animal model is crucial for the treatment of coronavirus disease 2019 (COVID-19). Here, we compared immunopathological changes in young and old rhesus macaques (RMs) before and after SARS-CoV-2 infection at the tissue level. Quantitative analysis of multiplex immunofluorescence staining images of formalin-fixed paraffin-embedded (FFPE) sections showed that SARS-CoV-2 infection specifically induced elevated levels of apoptosis, autophagy, and nuclear factor kappa-B (NF-κB) activation of angiotensin-converting enzyme 2 (ACE2)+ cells, and increased interferon α (IFN-α)- and interleukin 6 (IL-6)-secreting cells and C-X-C motif chemokine receptor 3 (CXCR3)+ cells in lung tissue of old RMs. This pathological pattern, which may be related to the age-related pro-inflammatory microenvironment in both lungs and spleens, was significantly correlated with the systemic accumulation of CXCR3+ cells in lungs, spleens, and peripheral blood. Furthermore, the ratio of CXCR3+ to T-box protein expression in T cell (T-bet)+ (CXCR3+/T-bet+ ratio) in CD8+ cells may be used as a predictor of severe COVID-19. These findings uncovered the impact of aging on the immunopathology of early SARS-CoV-2 infection and demonstrated the potential application of CXCR3+ cells in predicting severe COVID-19.


Assuntos
Linfócitos T CD8-Positivos/imunologia , COVID-19/imunologia , Microambiente Celular/imunologia , Pulmão/imunologia , Receptores CXCR3/imunologia , SARS-CoV-2/imunologia , Enzima de Conversão de Angiotensina 2/imunologia , Animais , Linfócitos T CD8-Positivos/patologia , COVID-19/patologia , Modelos Animais de Doenças , Inflamação/imunologia , Inflamação/patologia , Interferon-alfa/imunologia , Interleucina-6/imunologia , Pulmão/patologia , Pulmão/virologia , Macaca mulatta , Masculino
2.
Front Immunol ; 12: 716361, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34491250

RESUMO

Background: COVID-19 pathology is associated with exuberant inflammation, vascular damage, and activation of coagulation. In addition, complement activation has been described and is linked to disease pathology. However, few studies have been conducted in cancer patients. Objective: This study examined complement activation in response to COVID-19 in the setting of cancer associated thromboinflammation. Methods: Markers of complement activation (C3a, C5a, sC5b-9) and complement inhibitors (Factor H, C1-Inhibitor) were evaluated in plasma of cancer patients with (n=43) and without (n=43) COVID-19 and stratified based on elevated plasma D-dimer levels (>1.0 µg/ml FEU). Markers of vascular endothelial cell dysfunction and platelet activation (ICAM-1, thrombomodulin, P-selectin) as well as systemic inflammation (pentraxin-3, serum amyloid A, soluble urokinase plasminogen activator receptor) were analyzed to further evaluate the inflammatory response. Results: Increases in circulating markers of endothelial cell dysfunction, platelet activation, and systemic inflammation were noted in cancer patients with COVID-19. In contrast, complement activation increased in cancer patients with COVID-19 and elevated D-dimers. This was accompanied by decreased C1-Inhibitor levels in patients with D-dimers > 5 ug/ml FEU. Conclusion: Complement activation in cancer patients with COVID-19 is significantly increased in the setting of thromboinflammation. These findings support a link between coagulation and complement cascades in the setting of inflammation.


Assuntos
COVID-19/imunologia , Ativação do Complemento/imunologia , Inflamação/imunologia , Neoplasias/imunologia , SARS-CoV-2/imunologia , Trombose/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , COVID-19/sangue , COVID-19/virologia , Inativadores do Complemento/sangue , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Humanos , Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Ativação Plaquetária/imunologia , Estudos Retrospectivos , SARS-CoV-2/fisiologia , Trombose/sangue , Adulto Jovem
3.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361061

RESUMO

Sepsis is a sustained systemic inflammatory condition involving multiple organ failures caused by dysregulated immune response to infections. Sepsis induces substantial changes in energy demands at the cellular level leading to metabolic reprogramming in immune cells and stromal cells. Although sepsis-associated organ dysfunction and mortality have been partly attributed to the initial acute hyperinflammation and immunosuppression precipitated by a dysfunction in innate and adaptive immune responses, the late mortality due to metabolic dysfunction and immune paralysis currently represent the major problem in clinics. It is becoming increasingly recognized that intertissue and/or intercellular metabolic crosstalk via endocrine factors modulates maintenance of homeostasis, and pathological events in sepsis and other inflammatory diseases. Exosomes have emerged as a novel means of intercellular communication in the regulation of cellular metabolism, owing to their capacity to transfer bioactive payloads such as proteins, lipids, and nucleic acids to their target cells. Recent evidence demonstrates transfer of intact metabolic intermediates from cancer-associated fibroblasts via exosomes to modify metabolic signaling in recipient cells and promote cancer progression. Here, we review the metabolic regulation of endothelial cells and immune cells in sepsis and highlight the role of exosomes as mediators of cellular metabolic signaling in sepsis.


