Discuss the role which Neutrophils play in inflammatory diseases?
Describe two major pathways activated by insulin and the signalling mechanisms undermining their activation?
Neutrophils are the most abundant leukocytes in the circulation, and have been regarded as first line of defense in the innate arm of the immune system. They capture and destroy invading microorganisms, through phagocytosis and intracellular degradation, release of granules, and formation of neutrophil extracellular traps after detecting pathogens. Neutrophils also participate as mediators of inflammation. The classical view for these leukocytes is that neutrophils constitute a homogenous population of terminally differentiated cells with a unique function.
Neutrophils, also known as polymorphonuclear (PMN) leukocytes, are the most abundant cell type in human blood. They are produced in the bone marrow in large numbers,
Neutrophils respond to multiple signals and respond by producing several cytokines and other inflammatory factors that influence and regulate inflammation and also the immune systemOnce neutrophils have left the circulation and passed through the endothelium, they migrate towards inflamed tissue along a chemotactic gradient. Exposure of neutrophils to chemoattractants such as N-formylmethionyl-leucyl-phenylalanine (fMLP) and complement component 5a (C5a) induces cellular polarization of chemoreceptors and formation of actin-rich pseudopodia at the leading edge of the cell. At the site of infection, membrane receptors for complement proteins and immunoglobulins recognize and bind opsonized bacteria leading to the formation of pseudopodia, phagocytosis of the pathogen and destruction within the intracellular phagosome. Neutrophils possess an arsenal of proteases and can generate reactive oxygen species (ROS) in order to rapidly kill phagocytosed pathogens, but these toxic molecules can also damage host tissue following their release from inappropriately activated neutrophils in autoimmune diseases.
Two major pathways activated by insulin:-
1-Insulin stimulates the liver to store glucose in the form of glycogen. A large fraction of glucose absorbed from the small intestine is immediately taken up by hepatocytes, which convert it into the storage polymer glycogen.
Insulin has several effects in liver which stimulate glycogen synthesis. First, it activates the enzyme hexokinase, which phosphorylates glucose, trapping it within the cell. Coincidently, insulin acts to inhibit the activity of glucose-6-phosphatase. Insulin also activates several of the enzymes that are directly involved in glycogen synthesis, including phosphofructokinase and glycogen synthase. The net effect is clear: when the supply of glucose is abundant, insulin "tells" the liver to bank as much of it as possible for use later.
. Glucose storage and uptake
2- Insulin promotes synthesis of fatty acids in the liver. As discussed above, insulin is stimulatory to synthesis of glycogen in the liver. However, as glycogen accumulates to high levels (roughly 5% of liver mass), further synthesis is strongly suppressed.
When the liver is saturated with glycogen, any additional glucose taken up by hepatocytes is shunted into pathways leading to synthesis of fatty acids, which are exported from the liver as lipoproteins. The lipoproteins are ripped apart in the circulation, providing free fatty acids for use in other tissues, including adipocytes, which use them to synthesize triglyceride.
Regulation of lipid synthesis
Insulin promotes the uptake of fatty acids and the synthesis of lipids, whilst inhibiting lipolysis.
Recent studies indicate that lipid synthesis requires an increase in the transcription factor steroid regulatory element-binding protein (SREBP)-
However, the pathway leading to changes in SREBP expression are unknown. Insulin inhibits lipid metabolism through decreasing cellular concentrations of cAMP by activating a cAMP specific phosphodiesterase in adipocytes.