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1.
Front Immunol ; 12: 720192, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34456928

RESUMO

COVID-19 might lead to multi-organ failure and, in some cases, to death. The COVID-19 severity is associated with a "cytokine storm." Danger-associated molecular patterns (DAMPs) are proinflammatory molecules that can activate pattern recognition receptors, such as toll-like receptors (TLRs). DAMPs and TLRs have not received much attention in COVID-19 but can explain some of the gender-, weight- and age-dependent effects. In females and males, TLRs are differentially expressed, likely contributing to higher COVID-19 severity in males. DAMPs and cytokines associated with COVID-19 mortality are elevated in obese and elderly individuals, which might explain the higher risk for severer COVID-19 in these groups. Adenosine signaling inhibits the TLR/NF-κB pathway and, through this, decreases inflammation and DAMPs' effects. As vaccines will not be effective in all susceptible individuals and as new vaccine-resistant SARS-CoV-2 mutants might develop, it remains mandatory to find means to dampen COVID-19 disease severity, especially in high-risk groups. We propose that the regulation of DAMPs via adenosine signaling enhancement might be an effective way to lower the severity of COVID-19 and prevent multiple organ failure in the absence of severe side effects.


Assuntos
Alarminas/imunologia , COVID-19/fisiopatologia , Mediadores da Inflamação/imunologia , Adenosina/metabolismo , Alarminas/antagonistas & inibidores , Animais , COVID-19/complicações , COVID-19/imunologia , COVID-19/terapia , Humanos , Inflamação/prevenção & controle , Mediadores da Inflamação/antagonistas & inibidores , Insuficiência de Múltiplos Órgãos/etiologia , Insuficiência de Múltiplos Órgãos/prevenção & controle , Gravidade do Paciente , Transdução de Sinais , Receptores Toll-Like/antagonistas & inibidores , Receptores Toll-Like/imunologia
2.
PLoS One ; 16(7): e0254374, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34293006

RESUMO

While establishing worldwide collective immunity with anti SARS-CoV-2 vaccines, COVID-19 remains a major health issue with dramatic ensuing economic consequences. In the transition, repurposing existing drugs remains the fastest cost-effective approach to alleviate the burden on health services, most particularly by reducing the incidence of the acute respiratory distress syndrome associated with severe COVID-19. We undertook a computational repurposing approach to identify candidate therapeutic drugs to control progression towards severe airways inflammation during COVID-19. Molecular profiling data were obtained from public sources regarding SARS-CoV-2 infected epithelial or endothelial cells, immune dysregulations associated with severe COVID-19 and lung inflammation induced by other respiratory viruses. From these data, we generated a protein-protein interactome modeling the evolution of lung inflammation during COVID-19 from inception to an established cytokine release syndrome. This predictive model assembling severe COVID-19-related proteins supports a role for known contributors to the cytokine storm such as IL1ß, IL6, TNFα, JAK2, but also less prominent actors such as IL17, IL23 and C5a. Importantly our analysis points out to alarmins such as TSLP, IL33, members of the S100 family and their receptors (ST2, RAGE) as targets of major therapeutic interest. By evaluating the network-based distances between severe COVID-19-related proteins and known drug targets, network computing identified drugs which could be repurposed to prevent or slow down progression towards severe airways inflammation. This analysis confirmed the interest of dexamethasone, JAK2 inhibitors, estrogens and further identified various drugs either available or in development interacting with the aforementioned targets. We most particularly recommend considering various inhibitors of alarmins or their receptors, currently receiving little attention in this indication, as candidate treatments for severe COVID-19.


Assuntos
Alarminas/imunologia , Antivirais/farmacologia , COVID-19/complicações , Reposicionamento de Medicamentos , Pneumonia/complicações , Pneumonia/tratamento farmacológico , Antivirais/imunologia , Antivirais/uso terapêutico , Humanos , Pneumonia/imunologia
3.
Front Immunol ; 12: 653110, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248940