Assuntos
Células Endoteliais/patologia , Exossomos/patologia , Imunossupressão , Inflamação/patologia , Doenças Metabólicas/patologia , Sepse/fisiopatologia , Animais , Humanos , Inflamação/imunologia , Doenças Metabólicas/etiologia
4.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361066

RESUMO

Ceramides, a class of sphingolipids containing a backbone of sphingoid base, are the most important and effective structural component for the formation of the epidermal permeability barrier. While ceramides comprise approximately 50% of the epidermal lipid content by mass, the content is substantially decreased in certain inflammatory skin diseases, such as atopic dermatitis (AD), causing improper barrier function. It is widely accepted that the endocannabinoid system (ECS) can modulate a number of biological responses in the central nerve system, prior studies revealed that activation of endocannabinoid receptor CB1, a key component of ECS, triggers the generation of ceramides that mediate neuronal cell fate. However, as the impact of ECS on the production of epidermal ceramide has not been studied, we here investigated whether the ECS stimulates the generation of epidermal ceramides in an IL-4-treated in vitro model of skin inflammation using N-palmitoyl serinol (PS), an analog of the endocannabinoid N-palmitoyl ethanolamine. Accordingly, an IL-4-mediated decrease in cellular ceramide levels was significantly stimulated in human epidermal keratinocytes (KC) following PS treatment through both de novo ceramide synthesis- and sphingomyelin hydrolysis-pathways. Importantly, PS selectively increases ceramides with long-chain fatty acids (FAs) (C22-C24), which mainly account for the formation of the epidermal barrier, through activation of ceramide synthase (CerS) 2 and Cer3 in IL-4-mediated inflamed KC. Furthermore, blockade of cannabinoid receptor CB1 activation by AM-251 failed to stimulate the production of total ceramide as well as long-chain ceramides in response to PS. These studies demonstrate that an analog of endocannabinoid, PS, stimulates the generation of specific ceramide species as well as the total amount of ceramides via the endocannabinoid receptor CB1-dependent mechanism, thereby resulting in the enhancement of epidermal permeability barrier function.


Assuntos
Ceramidas/metabolismo , Inflamação/metabolismo , Queratinócitos/metabolismo , Propanolaminas/farmacologia , Propilenoglicóis/farmacologia , Receptor CB1 de Canabinoide/metabolismo , Pele/metabolismo , Células Cultivadas , Humanos , Técnicas In Vitro , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Propanolaminas/química , Propilenoglicóis/química , Pele/citologia , Pele/efeitos dos fármacos
5.
Int J Mol Sci ; 22(15)2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34361107

RESUMO

Chemotactic cytokines-chemokines-control immune cell migration in the process of initiation and resolution of inflammatory conditions as part of the body's defense system. Many chemokines also participate in pathological processes leading up to and exacerbating the inflammatory state characterizing chronic inflammatory diseases. In this review, we discuss the role of dendritic cells (DCs) and the central chemokine receptor CCR7 in the initiation and sustainment of selected chronic inflammatory diseases: multiple sclerosis (MS), rheumatoid arthritis (RA), and psoriasis. We revisit the binary role that CCR7 plays in combatting and progressing cancer, and we discuss how CCR7 and DCs can be harnessed for the treatment of cancer. To provide the necessary background, we review the differential roles of the natural ligands of CCR7, CCL19, and CCL21 and how they direct the mobilization of activated DCs to lymphoid organs and control the formation of associated lymphoid tissues (ALTs). We provide an overview of DC subsets and, briefly, elaborate on the different T-cell effector types generated upon DC-T cell priming. In the conclusion, we promote CCR7 as a possible target of future drugs with an antagonistic effect to reduce inflammation in chronic inflammatory diseases and an agonistic effect for boosting the reactivation of the immune system against cancer in cell-based and/or immune checkpoint inhibitor (ICI)-based anti-cancer therapy.


