RESUMO
Septic shock is a life-threatening clinical condition characterized by a robust immune inflammatory response to disseminated infection. Little is known about its impact on the transcriptome of distinct human tissues. To address this, we performed RNA sequencing of samples from the prefrontal cortex, hippocampus, heart, lung, kidney and colon of seven individuals who succumbed to sepsis and seven uninfected controls. We identified that the lungs and colon were the most affected organs. While gene activation dominated, strong inhibitory signals were also detected, particularly in the lungs. We found that septic shock is an extremely heterogeneous disease, not only when different individuals are investigated, but also when comparing different tissues of the same patient. However, several pathways, such as respiratory electron transport and other metabolic functions, revealed distinctive alterations, providing evidence that tissue specificity is a hallmark of sepsis. Strikingly, we found evident signals of accelerated ageing in our sepsis population.
RESUMO
Background: Cathelicidins are ancient and well-conserved antimicrobial peptides (AMPs) with intriguing immunomodulatory properties in both infectious and non-infectious inflammatory diseases. In addition to direct antimicrobial activity, cathelicidins also participate in several signaling pathways inducing both pro-inflammatory and anti-inflammatory effects. Acute kidney injury (AKI) is common in critically ill patients and is associated with high mortality and morbidity. Rhabdomyolysis is a major trigger of AKI. Objectives: Here, we investigated the role of cathelicidins in non-infectious Acute kidney Injury (AKI). Method: Using an experimental model of rhabdomyolysis, we induced AKI in wild-type and cathelicidin-related AMP knockout (CRAMP-/-) mice. Results: We previously demonstrated that CRAMP-/- mice, as opposed wild-type mice, are protected from AKI during sepsis induced by cecal ligation and puncture. Conversely, in the current study, we show that CRAMP-/- mice are more susceptible to the rhabdomyolysis model of AKI. A more in-depth investigation of wild-type and CRAMP-/- mice revealed important differences in the levels of several inflammatory mediators. Conclusion: Cathelicidins can induce a varied and even opposing repertoire of immune-inflammatory responses depending on the subjacent disease and the cellular context.
Assuntos
Injúria Renal Aguda/imunologia , Peptídeos Catiônicos Antimicrobianos/metabolismo , Rabdomiólise/complicações , Transdução de Sinais/imunologia , Injúria Renal Aguda/patologia , Animais , Peptídeos Catiônicos Antimicrobianos/genética , Modelos Animais de Doenças , Glicerol/administração & dosagem , Glicerol/toxicidade , Humanos , Inflamação/imunologia , Inflamação/patologia , Injeções Intramusculares , Rim/imunologia , Rim/patologia , Masculino , Camundongos , Camundongos Knockout , Rabdomiólise/induzido quimicamente , Rabdomiólise/imunologia , CatelicidinasRESUMO
Antimicrobial peptides (AMPs) are intriguing molecules, able to directly kill several microorganisms and to regulate multiple aspects of the immune response. Despite the extensive studies on the role of AMPs in the epithelial barrier, placing them as a pivotal line of defense against pathogen invasion, little attention has been directed to their role in the maintenance and modulation of the gut microbiota and, by consequence, of the homeostasis of extra intestinal tissues. Here, we review the recent literature about the microbiome-gut-brain axis, focusing on the role of AMPs in this scenario. We provide a straightforward revision of current data in order to provide an overview of the subject, discussing more in depth some points that, in our opinion, are crucial and have received little attention.
Assuntos
Encéfalo/metabolismo , Microbioma Gastrointestinal/fisiologia , Imunidade Inata/fisiologia , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Animais , Encéfalo/imunologia , Humanos , Absorção Intestinal/fisiologia , Proteínas Citotóxicas Formadoras de Poros/imunologiaRESUMO
The term "neuroinflammation" has been widely used to describe a series of acute or chronic conditions that cause inflammation in the central nervous system (CNS). Neurological damage can be a consequence of direct local injury or, secondary, of systemic or even distant inflammatory processes. In this respect, animal models have been developed to better understand the pathophysiology and, possibly, to evaluate more effective methods of treatment for these disorders. Animal models that promote alterations in blood-brain barrier permeability-the activation of microglia or astrocytes, modifications in neuropeptide expression, oxidative stress, increased apoptosis, release of inflammatory mediators, leukocyte infiltration, and brain edema-are likely to involve neuroinflammation and therefore can serve as useful models for human inflammatory CNS injury. This review describes the major animal models of neuroinflammation triggered by systemic or distant inflammatory processes. We will focus on animal models of acute neurologic damage; experimental models that lead to chronic neuroinflammation will not be addressed here.