RESUMO

To characterize transcriptomic changes in endothelial cells (ECs) infected by coronaviruses, and stimulated by DAMPs, the expressions of 1311 innate immune regulatomic genes (IGs) were examined in 28 EC microarray datasets with 7 monocyte datasets as controls. We made the following findings: The majority of IGs are upregulated in the first 12 hours post-infection (PI), and maintained until 48 hours PI in human microvascular EC infected by middle east respiratory syndrome-coronavirus (MERS-CoV) (an EC model for COVID-19). The expressions of IGs are modulated in 21 human EC transcriptomic datasets by various PAMPs/DAMPs, including LPS, LPC, shear stress, hyperlipidemia and oxLDL. Upregulation of many IGs such as nucleic acid sensors are shared between ECs infected by MERS-CoV and those stimulated by PAMPs and DAMPs. Human heart EC and mouse aortic EC express all four types of coronavirus receptors such as ANPEP, CEACAM1, ACE2, DPP4 and virus entry facilitator TMPRSS2 (heart EC); most of coronavirus replication-transcription protein complexes are expressed in HMEC, which contribute to viremia, thromboembolism, and cardiovascular comorbidities of COVID-19. ECs have novel trained immunity (TI), in which subsequent inflammation is enhanced. Upregulated proinflammatory cytokines such as TNFα, IL6, CSF1 and CSF3 and TI marker IL-32 as well as TI metabolic enzymes and epigenetic enzymes indicate TI function in HMEC infected by MERS-CoV, which may drive cytokine storms. Upregulated CSF1 and CSF3 demonstrate a novel function of ECs in promoting myelopoiesis. Mechanistically, the ER stress and ROS, together with decreased mitochondrial OXPHOS complexes, facilitate a proinflammatory response and TI. Additionally, an increase of the regulators of mitotic catastrophe cell death, apoptosis, ferroptosis, inflammasomes-driven pyroptosis in ECs infected with MERS-CoV and the upregulation of pro-thrombogenic factors increase thromboembolism potential. Finally, NRF2-suppressed ROS regulate innate immune responses, TI, thrombosis, EC inflammation and death. These transcriptomic results provide novel insights on the roles of ECs in coronavirus infections such as COVID-19, cardiovascular diseases (CVD), inflammation, transplantation, autoimmune disease and cancers.


Assuntos
Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Células Endoteliais/fisiologia , Inflamação/imunologia , Coronavírus da Síndrome Respiratória do Oriente Médio/fisiologia , Fator 2 Relacionado a NF-E2/metabolismo , SARS-CoV-2/fisiologia , Alarminas/imunologia , Animais , Conjuntos de Dados como Assunto , Células Endoteliais/virologia , Perfilação da Expressão Gênica , Humanos , Imunidade Inata , Imunização , Camundongos , Mielopoese , Estresse Oxidativo , Tromboembolia
4.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299310

RESUMO

Oxidative stress is a major contributor to the pathogenesis of various inflammatory diseases. Accumulating evidence has shown that oxidative stress is characterized by the overproduction of reactive oxygen species (ROS). Previous reviews have highlighted inflammatory signaling pathways, biomarkers, molecular targets, and pathogenetic functions mediated by oxidative stress in various diseases. The inflammatory signaling cascades are initiated through the recognition of host cell-derived damage associated molecular patterns (DAMPs) and microorganism-derived pathogen associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs). In this review, the effects of PRRs from the Toll-like (TLRs), the retinoic acid-induced gene I (RIG-I)-like receptors (RLRs) and the NOD-like (NLRs) families, and the activation of these signaling pathways in regulating the production of ROS and/or oxidative stress are summarized. Furthermore, important directions for future studies, especially for pathogen-induced signaling pathways through oxidative stress are also reviewed. The present review will highlight potential therapeutic strategies relevant to inflammatory diseases based on the correlations between ROS regulation and PRRs-mediated signaling pathways.


Assuntos
Inflamação/metabolismo , Receptores de Reconhecimento de Padrão/metabolismo , Alarminas/genética , Alarminas/imunologia , Alarminas/metabolismo , Animais , Autofagia , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/terapia , Proteína DEAD-box 58/genética , Proteína DEAD-box 58/imunologia , Proteína DEAD-box 58/metabolismo , Interações entre Hospedeiro e Microrganismos , Humanos , Inflamassomos/genética , Inflamassomos/imunologia , Inflamassomos/metabolismo , Inflamação/genética , Inflamação/imunologia , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/terapia , Modelos Biológicos , Proteínas NLR/genética , Proteínas NLR/imunologia , Proteínas NLR/metabolismo , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/terapia , Estresse Oxidativo , Padrões Moleculares Associados a Patógenos/imunologia , Padrões Moleculares Associados a Patógenos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Reconhecimento de Padrão/genética , Receptores de Reconhecimento de Padrão/imunologia , Transdução de Sinais , Receptores Toll-Like/genética , Receptores Toll-Like/imunologia , Receptores Toll-Like/metabolismo , Ativação Transcricional
5.
Genes Immun ; 22(3): 141-160, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34140652