Assuntos
Doenças Autoimunes/patologia , Células Dendríticas/imunologia , Inflamação/patologia , Neoplasias/patologia , Receptores CCR7/metabolismo , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , Transdução de Sinais
6.
Int J Mol Sci ; 22(15)2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34361102

RESUMO

Interactions between the intestinal microbiota, immune system and nervous system are essential for homeostasis in the gut. Inflammasomes contribute to innate immunity and brain-gut interactions, but their role in microbiota-neuro-immune interactions is not clear. Therefore, we investigated the effect of the inflammasome on visceral pain and local and systemic neuroimmune responses after antibiotic-induced changes to the microbiota. Wild-type (WT) and caspase-1/11 deficient (Casp1 KO) mice were orally treated for 2 weeks with an antibiotic cocktail (Abx, Bacitracin A and Neomycin), followed by quantification of representative fecal commensals (by qPCR), cecal short chain fatty acids (by HPLC), pathways implicated in the gut-neuro-immune axis (by RT-qPCR, immunofluorescence staining, and flow cytometry) in addition to capsaicin-induced visceral pain responses. Abx-treatment in WT-mice resulted in an increase in colonic macrophages, central neuro-immune interactions, colonic inflammasome and nociceptive receptor gene expression and a reduction in capsaicin-induced visceral pain. In contrast, these responses were attenuated in Abx-treated Casp1 KO mice. Collectively, the data indicate an important role for the inflammasome pathway in functional and inflammatory gastrointestinal conditions where pain and alterations in microbiota composition are prominent.


Assuntos
Caspase 1/fisiologia , Microbioma Gastrointestinal , Inflamassomos/imunologia , Inflamação/complicações , Neuroimunomodulação , Dor Visceral/patologia , Animais , Antibacterianos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Encéfalo/microbiologia , Encéfalo/patologia , Capsaicina/toxicidade , Colo/efeitos dos fármacos , Colo/imunologia , Colo/microbiologia , Colo/patologia , Feminino , Inflamassomos/efeitos dos fármacos , Inflamação/imunologia , Inflamação/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais , Dor Visceral/etiologia , Dor Visceral/metabolismo
7.
Cells ; 10(7)2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34360004

RESUMO

Microglia are the resident immune cells of the central nervous system contributing substantially to health and disease. There is increasing evidence that inflammatory microglia may induce or accelerate brain aging, by interfering with physiological repair and remodeling processes. Many viral infections affect the brain and interfere with microglia functions, including human immune deficiency virus, flaviviruses, SARS-CoV-2, influenza, and human herpes viruses. Especially chronic viral infections causing low-grade neuroinflammation may contribute to brain aging. This review elucidates the potential role of various neurotropic viruses in microglia-driven neurocognitive deficiencies and possibly accelerated brain aging.


Assuntos
Envelhecimento , Encéfalo/fisiopatologia , Inflamação/fisiopatologia , Microglia/virologia , Viroses/fisiopatologia , Animais , Encéfalo/imunologia , Encéfalo/virologia , COVID-19/imunologia , COVID-19/fisiopatologia , COVID-19/virologia , Humanos , Inflamação/imunologia , Inflamação/virologia , Microglia/imunologia , Microglia/patologia , SARS-CoV-2/fisiologia , Viroses/imunologia , Viroses/virologia
8.
Int J Mol Sci ; 22(15)2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34360662

RESUMO

A well-functioning placenta is crucial for normal gestation and regulates the nutrient, gas, and waste exchanges between the maternal and fetal circulations and is an important endocrine organ producing hormones that regulate both the maternal and fetal physiologies during pregnancy. Placental insufficiency is implicated in spontaneous preterm birth (SPTB). We proposed that deficits in the capacity of the placenta to maintain bioenergetic and metabolic stability during pregnancy may ultimately result in SPTB. To explore our hypothesis, we performed a RNA-seq study in male and female placentas from women with SPTB (<36 weeks gestation) compared to normal pregnancies (≥38 weeks gestation) to assess the alterations in the gene expression profiles. We focused exclusively on Black women (cases and controls), who are at the highest risk of SPTB. Six hundred and seventy differentially expressed genes were identified in male SPTB placentas. Among them, 313 and 357 transcripts were increased and decreased, respectively. In contrast, only 61 differentially expressed genes were identified in female SPTB placenta. The ingenuity pathway analysis showed alterations in the genes and canonical pathways critical for regulating inflammation, oxidative stress, detoxification, mitochondrial function, energy metabolism, and the extracellular matrix. Many upstream regulators and master regulators important for nutrient-sensing and metabolism were also altered in SPTB placentas, including the PI3K complex, TGFB1/SMADs, SMARCA4, TP63, CDKN2A, BRCA1, and NFAT. The transcriptome was integrated with published human placental metabolome to assess the interactions of altered genes and metabolites. Collectively, significant and biologically relevant alterations in the transcriptome were identified in SPTB placentas with fetal sex disparities. Altered energy metabolism, mitochondrial function, inflammation, and detoxification may underly the mechanisms of placental dysfunction in SPTB.