Assuntos
Inflamação/etiologia , Inflamação/patologia , Modelos Animais , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/patologia , Animais , Astrócitos/metabolismo , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Humanos , Microglia/metabolismo , Doenças do Sistema Nervoso/tratamento farmacológicoRESUMO
BACKGROUND: Intestinal ischemia reperfusion is a common clinical condition that causes functional impairment. Once tight junctions are damaged, barrier function is compromised, and the intestines become a source for entry of bacterial and inflammatory mediators into the circulation, leading to systemic inflammatory response syndrome, multiple organ failure, and death. It is possible that diazoxide could protect the intestines against ischemia reperfusion. The aim of this study is to determine whether diazoxide can provide protection in a rat model of intestinal ischemia reperfusion. METHODS: A total of 32 adult male specific pathogen-free Wistar rats were randomized into three groups: a control group, n = 6; a saline group, n = 13; and a diazoxide group, n = 13. The saline and diazoxide groups underwent clamping of the superior mesenteric artery for 1 h, with samples in all the groups being collected 12 h later. RESULTS: Intestinal histology showed greater damage in the intestinal ischemia reperfusion groups. mRNA expression of zonula occludens-1 and occludin (tight junction proteins) and interleukin-6 and cyclooxygenase-2 was the highest in the Saline group. The Diazoxide group showed a reduction in aspartate aminotransferase serum levels compared with the other groups. CONCLUSIONS: Increased expression of zonula occludens-1, occludin, and cyclooxygenase-2 suggested a greater regenerative effort because of more severe lesions in the saline group. In addition, increased expression of interleukin-6 in the saline group was suggestive of inflammation, indicating that diazoxide had protective effects in the diazoxide group. Reduced aspartate aminotransferase in the diazoxide group suggested liver protection. Diazoxide protects the intestines and liver from intestinal ischemia reperfusion lesions in rats.
Assuntos
Diazóxido/farmacologia , Isquemia Mesentérica/tratamento farmacológico , Substâncias Protetoras/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Aspartato Aminotransferases/sangue , Ciclo-Oxigenase 2/metabolismo , Diazóxido/uso terapêutico , Modelos Animais de Doenças , Coração/efeitos dos fármacos , Humanos , Interleucina-6/metabolismo , Mucosa Intestinal/irrigação sanguínea , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Artéria Mesentérica Superior/cirurgia , Isquemia Mesentérica/etiologia , Isquemia Mesentérica/patologia , Miocárdio/patologia , Ocludina/metabolismo , Substâncias Protetoras/uso terapêutico , Distribuição Aleatória , Ratos , Ratos Wistar , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/patologia , Organismos Livres de Patógenos Específicos , Junções Íntimas/metabolismo , Resultado do Tratamento , Proteína da Zônula de Oclusão-1/metabolismoRESUMO
Sepsis survivors suffer from additional morbidities, including higher disk of readmissions, nervous system disturbances and cognitive dysfunction, and increased mortality, even several years after the initial episode of sepsis. In many ways, the phenotype of sepsis survivors resembles the phenotype associated with accelerated aging. Since telomere shortening is a hallmark of aging, we investigated whether sepsis also leads to telomere shortening. Male balb/c mice were divided into two groups: the control group received 100 µl of normal saline intraperitoneally; the sepsis group received 15 mg/kg of bacterial lipopolysaccharide i.p. After 48 hours, animals were sacrificed to collect blood, spleen and kidney. The human component of our study utilized blood samples obtained from patients in the Trauma Department and samples collected 7 days later in those patients who developed sepsis. Telomere length was measured by quantitative PCR. Since oxidative stress is a known inducer of telomere shortening, thiobarbituric acid reactive substances and superoxide dismutase (SOD) activity were analyzed in order to evaluate oxidative stress burden. Induction of endotoxemia in mice resulted in significant telomere shortening in spleen and kidney. Blood cells from patients that progressed to sepsis also exhibited a statistically significant reduction of telomere length. Endotoxemia in mice also induced an early-onset increase in oxidative stress markers, but was not associated with a downregulation of telomerase protein expression. We conclude that endotoxemia and sepsis induce telomere shortening in various tissues and hypothesize that this may contribute to the pathogenesis of the delayed pathophysiological events in sepsis survivors.
