RESUMO
Sepsis often causes cell death via pyroptosis and hence results in septic cardiomyopathy. Triggering receptors expressed in myeloid cells-1 (TREM-1) may initiate cellular cascade pathways and, in turn, induce cell death and vital organ dysfunction in sepsis, but the evidence is limited. We set to investigate the role of TREM-1 on nucleotide-binding oligomerization domain-like receptors with pyrin domain-3 (NLRP3) inflammasome activation and cardiomyocyte pyroptosis in sepsis models using cardiac cell line (HL-1) and mice. In this study, TREM-1 was found to be significantly increased in HL-1 cells challenged with lipopolysaccharide (LPS). Pyroptosis was also significantly increased in the HL-1 cells challenged with lipopolysaccharide and an NLRP3 inflammasome activator, nigericin. The close interaction between TREM-1 and structural maintenance of chromosome 4 (SMC4) was also identified. Furthermore, inhibition of TREM-1 or SMC4 prevented the upregulation of NLRP3 and decreased Gasdermin-D, IL-1ß and caspase-1 cleavage. In mice subjected to caecal ligation and puncture, the TREM-1 inhibitor LR12 decreased the expression of NLRP3 and attenuated cardiomyocyte pyroptosis, leading to improved cardiac function and prolonged survival of septic mice. Our work demonstrates that, under septic conditions, TREM-1 plays a critical role in cardiomyocyte pyroptosis. Targeting TREM-1 and its associated molecules may therefore lead to novel therapeutic treatments for septic cardiomyopathy.
Assuntos
Inflamassomos , Miócitos Cardíacos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Piroptose , Sepse , Receptor Gatilho 1 Expresso em Células Mieloides , Animais , Humanos , Camundongos , Adenosina Trifosfatases/imunologia , Cardiomiopatias/etiologia , Cardiomiopatias/genética , Cardiomiopatias/imunologia , Caspase 1/genética , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/imunologia , Cromossomos Humanos Par 4/imunologia , Inflamassomos/agonistas , Inflamassomos/genética , Inflamassomos/imunologia , Lipopolissacarídeos/efeitos adversos , Lipopolissacarídeos/farmacologia , Células Mieloides/imunologia , Miócitos Cardíacos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/agonistas , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Piroptose/genética , Piroptose/imunologia , Sepse/complicações , Sepse/genética , Sepse/imunologia , Receptor Gatilho 1 Expresso em Células Mieloides/antagonistas & inibidores , Receptor Gatilho 1 Expresso em Células Mieloides/genética , Receptor Gatilho 1 Expresso em Células Mieloides/imunologiaRESUMO
"An International Meeting on Wolf-Hirschhorn Syndrome (WHS)" was held at The University Hospital La Paz in Madrid, Spain (October 13-14, 2017). One hundred and twenty-five people, including physicians, scientists and affected families, attended the meeting. Parent and patient advocates from the Spanish Association of WHS opened the meeting with a panel discussion to set the stage regarding their hopes and expectations for therapeutic advances. In keeping with the theme on therapeutic development, the sessions followed a progression from description of the phenotype and definition of therapeutic endpoints, to definition of genomic changes. These proceedings will review the major points of discussion.
Assuntos
Cromossomos Humanos Par 4/imunologia , Deficiências do Desenvolvimento/genética , Convulsões/genética , Síndrome de Wolf-Hirschhorn/genética , Deleção Cromossômica , Cromossomos Humanos Par 4/genética , Deficiências do Desenvolvimento/epidemiologia , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Fenótipo , Convulsões/epidemiologia , Convulsões/terapia , Espanha/epidemiologia , Síndrome de Wolf-Hirschhorn/epidemiologia , Síndrome de Wolf-Hirschhorn/terapiaRESUMO
The ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase (CD38) gene is a positional and functional candidate gene for the susceptibility to systemic lupus erythematosus (SLE) because CD38 gene maps in the described SLE risk region 4p15 and CD38 molecule is a leukocyte activation antigen and ectoenzyme involved in numerous immune functions. The aim of this study was to investigate the possible association of the polymorphisms located at positions 182 of intron 1 (C/G) and 418 (C/T, located in exon 3) of the CD38 gene with the susceptibility and clinical features of SLE. Genotyping of 276 Spanish patients with SLE and 194 controls was performed by polymerase chain reaction amplification-refractory mutation system techniques. No association between the polymorphisms studied and the susceptibility to SLE was found. However, when patients were stratified according to their clinical manifestations, a significant increase of CC individuals and a significant decrease of CG individuals among patients with discoid rash (67.9% vs. 53.1% in controls p = 0.02, pc > 0.05, odds ratio [OR] = 1.87, 95% confidence interval [95% CI] 1.05-3.35; and 23.5% vs. 40.2% in controls, p = 0.008, pc = 0.024, OR = 0.46 95% CI 0.24-0.85) were found. Logistic regression analysis identified CC genotype as an independent risk factor for discoid rash among patients with SLE (p = 0.01, OR = 2.23, 95% CI 1.19-4.18). In conclusion, a slight contribution of the polymorphism located in intron 1 of the CD38 gene in the clinical features of SLE could be postulated.