Assuntos
Metabolismo Energético , Inflamação/patologia , Doenças Placentárias/patologia , Placenta/patologia , Nascimento Prematuro/patologia , Transcriptoma , Adulto , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Masculino , Placenta/imunologia , Placenta/metabolismo , Doenças Placentárias/genética , Doenças Placentárias/imunologia , Doenças Placentárias/metabolismo , Gravidez , Nascimento Prematuro/genética , Nascimento Prematuro/imunologia , Nascimento Prematuro/metabolismo , Fatores Sexuais
9.
Front Immunol ; 12: 720109, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34367190

RESUMO

COVID-19 is a contagious viral disease caused by SARS-CoV-2 that led to an ongoing pandemic with massive global health and socioeconomic consequences. The disease is characterized primarily, but not exclusively, by respiratory clinical manifestations ranging from mild common cold symptoms, including cough and fever, to severe respiratory distress and multi-organ failure. Macrophages, a heterogeneous group of yolk-sac derived, tissue-resident mononuclear phagocytes of complex ontogeny present in all mammalian organs, play critical roles in developmental, homeostatic and host defense processes with tissue-dependent plasticity. In case of infection, they are responsible for early pathogen recognition, initiation and resolution of inflammation, as well as repair of tissue damage. Monocytes, bone-marrow derived blood-resident phagocytes, are recruited under pathological conditions such as viral infections to the affected tissue to defend the organism against invading pathogens and to aid in efficient resolution of inflammation. Given their pivotal function in host defense and the potential danger posed by their dysregulated hyperinflammation, understanding monocyte and macrophage phenotypes in COVID-19 is key for tackling the disease's pathological mechanisms. Here, we outline current knowledge on monocytes and macrophages in homeostasis and viral infections and summarize concepts and key findings on their role in COVID-19. While monocytes in the blood of patients with moderate COVID-19 present with an inflammatory, interferon-stimulated gene (ISG)-driven phenotype, cellular dysfunction epitomized by loss of HLA-DR expression and induction of S100 alarmin expression is their dominant feature in severe disease. Pulmonary macrophages in COVID-19 derived from infiltrating inflammatory monocytes are in a hyperactivated state resulting in a detrimental loop of pro-inflammatory cytokine release and recruitment of cytotoxic effector cells thereby exacerbating tissue damage at the site of infection.


Assuntos
COVID-19/imunologia , Antígenos HLA-DR/imunologia , Macrófagos/imunologia , Monócitos/imunologia , SARS-CoV-2/imunologia , COVID-19/patologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Macrófagos/patologia , Monócitos/patologia , Índice de Gravidade de Doença
10.
Oxid Med Cell Longev ; 2021: 9998697, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34457122

RESUMO

The pandemic of the coronavirus disease 2019 (COVID-19) has posed huge threats to healthcare systems and the global economy. However, the host response towards COVID-19 on the molecular and cellular levels still lacks full understanding and effective therapies are in urgent need. Here, we integrate three datasets, GSE152641, GSE161777, and GSE157103. Compared to healthy people, 314 differentially expressed genes were identified, which were mostly involved in neutrophil degranulation and cell division. The protein-protein network was established and two significant subsets were filtered by MCODE: ssGSEA and CIBERSORT, which comprehensively revealed the alternation of immune cell abundance. Weighted gene coexpression network analysis (WGCNA) as well as GO and KEGG analyses unveiled the role of neutrophils and T cells during the progress of the disease. Based on the hospital-free days after 45 days of follow-up and statistical methods such as nonnegative matrix factorization (NMF), submap, and linear correlation analysis, 31 genes were regarded as the signature of the peripheral blood of COVID-19. Various immune cells were identified to be related to the prognosis of the patients. Drugs were predicted for the genes in the signature by DGIdb. Overall, our study comprehensively revealed the relationship between the inflammatory response and the disease course, which provided strategies for the treatment of COVID-19.


Assuntos
COVID-19/genética , COVID-19/imunologia , Redes Reguladoras de Genes , Inflamação/genética , Inflamação/imunologia , SARS-CoV-2/imunologia , Transcriptoma , COVID-19/complicações , COVID-19/virologia , Estudos de Casos e Controles , Perfilação da Expressão Gênica , Humanos , Inflamação/virologia , Mapas de Interação de Proteínas
11.
FASEB J ; 35(10): e21843, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34464475

RESUMO

Robust inflammatory responses are critical to survival following respiratory infection, with current attention focused on the clinical consequences of the Coronavirus pandemic. Epigenetic factors are increasingly recognized as important determinants of immune responses, and EZH2 is a prominent target due to the availability of highly specific and efficacious antagonists. However, very little is known about the role of EZH2 in the myeloid lineage. Here, we show EZH2 acts in macrophages to limit inflammatory responses to activation, and in neutrophils for chemotaxis. Selective genetic deletion in macrophages results in a remarkable gain in protection from infection with the prevalent lung pathogen, pneumococcus. In contrast, neutrophils lacking EZH2 showed impaired mobility in response to chemotactic signals, and resulted in increased susceptibility to pneumococcus. In summary, EZH2 shows complex, and divergent roles in different myeloid lineages, likely contributing to the earlier conflicting reports. Compounds targeting EZH2 are likely to impair mucosal immunity; however, they may prove useful for conditions driven by pulmonary neutrophil influx, such as adult respiratory distress syndrome.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/imunologia , Inflamação/imunologia , Macrófagos/imunologia , Neutrófilos/imunologia , Animais , Células Cultivadas , Macrófagos/citologia , Camundongos Endogâmicos C57BL , Neutrófilos/citologia
12.
J Immunol ; 207(5): 1371-1376, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34380647