RESUMO
Sepsis, a leading cause of death worldwide, involves exacerbated proinflammatory responses and inefficient bacterial clearance. Phagocytic cells play a crucial part in the prevention of sepsis by clearing bacteria through host innate receptors. Here, we used a phage display library to identify two peptides in Escherichia coli that interact with host innate receptors. One of these peptides, encoded by the wzxE gene of E. coli K-12, was involved in the transbilayer movement of a trisaccharide-lipid intermediate in the assembly of enterobacterial common antigen. Peptide-receptor interactions induced CD16-mediated inhibitory immunoreceptor tyrosine-based activating motif signaling, blocking the production of ROS and bacterial killing. This CD16-mediated inhibitory signaling was abrogated in a WzxE(-/-) mutant of E. coli K-12, restoring the production of ROS and bacterial killing. Taken together, the two novel CD16 ligands identified negatively regulate bacterial killing and inflammation. Our findings may contribute toward the development of new immunotherapies for E. coli-mediated infectious diseases and inflammation.
Assuntos
Antígenos de Bactérias/imunologia , Infecções por Escherichia coli/imunologia , Proteínas de Escherichia coli/imunologia , Proteínas de Membrana Transportadoras/imunologia , Fagocitose , Receptores de IgG/imunologia , Animais , Escherichia coli , Humanos , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Biblioteca de Peptídeos , Fagócitos/imunologia , Sepse/prevenção & controle , Transdução de SinaisRESUMO
Sepsis, a leading cause of death worldwide, involves proinflammatory responses and inefficient bacterial clearance. Phagocytic cells play a crucial part in the prevention of sepsis by clearing bacteria through host innate receptors. Here we show that the FcRgamma adaptor, an immunoreceptor tyrosine-based activation motif (ITAM)-bearing signal transduction subunit of the Fc receptor family, has a deleterious effect on sepsis. FcRgamma(-/-) mice show increased survival during peritonitis, owing to markedly increased E. coli phagocytosis and killing and to lower production of the proinflammatory cytokine tumor necrosis factor (TNF)-alpha. The FcRgamma-associated receptor that inhibits E. coli phagocytosis is FcgammaRIII (also called CD16), and its absence protects mice from sepsis. FcgammaRIII binds E. coli, and this interaction induces FcRgamma phosphorylation, recruitment of the tyrosine phosphatase SHP-1 and phosphatidylinositide-3 kinase (PI3K) dephosphorylation. Decreased PI3K activity inhibits E. coli phagocytosis and increases TNF-alpha production through Toll-like receptor 4. We identified the phagocytic receptor negatively regulated by FcRgamma on macrophages as the class A scavenger receptor MARCO. E. coli-FcgammaRIII interaction induces the recruitment of SHP-1 to MARCO, thereby inhibiting E. coli phagocytosis. Thus, by binding FcgammaRIII, E. coli triggers an inhibitory FcRgamma pathway that both impairs MARCO-mediated bacterial clearance and activates TNF-alpha secretion.