RESUMO

When surveying the current literature on COVID-19, the "cytokine storm" is considered to be pathogenetically involved in its severe outcomes such as acute respiratory distress syndrome, systemic inflammatory response syndrome, and eventually multiple organ failure. In this review, the similar role of DAMPs is addressed, that is, of those molecules, which operate upstream of the inflammatory pathway by activating those cells, which ultimately release the cytokines. Given the still limited reports on their role in COVID-19, the emerging topic is extended to respiratory viral infections with focus on influenza. At first, a brief introduction is given on the function of various classes of activating DAMPs and counterbalancing suppressing DAMPs (SAMPs) in initiating controlled inflammation-promoting and inflammation-resolving defense responses upon infectious and sterile insults. It is stressed that the excessive emission of DAMPs upon severe injury uncovers their fateful property in triggering dysregulated life-threatening hyperinflammatory responses. Such a scenario may happen when the viral load is too high, for example, in the respiratory tract, "forcing" many virus-infected host cells to decide to commit "suicidal" regulated cell death (e.g., necroptosis, pyroptosis) associated with release of large amounts of DAMPs: an important topic of this review. Ironically, although the aim of this "suicidal" cell death is to save and restore organismal homeostasis, the intrinsic release of excessive amounts of DAMPs leads to those dysregulated hyperinflammatory responses-as typically involved in the pathogenesis of acute respiratory distress syndrome and systemic inflammatory response syndrome in respiratory viral infections. Consequently, as briefly outlined in this review, these molecules can be considered valuable diagnostic and prognostic biomarkers to monitor and evaluate the course of the viral disorder, in particular, to grasp the eventual transition precociously from a controlled defense response as observed in mild/moderate cases to a dysregulated life-threatening hyperinflammatory response as seen, for example, in severe/fatal COVID-19. Moreover, the pathogenetic involvement of these molecules qualifies them as relevant future therapeutic targets to prevent severe/ fatal outcomes. Finally, a theory is presented proposing that the superimposition of coronavirus-induced DAMPs with non-virus-induced DAMPs from other origins such as air pollution or high age may contribute to severe and fatal courses of coronavirus pneumonia.


Assuntos
Alarminas/imunologia , COVID-19/imunologia , Síndrome da Liberação de Citocina/imunologia , Síndrome do Desconforto Respiratório/imunologia , SARS-CoV-2/imunologia , Viroses/imunologia , Alarminas/metabolismo , COVID-19/metabolismo , COVID-19/virologia , Síndrome da Liberação de Citocina/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Modelos Imunológicos , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/metabolismo , SARS-CoV-2/fisiologia , Viroses/complicações , Viroses/metabolismo
6.
Transfusion ; 61(7): 2169-2178, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34181769

RESUMO

BACKGROUND: Despite the significant adverse clinical consequences of RBC alloimmunization, our understanding of the signals that induce immune responses to transfused RBCs remains incomplete. Though RBC storage has been shown to enhance alloimmunization in the hen egg lysozyme, ovalbumin, and human Duffy (HOD) RBC alloantigen mouse model, the molecular signals leading to immune activation in this system remain unclear. Given that the nonclassical major histocompatibility complex (MHC) Class I molecule CD1D can bind to multiple different lysophospholipids and direct immune activation, we hypothesized that storage of RBCs increases lysophospholipids known to bind CD1D, and further that recipient CD1D recognition of these altered lipids mediates storage-induced alloimmunization responses. STUDY DESIGN AND METHODS: We used a mass spectrometry-based approach to analyze the changes in lysophospholipids that are induced during storage of mouse RBCs. CD1D knockout (CD1D-KO) and wild-type (WT) control mice were transfused with stored HOD RBCs to measure the impact of CD1D deficiency on RBC alloimmunization. RESULTS: RBC storage results in alterations in multiple lysophospholipid species known to bind to CD1D and activate the immune system. Prior to transfusion, CD1D-deficient mice had lower baseline levels of polyclonal immunoglobulin (IgG) relative to WT mice. In response to stored RBC transfusion, CD1D-deficient mice generated similar levels of anti-HOD IgM and anti-HOD IgG. CONCLUSION: Although storage of RBCs leads to alteration of several lysophospholipids known to be capable of binding CD1D, storage-induced RBC alloimmunization responses are not impacted by recipient CD1D deficiency.


Assuntos
Antígenos CD1d/imunologia , Preservação de Sangue , Transfusão de Sangue , Eritrócitos/imunologia , Isoanticorpos/biossíntese , Isoantígenos/imunologia , Lisofosfolipídeos/sangue , Reação Transfusional/imunologia , Alarminas/sangue , Alarminas/imunologia , Animais , Especificidade de Anticorpos , Antígenos CD1d/genética , Antígenos CD1d/metabolismo , Sistema do Grupo Sanguíneo Duffy/genética , Sistema do Grupo Sanguíneo Duffy/imunologia , Feminino , Imunização , Imunoglobulina G/biossíntese , Imunoglobulina G/imunologia , Imunoglobulina M/biossíntese , Imunoglobulina M/imunologia , Isoanticorpos/imunologia , Lisofosfolipídeos/metabolismo , Masculino , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Camundongos Transgênicos , Muramidase/imunologia , Ovalbumina/imunologia , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/imunologia
7.
Ann Med ; 53(1): 777-785, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34042528