RESUMO

Inflammatory cytokine storm is a known cause for acute respiratory distress syndrome. In this study, we have investigated the role of IFN-γ in lethal lung inflammation using a mouse model of postinfluenza methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. To mimic the clinical scenario, animals were treated with antibiotics for effective bacterial control following MRSA superinfection. However, antibiotic therapy alone is not sufficient to improve survival of wild-type animals in this lethal acute respiratory distress syndrome model. In contrast, antibiotics induce effective protection in mice deficient in IFN-γ response. Mechanistically, we show that rather than inhibiting bacterial clearance, IFN-γ promotes proinflammatory cytokine response to cause lethal lung damage. Neutralization of IFN-γ after influenza prevents hyperproduction of TNF-α, and thereby protects against inflammatory lung damage and animal mortality. Taken together, the current study demonstrates that influenza-induced IFN-γ drives a stepwise propagation of inflammatory cytokine response, which ultimately results in fatal lung damage during secondary MRSA pneumonia, despite of antibiotic therapy.


Assuntos
Antibacterianos/uso terapêutico , Inflamação/imunologia , Vírus da Influenza A/fisiologia , Influenza Humana/imunologia , Interferon gama/metabolismo , Pulmão/imunologia , Infecções por Orthomyxoviridae/imunologia , Pneumonia Estafilocócica/imunologia , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/fisiologia , Animais , Células Cultivadas , Humanos , Influenza Humana/complicações , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infecções por Orthomyxoviridae/complicações , Pneumonia Estafilocócica/complicações , Infecções Estafilocócicas/complicações , Superinfecção , Fator de Necrose Tumoral alfa
13.
J Immunol ; 207(5): 1275-1287, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34389624

RESUMO

The airway epithelial cells (AECs) lining the conducting passageways of the lung secrete a variety of immunomodulatory factors. Among these, PGE2 limits lung inflammation and promotes bronchodilation. By contrast, IL-6 drives intense airway inflammation, remodeling, and fibrosis. The signaling that differentiates the production of these opposing mediators is not understood. In this study, we find that the production of PGE2 and IL-6 following stimulation of human AECs by the damage-associated molecular pattern extracellular ATP shares a common requirement for Ca2+ release-activated Ca2+ (CRAC) channels. ATP-mediated synthesis of PGE2 required activation of metabotropic P2Y2 receptors and CRAC channel-mediated cytosolic phospholipase A2 signaling. By contrast, ATP-evoked synthesis of IL-6 occurred via activation of ionotropic P2X receptors and CRAC channel-mediated calcineurin/NFAT signaling. In contrast to ATP, which elicited the production of both PGE2 and IL-6, the uridine nucleotide, UTP, stimulated PGE2 but not IL-6 production. These results reveal that human AECs employ unique receptor-specific signaling mechanisms with CRAC channels as a signaling nexus to regulate release of opposing immunomodulatory mediators. Collectively, our results identify P2Y2 receptors, CRAC channels, and P2X receptors as potential intervention targets for airway diseases.


Assuntos
Dinoprostona/metabolismo , Inflamação/imunologia , Interleucina-6/metabolismo , Mucosa Respiratória/metabolismo , Trifosfato de Adenosina/farmacocinética , Alarminas/metabolismo , Canais de Cálcio Ativados pela Liberação de Cálcio/metabolismo , Células Cultivadas , Humanos , Imunomodulação , Interleucina-6/genética , Fatores de Transcrição NFATC/metabolismo , Fosfolipases A2/metabolismo , Receptores Purinérgicos P2X/metabolismo , Mucosa Respiratória/patologia , Transdução de Sinais , Nucleotídeos de Uracila/metabolismo
14.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360939