Assuntos
Infecções por Escherichia coli/imunologia , Mediadores da Inflamação/fisiologia , Fagocitose/imunologia , Receptores de IgG/fisiologia , Sepse/imunologia , Transdução de Sinais/imunologia , Animais , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Linhagem Celular , Células Cultivadas , Infecções por Escherichia coli/metabolismo , Infecções por Escherichia coli/microbiologia , Escherichia coli K12/imunologia , Mediadores da Inflamação/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Proteína Tirosina Fosfatase não Receptora Tipo 6/fisiologia , Receptores de IgG/deficiência , Receptores de IgG/genética , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/fisiologia , Sepse/metabolismo , Sepse/microbiologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The collaboration between the microbiota, mucosa, and intestinal epithelium is crucial for defending against pathogens and external antigens. Dysbiosis disrupts this balance, allowing pathogens to thrive and potentially enter the bloodstream, triggering immune dysregulation and potentially leading to sepsis. Antimicrobial peptides like LL-37 and CRAMP are pivotal in innate immune defense. Their expression varies with infection severity, exhibiting a dual pro- and anti-inflammatory response. Understanding this dynamic is key to comprehending sepsis progression. In our study, we examined the inflammatory response in CRAMP knockout mice post-cecal ligation and puncture (CLP). We assessed its impact on brain tissue damage and the intestinal microbiota. Our findings revealed higher gene expression of S100A8 and S100A9 in the prefrontal cortex of wild-type mice versus CRAMP-knockout mice. This trend was consistent in the hippocampus and cerebellum, although protein concentrations remained constant. Notably, there was a notable increase in Escherichia coli, Lactobacillus spp., and Enterococcus faecalis populations in wild-type mice 24 h post-CLP compared to the CRAMP-deficient group. These results align with our previous data suggesting that the absence of CRAMP may confer protection in this sepsis model.
RESUMO
Antimicrobial peptides (AMPs) constitute a complex network of 10-100 amino acid sequence molecules widely distributed in nature. While over 300 AMPs have been described in mammals, cathelicidins and defensins remain the most extensively studied. Some publications have explored the role of AMPs in COVID-19, but these findings are preliminary, and in vivo studies are still lacking. In this study, we report the plasma levels of five AMPs (LL-37, α-defensin 1, α-defensin 3, ß-defensin 1, and ß-defensin 3), using the ELISA technique (MyBioSource, San Diego, CA, United States, kits MBS2601339 (beta-defensin 1), MBS2602513 (beta-defensin 3), MBS703879 (alpha-defensin 1), MBS706289 (alpha-defensin 3), MBS7234921 (LL37)), and the measurement of six cytokines (tumor necrosis factor-α, interleukin-1ß, interleukin-6, interleukin-10, interferon-γ, and monocyte chemoattractant protein-1), through the magnetic bead immunoassay Milliplex® and the MAGPIX® System (MilliporeSigma, Darmstadt, Germany, kit HCYTOMAG-60 K (cytokines)), in 15 healthy volunteers, 36 COVID-19 patients without Acute Kidney Injury (AKI) and 17 COVID-19 patients with AKI. We found increased levels of α-defensin 1, α-defensin 3 and ß-defensin 3, in our COVID-19 population, when compared to healthy controls, along with higher levels of interleukin-6, interleukin-10, interferon-γ, and monocyte chemoattractant protein-1. These findings suggest that these AMPs and cytokines may play a crucial role in the systemic inflammatory response and tissue damage characterizing severe COVID-19. The levels of α-defensin 1 and α-defensin 3 were significantly higher in COVID-19 AKI group in comparison to the non-AKI group. Furthermore, IL-10 and the product IL-10 × IL-1B showed excellent performance in discriminating AKI, with AUCs of 0.86 and 0.88, respectively. Among patients with COVID-19, AMPs may play a key role in the inflammation process and disease progression. Additionally, α-defensin 1 and α-defensin 3 may mediate the AKI process in these patients, representing an opportunity for further research and potential therapeutic alternatives in the future.
Assuntos
Injúria Renal Aguda , COVID-19 , alfa-Defensinas , beta-Defensinas , Animais , Humanos , beta-Defensinas/metabolismo , Interleucina-10 , Peptídeos Catiônicos Antimicrobianos/metabolismo , Quimiocina CCL2 , SARS-CoV-2/metabolismo , Peptídeos Antimicrobianos , Interleucina-6 , Interferon gama , Estado Terminal , Citocinas/metabolismo , Biomarcadores , Injúria Renal Aguda/diagnóstico , Mamíferos/metabolismoRESUMO
BACKGROUND: Septic shock is the first cause of death in Intensive Care Units. Despite experimental data showing increased inflammatory response of aged animals following infection, the current accepted hypothesis claims that aged patients are immunocompromised, when compared to young individuals. RESULTS: Here, we describe a prospective cohort study designed to analyze the immune profile of this population. CONCLUSION: Older people are as immunocompetent as the young individual, regarding the cytokines, chemokines and growth factors response to devastating infection.