RESUMO

The coronavirus SARS-CoV-2, the aetiological agent of COVID-19 disease, is representing a worldwide threat for the medical community and the society at large so that it is being defined as "the twenty-first-century disease". Often associated with a severe cytokine storm, leading to more severe cases, it is mandatory to block such occurrence early in the disease course, to prevent the patients from having more severe, sometimes fatal, outcomes. In this framework, early detection of "danger signals", possibly represented by alarmins, can represent one of the most promising strategies to effectively tailor the disease and to better understand the underlying mechanisms eventually leading to death or severe consequences. In light of such considerations, the present article aims at evaluating the role of alarmins in patients affected by COVID-19 disease and the relationship of such compounds with the most commonly reported comorbidities. The conducted researches demonstrated yet poor literature on this specific topic, however preliminarily confirming a role for danger signals in the amplification of the inflammatory reaction associated with SARS-CoV-2 infection. As such, a number of chronic conditions, including metabolic syndrome, gastrointestinal and respiratory diseases, in turn, associated with higher levels of alarmins, both foster the infection and predispose to a worse prognosis. According to these preliminary data, prompt detection of high levels of alarmins in patients with COVID-19 and co-morbidities could suggest an immediate intense anti-inflammatory treatment.Key messageAlarmins have a role in the amplification of the inflammatory reaction associated with SARS-CoV-2 infectiona prompt detection of high levels of alarmins in patients with COVID-19 could suggest an immediate intense anti-inflammatory treatment.


Assuntos
Alarminas/imunologia , COVID-19/imunologia , SARS-CoV-2/imunologia , Animais , COVID-19/virologia , Comorbidade , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/virologia , Humanos , Inflamação/imunologia , Inflamação/virologia , Prognóstico , Índice de Gravidade de Doença
8.
Nat Commun ; 12(1): 3229, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-34050181

RESUMO

Radiotherapy (RT)-induced tumoricidal immunity is severely limited when tumors are well-established. Here, we report that depleting SIRPα on intratumoral macrophages augments efficacy of RT to eliminate otherwise large, treatment-resistant colorectal (MC38) and pancreatic (Pan02 and KPC) tumors, inducing complete abscopal remission and long-lasting humoral and cellular immunity that prevent recurrence. SIRPα-deficient macrophages activated by irradiated tumor-released DAMPs exhibit robust efficacy and orchestrate an anti-tumor response that controls late-stage tumors. Upon RT-mediated activation, intratumoral SIRPα-deficient macrophages acquire potent proinflammatory features and conduct immunogenic antigen presentation that confer a tumoricidal microenvironment highly infiltrated by tumor-specific cytotoxic T cells, NK cells and inflammatory neutrophils, but with limited immunosuppressive regulatory T cells, myeloid derived suppressor cells and post-radiation wound-healing. The results demonstrate that SIRPα is a master regulator underlying tumor resistance to RT and provide proof-of-principle for SIRPα-deficient macrophage-based therapies to treat a broad spectrum of cancers, including those at advanced stages with low immunogenicity and metastases.


Assuntos
Neoplasias/terapia , Tolerância a Radiação/imunologia , Receptores Imunológicos/metabolismo , Linfócitos T Citotóxicos/imunologia , Macrófagos Associados a Tumor/imunologia , Alarminas/imunologia , Alarminas/metabolismo , Alarminas/efeitos da radiação , Animais , Apresentação do Antígeno , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Imunoterapia/métodos , Masculino , Camundongos , Camundongos Knockout , Neoplasias/imunologia , Neoplasias/patologia , Estudo de Prova de Conceito , Receptores Imunológicos/genética , Microambiente Tumoral/imunologia , Microambiente Tumoral/efeitos da radiação , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/transplante
9.
Immunity ; 54(5): 1083-1095.e7, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33891889

RESUMO

Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening post-infectious complication occurring unpredictably weeks after mild or asymptomatic SARS-CoV-2 infection. We profiled MIS-C, adult COVID-19, and healthy pediatric and adult individuals using single-cell RNA sequencing, flow cytometry, antigen receptor repertoire analysis, and unbiased serum proteomics, which collectively identified a signature in MIS-C patients that correlated with disease severity. Despite having no evidence of active infection, MIS-C patients had elevated S100A-family alarmins and decreased antigen presentation signatures, indicative of myeloid dysfunction. MIS-C patients showed elevated expression of cytotoxicity genes in NK and CD8+ T cells and expansion of specific IgG-expressing plasmablasts. Clinically severe MIS-C patients displayed skewed memory T cell TCR repertoires and autoimmunity characterized by endothelium-reactive IgG. The alarmin, cytotoxicity, TCR repertoire, and plasmablast signatures we defined have potential for application in the clinic to better diagnose and potentially predict disease severity early in the course of MIS-C.