RESUMO

Air pollution-related particulate matter (PM) exposure reportedly enhances allergic airway inflammation. Some studies have shown an association between PM exposure and a risk for allergic rhinitis (AR). However, the effect of PM for AR is not fully understood. An AR mouse model was developed by intranasal administration of 100 µg/mouse PM with a less than or equal to 2.5 µm in aerodynamic diameter (PM2.5) solution, and then by intraperitoneal injection of ovalbumin (OVA) with alum and intranasal challenging with 10 mg/mL OVA. The effects of PM2.5 on oxidative stress and inflammatory response via the Nrf2/NF-κB signaling pathway in mice with or without AR indicating by histological, serum, and protein analyses were examined. PM2.5 administration enhanced allergic inflammatory cell expression in the nasal mucosa through increasing the expression of inflammatory cytokine and reducing the release of Treg cytokine in OVA-induced AR mice, although PM2.5 exposure itself induced neither allergic responses nor damage to nasal and lung tissues. Notably, repeated OVA-immunization markedly impaired the nasal mucosa in the septum region. Moreover, AR with PM2.5 exposure reinforced this impairment in OVA-induced AR mice. Long-term PM2.5 exposure strengthened allergic reactions by inducing the oxidative through malondialdehyde production. The present study also provided evidence, for the first time, that activity of the Nrf2 signaling pathway is inhibited in PM2.5 exposed AR mice. Furthermore, PM2.5 exposure increased the histopathological changes of nasal and lung tissues and related the inflammatory cytokine, and clearly enhanced PM2.5 phagocytosis by alveolar macrophages via activating the NF-κB signaling pathway. These obtained results suggest that AR patients may experience exacerbation of allergic responses in areas with prolonged PM2.5 exposure.


Assuntos
Poluição do Ar/efeitos adversos , Inflamação/imunologia , Estresse Oxidativo/efeitos dos fármacos , Material Particulado/toxicidade , Rinite Alérgica/imunologia , Animais , Citocinas/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fator 2 Relacionado a NF-E2/imunologia , NF-kappa B/imunologia , Ovalbumina/imunologia
15.
Lancet Neurol ; 20(9): 729-738, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34418400

RESUMO

BACKGROUND: Tolebrutinib is an oral, CNS-penetrant, irreversible inhibitor of Bruton's tyrosine kinase, an enzyme expressed in B lymphocytes and myeloid cells including microglia, which are major drivers of inflammation in multiple sclerosis. We aimed to determine the dose-response relationship between tolebrutinib and the reduction in new active brain MRI lesions in patients with relapsing multiple sclerosis. METHODS: We did a 16-week, phase 2b, randomised, double-blind, placebo-controlled, crossover, dose-finding trial at 40 centres (academic sites, specialty clinics, and general neurology centres) in ten countries in Europe and North America. Eligible participants were adults aged 18-55 years with diagnosed relapsing multiple sclerosis (either relapsing-remitting or relapsing secondary progressive multiple sclerosis), and one or more of the following criteria: at least one relapse within the previous year, at least two relapses within the previous 2 years, or at least one active gadolinium-enhancing brain lesion in the 6 months before screening. Exclusion criteria included a diagnosis of primary progressive multiple sclerosis or a diagnosis of secondary progressive multiple sclerosis without relapse. We used a two-step randomisation process to randomly assign eligible participants (1:1) to two cohorts, then further randomly assign participants in each cohort (1:1:1:1) to four tolebrutinib dose groups (5, 15, 30, and 60 mg administered once daily as an oral tablet). Cohort 1 received tolebrutinib for 12 weeks, then matched placebo (ie, identical looking tablets) for 4 weeks; cohort 2 received 4 weeks of placebo followed by 12 weeks of tolebrutinib. Participants and investigators were masked for dose and tolebrutinib-placebo administration sequence; investigators, study team members, and study participants did not have access to unmasked data. MRI scans were done at screening and every 4 weeks over 16 weeks. The primary efficacy endpoint was the number of new gadolinium-enhancing lesions detected on the scan done after 12 weeks of tolebrutinib treatment (assessed at week 12 for cohort 1 and week 16 for cohort 2), relative to the scan done 4 weeks previously, and compared with the lesions accumulated during 4 weeks of placebo run-in period in cohort 2. Efficacy data were analysed in a modified intention-to-treat population, using a two-step multiple comparison procedure with modelling analysis. Safety was assessed for all participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT03889639), EudraCT (2018-003927-12), and WHO (U1111-1220-0572), and has been completed. FINDINGS: Between May 14, 2019, and Jan 2, 2020, we enrolled and randomly assigned 130 participants to tolebrutinib: 33 to 5 mg, 32 to 15 mg, 33 to 30 mg, and 32 to 60 mg. 129 (99%) completed the treatment regimen and 126 were included in the primary analysis. At treatment week 12, there was a dose-dependent reduction in the number of new gadolinium-enhancing lesions (mean [SD] lesions per patient: placebo, 1·03 [2·50]; 5 mg, 1·39 [3·20]; 15 mg, 0·77 [1·48]; 30 mg, 0·76 [3·31]; 60 mg, 0·13 [0·43]; p=0·03). One serious adverse event was reported (one patient in the 60 mg group was admitted to hospital because of a multiple sclerosis relapse). The most common non-serious adverse event during tolebrutinib treatment was headache (in one [3%] of 33 in the 5 mg group; three [9%] of 32 in the 15 mg group; one [3%] of 33 in the 30 mg group; and four [13%] of 32 in the 60 mg group). No safety-related discontinuations or treatment-related deaths occurred. INTERPRETATION: 12 weeks of tolebrutinib treatment led to a dose-dependent reduction in new gadolinium-enhancing lesions, the 60 mg dose being the most efficacious, and the drug was well tolerated. Reduction of acute inflammation, combined with the potential to modulate the immune response within the CNS, provides a scientific rationale to pursue phase 3 clinical trials of tolebrutinib in patients with relapsing and progressive forms of multiple sclerosis. FUNDING: Sanofi.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Sistema Nervoso Central/efeitos dos fármacos , Inflamação/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde , Inibidores de Proteínas Quinases/farmacologia , Adulto , Sistema Nervoso Central/diagnóstico por imagem , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/patologia , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Inflamação/diagnóstico por imagem , Inflamação/imunologia , Inflamação/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Recidiva , Adulto Jovem
16.
Nat Immunol ; 22(9): 1152-1162, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34385712