RESUMO
BACKGROUND: The progression and severity of COVID-19 vary significantly in the population. While the hallmarks of SARS-CoV-2 and severe COVID-19 within routine laboratory parameters are emerging, the impact of sex and age on these profiles is still unknown. METHODS: A multidimensional analysis was performed involving millions of records of laboratory parameters and diagnostic tests for 178 887 individuals from Brazil, of whom 33 266 tested positive for SARS-CoV-2. Analyzed data included those relating to complete blood cell count, electrolytes, metabolites, arterial blood gases, enzymes, hormones, cancer biomarkers, and others. FINDINGS: COVID-19 induced similar alterations in laboratory parameters in males and females. CRP and ferritin were increased, especially in older men with COVID-19, whereas abnormal liver function tests were common across several age groups, except for young women. Low peripheral blood basophils and eosinophils were more common in the elderly with COVID-19. Both male and female COVID-19 patients admitted to intensive care units displayed alterations in the coagulation system, and higher values for neutrophils, CRP, and lactate dehydrogenase. CONCLUSIONS: Our study uncovered the laboratory profiles of a large cohort of COVID-19 patients, which formed the basis of discrepancies influenced by aging and biological sex. These profiles directly linked COVID-19 disease presentation to an intricate interplay between sex, age, and immune activation.
Assuntos
COVID-19/sangue , Inflamação/etiologia , SARS-CoV-2 , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Proteína C-Reativa/análise , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Caracteres Sexuais , Adulto JovemRESUMO
Sepsis is a major health problem and a leading cause of death worldwide. In recent years, a crescendo of attention has been directed to the mechanisms of cell death that develop during this disease, since these are viewed as important contributors to the proinflammatory and anti-inflammatory responses associated with poor outcome. Here we discuss mechanisms of cell death evident severe bacterial infection and sepsis including necrosis, apoptosis, pyroptosis, and extracellular trap-associated neutrophil death, with a particular emphasis on lymphocyte apoptosis and its contribution to the immunosuppressed phenotype of late sepsis. Individual bacterial pathogens express virulence factors that modulate cell death pathways and influence the sepsis phenotype. A greater knowledge of cell death pathways in sepsis informs the potential for future therapies designed to ameliorate immune dysfunction in this syndrome.
Assuntos
Apoptose/imunologia , Infecções Bacterianas/imunologia , Inflamação/imunologia , Sepse/imunologia , Animais , Apoptose/fisiologia , Infecções Bacterianas/metabolismo , Morte Celular/imunologia , Humanos , Inflamação/fisiopatologia , Modelos Imunológicos , Sepse/metabolismo , Sepse/fisiopatologiaRESUMO
Cathelicidins are mammalian defense peptides with direct antimicrobial activity and the potential to exert other immunomodulatory effects during the innate immune response. One such function of human cathelicidin is direct binding and inhibition of bacterially derived lipopolysaccharide (LPS), a ligand of toll-like receptor 4 (TLR4) . Here, we show that physiological concentrations of exogenous murine cathelicidin blunt activation of p38 and ERK mitogen-activated protein kinases (MAPKs) and decrease tumor necrosis factor-alpha (TNFalpha) release in murine macrophages exposed to LPS, but also other TLR agonists such as lipoteichoic acid and flagellin. In this context, CRAMP is capable of aborting MyD88 synthesis and MyD88/IRAK (interleukin-1 receptor-associated kinase)-4 association in the stimulated macrophages. Exogenous CRAMP can reverse diminished MAPK activation associated with LPS tolerance. By analyzing macrophages from CRAMP(-/-) mice, we find their endogenous production of cathelicidin does not inhibit LPS MAPK and cytokine activation, rather CRAMP(-/-) cells show slightly diminished responses. CRAMP deficiency does not render mice more susceptible to lethal LPS challenge. These studies indicate the immunomodulatory effects of cathelicidin on macrophage TLR response may vary both on the exogenous vs endogenous origin of peptide and the prior activation state of the cell.
