Leukotriene B4 enhances innate immune defense against the puerperal sepsis agent Streptococcus pyogenes
| Autor: | Elyara M. Soares, Lisa M. Rogers, Carlos H. Serezani, David M. Aronoff, Lúcia Helena Faccioli, Katie L. Mason |
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| Rok vydání: | 2013 |
| Předmět: |
Adult
Adolescent Leukotriene B4 Immunology Biology medicine.disease_cause Article Sepsis STREPTOCOCCUS PYOGENES chemistry.chemical_compound Mice Young Adult Streptococcal Infections medicine Immunology and Allergy Macrophage Animals Humans Genetic Predisposition to Disease Cells Cultured Mice Knockout Leukotriene Innate immune system Arachidonate 5-Lipoxygenase Lipid signaling medicine.disease Immunity Innate Up-Regulation Mice Inbred C57BL chemistry Streptococcus pyogenes Puerperal Infection Female Intracellular |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| ISSN: | 1550-6606 |
| Popis: | Puerperal sepsis is a leading cause of maternal mortality worldwide. Streptococcus pyogenes [group A Streptococcus; (GAS)] is a major etiologic agent of severe postpartum sepsis, yet little is known regarding the pathogenesis of these infections. Tissue macrophages provide innate defense against GAS, and their actions are highly regulated. The intracellular second messenger cAMP can negatively regulate macrophage actions against GAS. Because leukotriene (LT) B4 has been shown to suppress intracellular cAMP in macrophages, we hypothesized that it could enhance innate defenses against GAS. We assessed the capacity of LTB4 to modulate antistreptococcal actions of human macrophages, including placental and decidual macrophages and used a novel intrauterine infection model of GAS in mice lacking the 5-lipoxygenase enzyme to determine the role of endogenous LTs in host defense against this pathogen. Animals lacking 5-lipoxygenase were significantly more vulnerable to intrauterine GAS infection than were wild-type mice and showed enhanced dissemination of bacteria out of the uterus and a more robust inflammatory response than did wild-type mice. In addition, LTB4 reduced intracellular cAMP levels via the BLT1 receptor and was a potent stimulant of macrophage phagocytosis and NADPH oxidase–dependent intracellular killing of GAS. Importantly, interference was observed between the macrophage immunomodulatory actions of LTB4 and the cAMP-inducing lipid PGE2, suggesting that interplay between pro- and anti-inflammatory compounds may be important in vivo. This work underscores the potential for pharmacological targeting of lipid mediator signaling cascades in the treatment of invasive GAS infections. |
| Databáze: | OpenAIRE |
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