RESUMO

The transcription factor TCF-1 is essential for the development and function of regulatory T (Treg) cells; however, its function is poorly understood. Here, we show that TCF-1 primarily suppresses transcription of genes that are co-bound by Foxp3. Single-cell RNA-sequencing analysis identified effector memory T cells and central memory Treg cells with differential expression of Klf2 and memory and activation markers. TCF-1 deficiency did not change the core Treg cell transcriptional signature, but promoted alternative signaling pathways whereby Treg cells became activated and gained gut-homing properties and characteristics of the TH17 subset of helper T cells. TCF-1-deficient Treg cells strongly suppressed T cell proliferation and cytotoxicity, but were compromised in controlling CD4+ T cell polarization and inflammation. In mice with polyposis, Treg cell-specific TCF-1 deficiency promoted tumor growth. Consistently, tumor-infiltrating Treg cells of patients with colorectal cancer showed lower TCF-1 expression and increased TH17 expression signatures compared to adjacent normal tissue and circulating T cells. Thus, Treg cell-specific TCF-1 expression differentially regulates TH17-mediated inflammation and T cell cytotoxicity, and can determine colorectal cancer outcome.


Assuntos
Neoplasias do Colo/patologia , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/imunologia , Animais , Proliferação de Células/fisiologia , Fatores de Transcrição Forkhead/imunologia , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Fator 1-alfa Nuclear de Hepatócito/genética , Memória Imunológica/imunologia , Inflamação/imunologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Transcrição Genética/genética , Proteínas Supressoras de Tumor/metabolismo
17.
Int J Mol Sci ; 22(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34360541

RESUMO

Photodamage-induced and viral keratitis could benefit from treatment with novel nonsteroid anti-inflammatory agents. Therefore, we determined whether human corneal epithelial cells (HCECs) express members of the endocannabinoid system (ECS), and examined how the endocannabinoid anandamide (AEA, N-arachidonoyl ethanolamine) influences the Toll-like receptor 3 (TLR3) agonism- or UVB irradiation-induced inflammatory response of these cells. Other than confirming the presence of cannabinoid receptors, we show that endocannabinoid synthesizing and catabolizing enzymes are also expressed in HCECs in vitro, as well as in the epithelial layer of the human cornea in situ, proving that they are one possible source of endocannabinoids. p(I:C) and UVB irradiation was effective in promoting the transcription and secretion of inflammatory cytokines. Surprisingly, when applied alone in 100 nM and 10 µM, AEA also resulted in increased pro-inflammatory cytokine production. Importantly, AEA further increased levels of these cytokines in the UVB model, whereas its lower concentration partially prevented the transcriptional effect of p(I:C), while not decreasing the p(I:C)-induced cytokine release. HCECs express the enzymatic machinery required to produce endocannabinoids both in vitro and in situ. Moreover, our data show that, despite earlier reports about the anti-inflammatory potential of AEA in murine cornea, its effects on the immune phenotype of human corneal epithelium may be more complex and context dependent.