Assuntos
COVID-19/imunologia , COVID-19/patologia , SARS-CoV-2/imunologia , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Síndrome de Resposta Inflamatória Sistêmica/patologia , Adolescente , Alarminas/imunologia , Autoanticorpos/imunologia , Linfócitos T CD8-Positivos/imunologia , Criança , Pré-Escolar , Citotoxicidade Imunológica/genética , Endotélio/imunologia , Endotélio/patologia , Humanos , Células Matadoras Naturais/imunologia , Células Mieloides/imunologia , Plasmócitos/imunologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Índice de Gravidade de Doença
10.
Molecules ; 26(6)2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33803783

RESUMO

Inflammasomes are immune cytosolic oligomers involved in the initiation and progression of multiple pathologies and diseases. The tight regulation of these immune sensors is necessary to control an optimal inflammatory response and recover organism homeostasis. Prolonged activation of inflammasomes result in the development of chronic inflammatory diseases, and the use of small drug-like inhibitory molecules are emerging as promising anti-inflammatory therapies. Different aspects have to be taken in consideration when designing inflammasome inhibitors. This review summarizes the different techniques that can be used to study the mechanism of action of potential inflammasome inhibitory molecules.


Assuntos
Inflamassomos/efeitos dos fármacos , Alarminas/imunologia , Alarminas/metabolismo , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Simulação por Computador , Citocinas/metabolismo , Desenho de Fármacos , Humanos , Imunidade Inata , Técnicas Imunológicas , Inflamassomos/imunologia , Inflamassomos/metabolismo , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Modelos Biológicos , Padrões Moleculares Associados a Patógenos/imunologia , Padrões Moleculares Associados a Patógenos/metabolismo , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade
11.
Front Immunol ; 12: 621627, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33708213

RESUMO

Sepsis is a life-threatening clinical syndrome that results from an overwhelming immune response to infection. During sepsis, immune cells are activated by sensing pathogen-associated molecular patterns and damage-associated molecular patterns (DAMPs) through pattern recognizing receptors (PRRs). Regulation of the immune response is essential to preventing or managing sepsis. Sialic acid-binding immunoglobulin-type lectin-G (Siglec-G), a CD33 group of Siglec expressed in B-1a cells and other hematopoietic cells, plays an important immunoregulatory role. B-1a cells, a subtype of B lymphocytes, spontaneously produce natural IgM which confers protection against infection. B-1a cells also produce IL-10, GM-CSF, and IL-35 to control inflammation. Sialic acids are present on cell membranes, receptors, and glycoproteins. Siglec-G binds to the sialic acid residues on the B cell receptor (BCR) and controls BCR-mediated signal transduction, thereby maintaining homeostasis of Ca++ influx and NFATc1 expression. Siglec-G inhibits NF-κB activation in B-1a cells and regulates B-1a cell proliferation. In myeloid cells, Siglec-G inhibits DAMP-mediated inflammation by forming a ternary complex with DAMP and CD24. Thus, preserving Siglec-G's function could be a novel therapeutic approach in sepsis. Here, we review the immunoregulatory functions of Siglec-G in B-1a cells and myeloid cells in sepsis. A clear understanding of Siglec-G is important to developing novel therapeutics in treating sepsis.


Assuntos
Linfócitos B/imunologia , Receptores de Antígenos de Linfócitos B/metabolismo , Sepse/imunologia , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/metabolismo , Alarminas/imunologia , Animais , Resistência à Doença , Humanos , Receptores de Antígenos de Linfócitos B/genética , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/genética , Transdução de Sinais
12.
Int J Mol Sci ; 22(3)2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33525345

RESUMO

Chronic inflammation contributes to the development and progression of various tumors. Especially where the inflammation is mediated by cells of the innate immune system, the NLRP3 inflammasome plays an important role, as it senses and responds to a variety of exogenous and endogenous pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). The NLRP3 inflammasome is responsible for the maturation and secretion of the proinflammatory cytokines interleukin-1ß (IL-1ß) and IL-18 and for the induction of a type of inflammatory cell death known as pyroptosis. Overactivation of the NLRP3 inflammasome can be a driver of various diseases. Since leukemia is known to be an inflammation-driven cancer and IL-1ß is produced in elevated levels by leukemic cells, research on NLRP3 in the context of leukemia has increased in recent years. In this review, we summarize the current knowledge on leukemia-promoting inflammation and, in particular, the role of the NLRP3 inflammasome in different types of leukemia. Furthermore, we examine a connection between NLRP3, autophagy and leukemia.