Assuntos
Catelicidinas/metabolismo , Macrófagos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Receptor 4 Toll-Like/metabolismo , Animais , Peptídeos Catiônicos Antimicrobianos , Catelicidinas/genética , Catelicidinas/imunologia , Células Cultivadas , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Flagelina/farmacologia , Humanos , Imunidade Inata , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/genética , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/metabolismo , Transdução de Sinais/imunologia , Ácidos Teicoicos/farmacologia , Receptor 4 Toll-Like/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Among the clinical manifestations observed in septic patients, sepsis-associated encephalopathy (SAE) is probably the most obscure and poorly explored. It is well established, however, that SAE is more prevalent in aged individuals and related to a worse outcome. In this context, we decided to investigate the acute effects of sepsis, induced by cecal ligation and puncture (CLP), on the cerebral transcriptional profile of young and old rats. The idea was to highlight important signaling pathways possibly implicated in the early stages of SAE. Global gene expression analysis of three different brain regions (hippocampus, cerebellum, and cortex) indicated a relatively small interference of sepsis at the transcriptional level. Cerebellum tissue was the least affected by sepsis in aged rats. The increased expression of S100a8, Upp1, and Mt2a in all three brain regions of young septic rats indicate that these genes may be involved in the first line of response to sepsis in the younger brain. On the other hand, altered expression of a network of genes involved in sensory perception of smell in the cortex of aged rats, but not in young ones, indicates an earlier disruption of cortex function, possibly more sensitive to the systemic inflammation. The expression of S100a8 at the protein level was confirmed in all brain regions, with clear-up regulation in septic aged cortex. Taken together, our results indicate that the transcriptional response of the central nervous system to early sepsis varies between distinct brain regions and that the cortex is affected earlier in aged animals, in line with early neurological manifestations observed in older patients.
Assuntos
Envelhecimento , Mapeamento Encefálico , Perfilação da Expressão Gênica , Sepse/complicações , Fatores Etários , Animais , Cerebelo/patologia , Córtex Cerebral/patologia , Hipocampo/patologia , Ratos , Sepse/genética , Encefalopatia Associada a Sepse/genética , Transdução de SinaisRESUMO
Direct bacterial recognition by innate receptors is crucial for bacterial clearance. Here, we show that the IgA receptor CD89 is a major innate receptor that directly binds bacteria independently of its cognate ligands IgA and c-reactive protein (CRP). This binding is only partially inhibited by serum IgA and induces bacterial phagocytosis by CD11c+ dendritic cells and monocytes and/or macrophages, suggesting a physiological role in innate host defense. Blood phagocytes from common variable immunodeficiency patients bind, internalize, and kill bacteria in a CD89-dependent manner, confirming the IgA independence of this mechanism. In vivo, CD89 transgenic mice are protected in two different models of sepsis: a model of pneumonia and the cecal ligation and puncture (CLP) polymicrobial model of infection. These data identify CD89 as a first-line innate receptor for bacterial clearance before adaptive responses can be mounted. Fc receptors may emerge as a class of innate receptors for various bacteria with pleiotropic roles.