Assuntos
Anti-Inflamatórios/farmacologia , Ácidos Araquidônicos/farmacologia , Endocanabinoides/farmacologia , Epitélio Corneano/imunologia , Inflamação/imunologia , Alcamidas Poli-Insaturadas/farmacologia , Receptor 3 Toll-Like/agonistas , Raios Ultravioleta , Bloqueadores dos Canais de Cálcio/farmacologia , Epitélio Corneano/efeitos dos fármacos , Epitélio Corneano/metabolismo , Epitélio Corneano/efeitos da radiação , Regulação da Expressão Gênica , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/radioterapia
18.
Biomed Res Int ; 2021: 9987931, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34423043

RESUMO

Objective: Respiratory failure is the leading cause of mortality in COVID-19 patients, characterized by a generalized disbalance of inflammation. The aim of this study was to investigate the relationship between immune-inflammatory index and mortality in PSI IV-V patients with COVID-19. Methods: We retrospectively reviewed the medical records of COVID-19 patients from Feb. to Apr. 2020 in the Zhongfa Xincheng Branch of Tongji Hospital, Wuhan, China. Patients who presented high severity of COVID-19-related pneumonia were enrolled for further analysis according to the Pneumonia Severity Index (PSI) tool. Results: A total of 101 patients diagnosed with COVID-19 were identified at initial research. The survival analysis revealed that mortality of the PSI IV-V cohort was significantly higher than the PSI I-III group (p = 0.0003). The overall mortality in PSI IV-V patients was 32.1% (9/28). The fatal cases of the PSI IV-V group had a higher level of procalcitonin (p = 0.022) and neutrophil-to-lymphocyte ratio (p = 0.033) compared with the survivors. Procalcitonin was the most sensitive predictor of mortality for the severe COVID-19 population with area under receiver operating characteristic curve of 0.78, higher than the neutrophil-to-lymphocyte ratio (0.75) and total lymphocyte (0.68) and neutrophil (0.67) counts. Conclusion: Procalcitonin and neutrophil-to-lymphocyte ratio may potentially be effective predictors for mortality in PSI IV-V patients with COVID-19. Increased procalcitonin and neutrophil-to-lymphocyte ratio were associated with greater risk of mortality.


Assuntos
COVID-19/imunologia , COVID-19/fisiopatologia , Pandemias , SARS-CoV-2 , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , COVID-19/mortalidade , China/epidemiologia , Estudos de Coortes , Feminino , Humanos , Inflamação/imunologia , Inflamação/fisiopatologia , Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Pneumonia Viral/imunologia , Pneumonia Viral/mortalidade , Pneumonia Viral/fisiopatologia , Pró-Calcitonina/sangue , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Análise de Sobrevida
19.
Life Sci ; 283: 119871, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34352260

RESUMO

Non-communicable, chronic respiratory diseases (CRDs) affect millions of individuals worldwide. The course of these CRDs (asthma, chronic obstructive pulmonary disease, and cystic fibrosis) are often punctuated by microbial infections that may result in hospitalization and are associated with increased risk of morbidity and mortality, as well as reduced quality of life. Interleukin-13 (IL-13) is a key protein that regulates airway inflammation and mucus hypersecretion. There has been much interest in IL-13 from the last two decades. This cytokine is believed to play a decisive role in the exacerbation of inflammation during the course of viral infections, especially, in those with pre-existing CRDs. Here, we discuss the common viral infections in CRDs, as well as the potential role that IL-13 plays in the virus-induced disease pathogenesis of CRDs. We also discuss, in detail, the immune-modulation potential of IL-13 that could be translated to in-depth studies to develop IL-13-based therapeutic entities.


Assuntos
Influenza Humana/imunologia , Interleucina-13/imunologia , Pneumopatias/imunologia , Doença Crônica , Humanos , Inflamação/imunologia , Inflamação/patologia , Influenza Humana/patologia , Pneumopatias/patologia , Muco/imunologia
20.
Nat Rev Rheumatol ; 17(9): 550-564, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34345021

RESUMO

Interactions between lymphocytes and stromal cells have an important role in immune cell development and responses. During inflammation, stromal cells contribute to inflammation, from induction to chronicity or resolution, through direct cell interactions and through the secretion of pro-inflammatory and anti-inflammatory mediators. Stromal cells are imprinted with tissue-specific phenotypes and contribute to site-specific lymphocyte recruitment. During chronic inflammation, the modified pro-inflammatory microenvironment leads to changes in the stromal cells, which acquire a pathogenic phenotype. At the site of inflammation, infiltrating B cells and T cells interact with stromal cells. These interactions induce a plasma cell-like phenotype in B cells and T cells, associated with secretion of immunoglobulins and inflammatory cytokines, respectively. B cells and T cells also influence the stromal cells, inducing cell proliferation, molecular changes and cytokine production. This positive feedback loop contributes to disease chronicity. This Review describes the importance of these cell interactions in chronic inflammation, with a focus on human disease, using three selected autoimmune and inflammatory diseases: rheumatoid arthritis, psoriatic arthritis (and psoriasis) and systemic lupus erythematosus. Understanding the importance and disease specificity of these interactions could provide new therapeutic options.


Assuntos
Doenças Autoimunes/patologia , Inflamação/patologia , Linfócitos/patologia , Doenças Reumáticas/patologia , Células Estromais/patologia , Animais , Doenças Autoimunes/imunologia , Humanos , Inflamação/imunologia , Doenças Reumáticas/imunologia
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