Assuntos
Carcinogênese/imunologia , Inflamassomos/imunologia , Inflamação/imunologia , Leucemia/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Alarminas/genética , Alarminas/imunologia , Animais , Autofagia/genética , Autofagia/imunologia , Carcinogênese/genética , Carcinogênese/patologia , Progressão da Doença , Regulação Leucêmica da Expressão Gênica , Humanos , Imunidade Inata , Inflamassomos/genética , Inflamação/complicações , Inflamação/genética , Inflamação/patologia , Interleucina-18/genética , Interleucina-18/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Leucemia/etiologia , Leucemia/genética , Leucemia/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Padrões Moleculares Associados a Patógenos/imunologia , Padrões Moleculares Associados a Patógenos/metabolismo , Piroptose/genética , Piroptose/imunologia , Transdução de Sinais
13.
Arch Pharm Res ; 44(1): 16-35, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33534121

RESUMO

Inflammasomes are cytosolic pattern recognition receptors that recognize pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) derived from invading pathogens and damaged tissues, respectively. Upon activation, the inflammasome forms a complex containing a receptor protein, an adaptor, and an effector to induce the autocleavage and activation of procaspase-1 ultimately culminating in the maturation and secretion of IL-1ß and IL-18 and pyroptosis. Inflammasome activation plays an important role in host immune responses to pathogen infections and tissue repair in response to cellular damage. The NLRP3 inflammasome is a well-characterized pattern recognition receptor and is well known for its critical role in the regulation of immunity and the development and progression of various inflammatory diseases. In this review, we summarize recent efforts to develop therapeutic applications targeting the NLRP3 inflammasome to cure and prevent chronic inflammatory diseases. This review extensively discusses NLRP3 inflammasome-related diseases and current development of small molecule inhibitors providing beneficial information on the design of therapeutic strategies for NLRP3 inflammasome-related diseases. Additionally, small molecule inhibitors are classified depending on direct or indirect targeting mechanism to describe the current status of the development of pharmacological inhibitors.


Assuntos
Anti-Inflamatórios/farmacologia , Doença Crônica/tratamento farmacológico , Inflamassomos/antagonistas & inibidores , Inflamação/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Alarminas/imunologia , Alarminas/metabolismo , Animais , Anti-Inflamatórios/uso terapêutico , Modelos Animais de Doenças , Humanos , Inflamassomos/imunologia , Inflamassomos/metabolismo , Inflamação/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Padrões Moleculares Associados a Patógenos/imunologia , Padrões Moleculares Associados a Patógenos/metabolismo , Piroptose/efeitos dos fármacos , Piroptose/imunologia
14.
Microbiol Mol Biol Rev ; 85(1)2021 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-33441488

RESUMO

The P2X7 receptor (P2RX7) is an important molecule that functions as a danger sensor, detecting extracellular nucleotides from injured cells and thus signaling an inflammatory program to nearby cells. It is expressed in immune cells and plays important roles in pathogen surveillance and cell-mediated responses to infectious organisms. There is an abundance of literature on the role of P2RX7 in inflammatory diseases and the role of these receptors in host-pathogen interactions. Here, we describe the current knowledge of the role of P2RX7 in the host response to a variety of pathogens, including viruses, bacteria, fungi, protozoa, and helminths. We describe in vitro and in vivo evidence for the critical role these receptors play in mediating and modulating immune responses. Our observations indicate a role for P2X7 signaling in sensing damage-associated molecular patterns released by nearby infected cells to facilitate immunopathology or protection. In this review, we describe how P2RX7 signaling can play critical roles in numerous cells types in response to a diverse array of pathogens in mediating pathogenesis and immunity to infectious agents.


Assuntos
Interações Hospedeiro-Patógeno/imunologia , Receptores Purinérgicos P2X7/imunologia , Transdução de Sinais/imunologia , Alarminas/imunologia , Animais , Bactérias/imunologia , Fungos/imunologia , Helmintos/imunologia , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Inflamação/imunologia , Parasitos/imunologia , Vírus/imunologia
15.
Am J Respir Cell Mol Biol ; 64(5): 547-556, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33332993

RESUMO

Over the last several decades, our understanding of regulated-cell-death (RCD) pathways has increased dramatically. In addition to apoptosis and accidental cell death (primary necrosis), a diverse spectrum of RCD pathways has been delineated. In the lung, airway macrophages are critical for maintaining the functionality of airways via the clearance of inhaled particles, cell debris, and infectious agents. Exposure of these cells to pathogenic organisms or particles can induce a variety of RCD pathways that promote the release of danger signals into the lung. These responses have evolved to trigger the innate and adaptive arms of the immune system and thus offer protection against pathogens; yet they can also contribute to the development of lung injury and pathogenic immune responses. In this review, we discuss recent studies that suggest a critical role for airway-macrophage RCD pathways in promoting the release of pulmonary danger signals in health and disease.


