Neutrophils Survival Molecules and Apoptosis in the Absence of Survival Signals
Death molecules in neutrophils have been described on my last blog, and survival molecules in neutrophils need to be discussed further. Although prolonged neutrophil survival is preferred under conditions of bacterial or fungal infection, delayed neutrophil apoptosis can also result in several acute and chronic in ammatory diseases, and always lead to unwanted tissue damage. Exposure of cells to pro-survival stimuli, such as G-CSF, (GM)-CSF and (IFN)-gamma, seems to mediate the retardation of mature neutrophils apoptosis.
Activation of tyrosine kinases lead by GM-CSF stimulation in neutrophils and Lyn plays a crucial role in transducing GM-CSF survival signals. The downstream pathways activated by tyrosine kinases include JAK/STAT, PI3K and MAPK pathways in neutrophils. GM-CSF stimulation is able to result in phosphorylation of Jak2 and activation of several STAT proteins. It also triggers the activation of the PI3K signaling pathway. PI3K inhibitors not only can impact Akt phosphorylation upon GM-CSF simulation which is an important downstream effector of PI3K, but also reduce the Mcl-1 protein expression. LY294002. Furthermore, GM-CSF simulation was shown to result in the cytosolic accumulation of Bad and the phosphorylation of Bax. The regulations of GM-CSF-induced survival by PI3K signaling pathway include control of expression, phosphorylation and subcellular localization of Bcl-2 family members. Bcl-2 inhibitor. Extracellular signal-regulated kinase (ERK) can also be activated by GM-CSF, and pharmacological ERK inhibitors prevent survival induced by these survival factors. Nutlin-3. Besides these, cAMP may be elevated by PKA and PKB, two kinases which are activated survival downstream of GPCRs. NF-kabbaB was shown to be involved in enhancing neutrophil survival and its transcriptional activity can be induced by activation of PI3K and MAPK pathways.
Spontaneous neutrophil apoptosis is crucial for maintaining homeostatic neutrophil numbers. Studies using inhibitors against the JAK/STAT, PI3K or MAPK pathway didn't show a notable increase in viability of spontaneously dying neutrophils, proving that these signaling pathways are not involved in spontaneous apoptosis.
In ROS-induced neutrophil apoptosis, an increased redox balance within neutrophils results in manifold induction of the death machinery. The increase in ROS in neutrophils may be due to decreased glutathione, which directly inhibit caspase-8 and caspase-3 activity. Increased ceramide levels were shown to be lead by acid sphingomyelinase which was activated by ROS in neutrophils. Ceramide contributes to neutrophil apoptosis through increasing caspase-3/ -8, -9 activity. At the molecular level, neutrophils are highly susceptible to FAS-induced apoptosis which seems same to many other cells. ABT-263. Only aggregated or membrane-bound FASL, a functional FAS receptor, can induce apoptosis. As FAS and its receptor ligation, caspase-8 was activated followed by increased caspase-3 activity. Neutrophils are demonstrated to employ the mitochondria-dependent death machinery for execution of FAS-induced apoptosis. In contrast to FAS-mediated neutrophil apoptosis, TNFalpha-induced neutrophil apoptosis seems really different from many other cells. This kind of neutrophil apoptosis is mediated by caspase activity and does not engage the mitochondrial death pathway. Furthermore, TNF-alpha stimulation could induce a rapid rise in the levels of intracellular ROS in neutrophils.
References:
J Immunol 2003; 170: 1027–1033.
Blood 2004; 104: 2557–2564.
Blood 2008; 111: 878–884.
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Activation of tyrosine kinases lead by GM-CSF stimulation in neutrophils and Lyn plays a crucial role in transducing GM-CSF survival signals. The downstream pathways activated by tyrosine kinases include JAK/STAT, PI3K and MAPK pathways in neutrophils. GM-CSF stimulation is able to result in phosphorylation of Jak2 and activation of several STAT proteins. It also triggers the activation of the PI3K signaling pathway. PI3K inhibitors not only can impact Akt phosphorylation upon GM-CSF simulation which is an important downstream effector of PI3K, but also reduce the Mcl-1 protein expression. LY294002. Furthermore, GM-CSF simulation was shown to result in the cytosolic accumulation of Bad and the phosphorylation of Bax. The regulations of GM-CSF-induced survival by PI3K signaling pathway include control of expression, phosphorylation and subcellular localization of Bcl-2 family members. Bcl-2 inhibitor. Extracellular signal-regulated kinase (ERK) can also be activated by GM-CSF, and pharmacological ERK inhibitors prevent survival induced by these survival factors. Nutlin-3. Besides these, cAMP may be elevated by PKA and PKB, two kinases which are activated survival downstream of GPCRs. NF-kabbaB was shown to be involved in enhancing neutrophil survival and its transcriptional activity can be induced by activation of PI3K and MAPK pathways.
Spontaneous neutrophil apoptosis is crucial for maintaining homeostatic neutrophil numbers. Studies using inhibitors against the JAK/STAT, PI3K or MAPK pathway didn't show a notable increase in viability of spontaneously dying neutrophils, proving that these signaling pathways are not involved in spontaneous apoptosis.
In ROS-induced neutrophil apoptosis, an increased redox balance within neutrophils results in manifold induction of the death machinery. The increase in ROS in neutrophils may be due to decreased glutathione, which directly inhibit caspase-8 and caspase-3 activity. Increased ceramide levels were shown to be lead by acid sphingomyelinase which was activated by ROS in neutrophils. Ceramide contributes to neutrophil apoptosis through increasing caspase-3/ -8, -9 activity. At the molecular level, neutrophils are highly susceptible to FAS-induced apoptosis which seems same to many other cells. ABT-263. Only aggregated or membrane-bound FASL, a functional FAS receptor, can induce apoptosis. As FAS and its receptor ligation, caspase-8 was activated followed by increased caspase-3 activity. Neutrophils are demonstrated to employ the mitochondria-dependent death machinery for execution of FAS-induced apoptosis. In contrast to FAS-mediated neutrophil apoptosis, TNFalpha-induced neutrophil apoptosis seems really different from many other cells. This kind of neutrophil apoptosis is mediated by caspase activity and does not engage the mitochondrial death pathway. Furthermore, TNF-alpha stimulation could induce a rapid rise in the levels of intracellular ROS in neutrophils.
References:
J Immunol 2003; 170: 1027–1033.
Blood 2004; 104: 2557–2564.
Blood 2008; 111: 878–884.
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