Regulation of constitutive neutrophil apoptosis by the α,β-unsaturated aldehydes acrolein and 4-hydroxynonenal

Abstract

Reactive alpha,beta-unsaturated aldehydes are major components of common environmental pollutants and are products of lipid oxidation. Although these aldehydes have been demonstrated to induce apoptotic cell death in various cell types, we recently observed that the alpha,beta-unsaturated aldehyde acrolein (ACR) can inhibit constitutive apoptosis of polymorphonuclear neutrophils and thus potentially contribute to chronic inflammation. The present study was designed to investigate the biochemical mechanisms by which two representative alpha,beta-unsaturated aldehydes, ACR and 4-hydroxynonenal (HNE), regulate neutrophil apoptosis. Whereas low concentrations of either aldehyde (<10 microM) mildly promoted apoptosis in neutrophils (reflected by increased phosphatidylserine exposure, caspase-3 activation, and mitochondrial cytochrome c release), higher concentrations prevented critical features of apoptosis (caspase-3 activation, phosphatidylserine exposure) and caused delayed neutrophil cell death with characteristics of necrosis/oncosis. Inhibition of caspase-3 activation by either aldehyde occurred despite increases in mitochondrial cytochrome c release and occurred in close association with depletion of cellular GSH and with cysteine modifications within caspase-3. However, procaspase-3 processing was also prevented, because of inhibited activation of caspases-9 and -8 under similar conditions, suggesting that ACR (and to a lesser extent HNE) can inhibit both intrinsic (mitochondria dependent) and extrinsic mechanisms of neutrophil apoptosis at initial stages. Collectively, our results indicate that alpha,beta-unsaturated aldehydes can inhibit constitutive neutrophil apoptosis by common mechanisms, involving changes in cellular GSH status resulting in reduced activation of initiator caspases as well as inactivation of caspase-3 by modification of its critical cysteine residue.

Cigarette smoke (CS) and nicotine delay neutrophil spontaneous death via suppressing production of diphosphoinositol pentakisphosphate

“…We used Annexin V, an anticoagulant protein with high affinity and selectivity for phosphatidylserine (PS), to detect PS exteriorization, and propidium iodide (PI), a membrane impermeable dye, to monitor cell membrane integrity. Consistent with previous reports (8)(9)(10)(11), CSE and nicotine significantly reduced neutrophil spontaneous death. The most significant effects were observed at 36 h and 54 h (Fig.…”

“…Some of the chemical constituents of cigarette smoke (CS), such as nicotine and acrolein, have been shown to directly delay neutrophil spontaneous death (9)(10)(11), providing a mechanism for the massive accumulation of neutrophils in the lungs of smoke-induced COPD patients. Here, we investigate the mechanism by which CS reduces neutrophil spontaneous death.…”

Redox-based regulation of signal transduction: Principles, pitfalls, and promises

“…Cysteines also are uniquely targeted by alkylating species (such as cyclopentenone prostaglandins, acrolein), hydroxynonenal and avicins (which can be formed endogenously, or encountered through environmental insults [41,42]), and by acylation (which has important roles in localizing proteins to the membranes [43]). While a protein can have many cysteine residues, few are reactive (typically those in the thiolate, S − form).…”

“…A recent study demonstrated that caspase-3 activation during TNFα-induced apoptosis was negatively regulated by Sglutathionylation, and could be reversed through the thiol transferase activity of Grx [135]. Not suprisingly, caspase activation can also be negatively regulated by direct cysteine alkylation with biologically generated electrophiles, such as acrolein or hydroxynonenal [42,136].…”

Cigarette Smoke Alters Respiratory Syncytial Virus–Induced Apoptosis and Replication

“…Both acrolein and ROS can deplete cellular glutathione. This is the mechanism by which acrolein inhibits neutrophil caspase activation and apoptosis (15,16). Cigarette smoke depletes glutathione by irreversibly reacting with glutathione derivatives and binding them to acrolein (17).…”