Assuntos
Alarminas/imunologia , Proteínas Reguladoras de Apoptose/imunologia , Lesão Pulmonar/imunologia , Pulmão/imunologia , Macrófagos Alveolares/imunologia , Síndrome do Desconforto Respiratório/imunologia , Imunidade Adaptativa , Alarminas/genética , Animais , Apoptose/genética , Apoptose/imunologia , Proteínas Reguladoras de Apoptose/genética , Citocinas/genética , Citocinas/imunologia , Células Epiteliais/imunologia , Células Epiteliais/patologia , Regulação da Expressão Gênica , Humanos , Imunidade Inata , Pulmão/patologia , Lesão Pulmonar/genética , Lesão Pulmonar/patologia , Macrófagos Alveolares/patologia , Necrose/genética , Necrose/imunologia , Necrose/patologia , Piroptose/genética , Piroptose/imunologia , Síndrome do Desconforto Respiratório/genética , Síndrome do Desconforto Respiratório/patologia , Transdução de Sinais
16.
Neuroimmunomodulation ; 27(2): 80-86, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33341814

RESUMO

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) pandemic has affected millions of people worldwide. The pathophysiology of this virus is not very clearly known, thus, enormous efforts are being made by the scientific community to delineate its evading mechanism. In this review, we have summarized the hyperinflammation and humoral and cell-mediated immune response generated in human body after infection with the SARS-CoV-2 virus. The inflammatory response generated after infection by increased proinflammatory cytokines and chemokines, and complement proteins activation may likely contribute to disease severity. We also discussed the other factors that may affect immunity and could be important comorbidities in the disease severity and outcome.


Assuntos
COVID-19/imunologia , Imunidade Celular/imunologia , Imunidade Humoral/imunologia , Imunidade Inata/imunologia , Inflamação/imunologia , Imunidade Adaptativa/imunologia , Alarminas/imunologia , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Ativação do Complemento/imunologia , Síndrome da Liberação de Citocina/imunologia , Humanos , Células Matadoras Naturais/imunologia , SARS-CoV-2 , Índice de Gravidade de Doença
17.
Front Immunol ; 11: 581445, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33133101

RESUMO

Initially described as Th2 promoter cytokine, more recently, IL-33 has been recognized as an alarmin, mainly in epithelial and endothelial cells. While localized in the nucleus acting as a gene regulator, it can be also released after injury, stress or inflammatory cell death. As proinflammatory signal, IL-33 binds to the surface receptor ST2, which enhances mast cell, Th2, regulatory T cell, and innate lymphoid cell type 2 functions. Besides these Th2 roles, free IL-33 can activate CD8+ T cells during ongoing Th1 immune responses to potentiate its cytotoxic function. Celiac Disease (CD) is a chronic inflammatory disorder characterized by a predominant Th1 response leading to multiple pathways of mucosal damage in the proximal small intestine. By immunofluorescence and western blot analysis of duodenal tissues, we found an increased expression of IL-33 in duodenal mucosa of active CD (ACD) patients. Particularly, locally digested IL-33 releases active 18/21kDa fragments which can contribute to expand the proinflammatory signal. Endothelial (CD31+) and mesenchymal, myofibroblast and pericyte cells from microvascular structures in villi and crypts, showed IL-33 nuclear location; while B cells (CD20+) showed a strong cytoplasmic staining. Both ST2 forms, ST2L and sST2, were also upregulated in duodenal mucosa of CD patients. This was accompanied by increased number of CD8+ST2+ T cells and the expression of T-bet in some ST2+ intraepithelial lymphocytes and lamina propria cells. IL-33 and sST2 mRNA levels correlated with IRF1, an IFN induced factor relevant in responses to viral infections and interferon mediated proinflammatory responses highly represented in duodenal tissues in ACD. These findings highlight the potential contribution of IL-33 and its fragments to exacerbate the proinflammatory circuit and potentiate the cytotoxic activity of CD8+ T cells in CD pathology.


Assuntos
Alarminas/imunologia , Doença Celíaca/imunologia , Inflamação/imunologia , Interleucina-33/imunologia , Intestino Delgado/imunologia , Animais , Linfócitos B/imunologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Citocinas/imunologia , Células HT29 , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1/imunologia , Mucosa Intestinal/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/imunologia , Células Th2/imunologia
18.
Elife ; 92020 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-33216713

RESUMO

The NLRP3 inflammasome is a multi-molecular protein complex that converts inactive cytokine precursors into active forms of IL-1ß and IL-18. The NLRP3 inflammasome is frequently associated with the damaging inflammation of non-communicable disease states and is considered an attractive therapeutic target. However, there is much regarding the mechanism of NLRP3 activation that remains unknown. Chloride efflux is suggested as an important step in NLRP3 activation, but which chloride channels are involved is still unknown. We used chemical, biochemical, and genetic approaches to establish the importance of chloride channels in the regulation of NLRP3 in murine macrophages. Specifically, we identify LRRC8A, an essential component of volume-regulated anion channels (VRAC), as a vital regulator of hypotonicity-induced, but not DAMP-induced, NLRP3 inflammasome activation. Although LRRC8A was dispensable for canonical DAMP-dependent NLRP3 activation, this was still sensitive to chloride channel inhibitors, suggesting there are additional and specific chloride sensing and regulating mechanisms controlling NLRP3.


