Activation of inflammasome and protein secretion by endogenous danger and microbe-derived signals in human macrophages
Year: 2015
Type: dissertation
Abstract: Pathogenic micro-organisms have the potential to invade the body and damage the host. The innate immune system is the first defense mechanism to respond in such case. Principal innate immune effector cells macrophages detect the presence of microbe-derived, or endogenous molecules in inappropriate compartments. This recognition leads to the activation of macrophages triggering their defense reactions including secretion of proteins. Inflammasome is an intracellular protein complex that is assembled in macrophages promoting the secretion of an important inflammatory cytokine, interleukin(IL)-1β. Activation of the innate immune response is crucial in immediate host defense, and it also regulates the activation of the adaptive immune response later in infection. However, secretory responses from activated macrophages, or molecular signaling pathways leading to the activation of the inflammasome have not been fully characterized. This study aimed for exploring proteins secreted from human macrophages exposed to endogenous danger signals alone, and in combination with microbe-derived signals. Macrophages were activated with endogenous molecules monosodium urate (MSU) and adenosine triphosphate (ATP). MSU and ATP encountered in extracellular environment are both danger signals to the innate immune system, indicating tissue damage or metabolic dysfunction. The results show that exposing macrophages to MSU or ATP induces a robust protein secretion. Simultaneous detection of MSU with bacteria-derived lipopolysaccharide activates the secretion of inflammatory and defense proteins. Macrophages exposed to ATP display a rapid secretion of vesicles, and this secretion is dependent on the activity of proteins called calpains. Calpains are also required for ATP-induced inflammasome activation in macrophages. Second aim of this study was to explore inflammatory response of macrophages from healthy subjects with a history of reactive arthritis (ReA), an inflammatory joint disease, upon detection of microbe-derived signals. The results show that inflammasome activation is normal, but the secretion of two inflammatory cytokines, tumor necrosis factor and IL-23, is lower from macrophages of former ReA subjects compared to the release of these cytokines from cells of healthy controls. Thirdly this study aimed for unraveling signaling pathways activated by fungal-derived trichothecene mycotoxins in human macrophages. Trichothecene mycotoxins represent an exogenous danger signal to the innate immune system evoking an inflammatory response. The results of this study reveal that trichothecene mycotoxins activate the NLRP3 inflammasome in macrophages. This study provides new information about early innate immune responses that is useful in the discovery of treatments for diseases whose pathogenesis is associated to disturbances in the innate immune system.
Source: Työväentutkimus Vuosikirja
Author: Elina Välimäki
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1710642637