Assuntos
Antígenos CD/metabolismo , Escherichia coli/fisiologia , Receptores Fc/metabolismo , Sepse/prevenção & controle , Streptococcus pneumoniae/fisiologia , Animais , Antígenos CD/genética , Proteína C-Reativa/metabolismo , Citocinas/metabolismo , Células Dendríticas/citologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Hospedeiro Imunocomprometido , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Imunoglobulina A/metabolismo , Estimativa de Kaplan-Meier , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Monócitos/citologia , Monócitos/imunologia , Monócitos/metabolismo , Fagocitose , Pneumonia/mortalidade , Pneumonia/patologia , Receptores Fc/genética , Sepse/imunologiaRESUMO
Antimicrobial peptides are key components of the innate immune system. They act as broad-spectrum antimicrobial agents against Gram-positive and -negative bacteria, viruses, and fungi. More recently, antimicrobial peptides have been ascribed immunomodulatory functions, including roles in wound healing, induction of cytokines, and altering host gene expression. Cathelicidins are a class of antimicrobial peptide found in humans, mice, and rats, among others. Known as LL-37 in humans and cathelin-related antimicrobial peptide (CRAMP) in rodents, cathelicidins are produced by many different cells, including macrophages, neutrophils, and epithelial cells. The role of cathelicidins is somewhat confounding, as they exhibit both pro-and anti-inflammatory activity. A major obstacle in the study of cathelicidins is the inability of exogenous LL-37 or CRAMP to mimic the activity of their endogenous counterparts. Nevertheless, studies have shown that LL-37 is recognized by multiple receptors, and may stabilize or modulate Toll-like receptor signaling. In addition, cathelicidins play a role in apoptosis, inflammasome activation, and phagocytosis. However, many studies are revealing the dual effects of cathelicidins. For example, CRAMP appears to be protective in models of group A Streptococcus skin infection, pneumonia, and meningitis, but detrimental in cases of severe bacterial infection, such as septic shock. It is becoming increasingly clear that the activity of cathelicidins is modulated by complex interactions with the microenvironment, as well as the disease background. This article reviews what is currently known about the activity of cathelicidins in an attempt to understand their complex roles in systemic diseases.
Assuntos
Catelicidinas/metabolismo , Inflamação/etiologia , Inflamação/metabolismo , Animais , Catelicidinas/genética , Citocinas/metabolismo , Regulação da Expressão Gênica , Humanos , Mediadores da Inflamação/metabolismo , Transdução de SinaisRESUMO
Aging is a continuous process promoted by both intrinsic and extrinsic factors that each trigger a multitude of molecular events. Increasing evidence supports a central role for inflammation in this progression. Here, we discuss how the low-grade chronic inflammation that characterizes aging is tightly interconnected with other important aspects of this process, such as DNA damage, mitochondrial dysfunction, and epigenetic changes. Similarly, inflammation also plays a critical role in many morbid conditions that affect patients who are admitted to Intensive Care. Although the inflammatory response is low grade and persistent in healthy aging while it is acute and severe in critically ill states, we hypothesize that both situations have important interconnections. Here, we performed an extensive review of the literature to investigate this potential link. Because sepsis is the most extensively studied disease and is the leading cause of death in Critical Care, we focus our discussion on comparing the inflammatory profile of healthy older people with that of patients in septic shock to explain why we believe that both situations have synergistic effects, leading to critically ill aged patients having a worse prognosis when compared with critically ill young patients.
RESUMO
Sepsis is a major cause of death and its incidence and mortality increase exponentially with age. Most gene expression studies in sepsis have focused in protein-coding genes and the expression patterns, and potential roles of long noncoding RNAs (lncRNAs) have not been investigated yet. In this study, we performed co-expression network analysis of protein-coding and lncRNAs measured in neutrophil granulocytes from adult and elderly septic patients, along with age-matched healthy controls. We found that the genes displaying highest network similarity are predominantly differently expressed in sepsis and are enriched in loci encoding proteins with structural or regulatory functions related to protein translation and mitochondrial energetic metabolism. A number of lncRNAs are strongly connected to genes from these pathways and may take part in regulatory loops that are perturbed in sepsis. Among those, the ribosomal pseudogenes RP11-302F12.1 and RPL13AP7 are differentially expressed and appear to have a regulatory role on protein translation in both the elderly and adults, and lncRNAs MALAT1, LINC00355, MYCNOS, and AC010970.2 display variable connection strength and inverted expression patterns between adult and elderly networks, suggesting that they are the best candidates to be further studied to understand the mechanisms by which the immune response is impaired by age. In summary, we report the expression of lncRNAs that are deregulated in patients with sepsis, including subsets that display hub properties in molecular pathways relevant to the disease pathogenesis and that may participate in gene expression regulatory circuits related to the poorer disease outcome observed in elderly subjects.