Assuntos
Alarminas/imunologia , Inflamassomos/imunologia , Inflamação/imunologia , Proteínas de Membrana/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Animais , Canais de Cloreto/genética , Canais de Cloreto/metabolismo , Cloretos/imunologia , Feminino , Humanos , Inflamassomos/genética , Inflamação/genética , Macrófagos/imunologia , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Pressão Osmótica
19.
Int J Mol Sci ; 21(22)2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33228152

RESUMO

The skin represents the first line of defense and innate immune protection against pathogens. Skin normally provides a physical barrier to prevent infection by pathogens; however, wounds, microinjuries, and minor barrier impediments can present open avenues for invasion through the skin. Accordingly, wound repair and protection from invading pathogens are essential processes in successful skin barrier regeneration. To repair and protect wounds, skin promotes the development of a specific and complex immunological microenvironment within and surrounding the disrupted tissue. This immune microenvironment includes both innate and adaptive processes, including immune cell recruitment to the wound and secretion of extracellular factors that can act directly to promote wound closure and wound antimicrobial defense. Recent work has shown that this immune microenvironment also varies according to the specific context of the wound: the microbiome, neuroimmune signaling, environmental effects, and age play roles in altering the innate immune response to wounding. This review will focus on the role of these factors in shaping the cutaneous microenvironment and how this ultimately impacts the immune response to wounding.


Assuntos
Alarminas/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Microbiota/imunologia , Padrões Moleculares Associados a Patógenos/imunologia , Cicatrização/imunologia , Ferimentos não Penetrantes/imunologia , Imunidade Adaptativa , Alarminas/genética , Animais , Plaquetas/imunologia , Plaquetas/microbiologia , Armadilhas Extracelulares , Humanos , Imunidade Inata , Macrófagos/imunologia , Macrófagos/microbiologia , Neutrófilos/imunologia , Neutrófilos/microbiologia , Padrões Moleculares Associados a Patógenos/metabolismo , Regeneração/genética , Regeneração/imunologia , Pele/imunologia , Pele/microbiologia , Pele/patologia , Receptores Toll-Like/genética , Receptores Toll-Like/imunologia , Cicatrização/genética , Ferimentos não Penetrantes/genética , Ferimentos não Penetrantes/microbiologia , Ferimentos não Penetrantes/patologia
20.
Dig Liver Dis ; 52(12): 1383-1389, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33023827

RESUMO

The microbiota-gut-liver-lung axis plays a bidirectional role in the pathophysiology of a number of infectious diseases. During the course of severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and 2 (SARS-CoV-2) infection, this pathway is unbalanced due to intestinal involvement and systemic inflammatory response. Moreover, there is convincing preliminary evidence linking microbiota-gut-liver axis perturbations, proinflammatory status, and endothelial damage in noncommunicable preventable diseases with coronavirus disease 2019 (Covid-19) severity. Intestinal damage due to SARS-CoV-2 infection, systemic inflammation-induced dysfunction, and IL-6-mediated diffuse vascular damage may increase intestinal permeability and precipitate bacterial translocation. The systemic release of damage- and pathogen-associated molecular patterns (e.g. lipopolysaccharides) and consequent immune-activation may in turn auto-fuel vicious cycles of systemic inflammation and tissue damage. Thus, intestinal bacterial translocation may play an additive/synergistic role in the cytokine release syndrome in Covid-19. This review provides evidence on gut-liver axis involvement in Covid-19 as well as insights into the hypothesis that intestinal endotheliitis and permeability changes with bacterial translocation are key pathophysiologic events modulating systemic inflammatory response. Moreover, it presents an overview of readily applicable measures for the modulation of the gut-liver axis and microbiota in clinical practice.


Assuntos
Translocação Bacteriana/imunologia , COVID-19/imunologia , Síndrome da Liberação de Citocina/imunologia , Microbioma Gastrointestinal/imunologia , Mucosa Intestinal/metabolismo , Lipopolissacarídeos/metabolismo , Fígado/metabolismo , Permeabilidade , Alarminas/imunologia , Alarminas/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/metabolismo , Síndrome da Liberação de Citocina/metabolismo , Progressão da Doença , Humanos , Imunidade/imunologia , Inflamação , Interleucina-6/imunologia , Lipopolissacarídeos/imunologia , Fígado/imunologia , Pulmão/imunologia , Pulmão/metabolismo , Microbiota/imunologia , Padrões Moleculares Associados a Patógenos/imunologia , Padrões Moleculares Associados a Patógenos/metabolismo , SARS-CoV-2/metabolismo , Serina Endopeptidases/metabolismo
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