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Quantification of Monocyte Chemotactic Activity In Vivo and Characterization of Blood Monocyte Derived Macrophages
Published on: August 12, 2019
The arachidonate-dependent survival signaling preventing toxicity in monocytes/macrophages exposed to peroxynitrite
Orazio Cantoni1, Ilaria Tommasini, Liana Cerioni
1Istituto di Farmacologia e Farmacognosia, Università degli Studi di Urbino Carlo Bo, Urbino, Italy.
Abstract:
Cells belonging to the monocyte/macrophage lineage are in general highly resistant to peroxynitrite. Resistance is not dependent on the scavenging of peroxynitrite itself, or of other secondary reactive species, but is rather associated with the prompt activation of a survival signaling leading to the prevention of toxicity in cells otherwise committed to mitochondrial permeability transition (MPT)-dependent necrosis. The signaling pathway is triggered by cytosolic phospholipase A2-released arachidonic acid, leading to the sequential activation of 5-lipoxygenase (5-LO) and protein kinase C alpha, an event associated with the cytosolic accumulation of Bad. Hence, inhibition of 5-LO (or that of any of the aforementioned enzymes involved in the signaling cascade) was associated with the mitochondrial accumulation of Bad and Bax and with a rapid MPT-dependent toxicity. These results contribute to the definition of the mechanism(s) whereby monocytes/macrophages survive to peroxynitrite in inflamed tissues and provide insights for the development of novel anti-inflammatory therapies based on the suppression of inflammatory cell survival.
Insights
Monocyte/macrophage cells resist peroxynitrite via a survival pathway involving arachidonic acid, 5-lipoxygenase (5-LO), and protein kinase C alpha. Inhibiting this pathway triggers cell death, offering insights into anti-inflammatory therapies.
Area of Science:
- Cellular and Molecular Biology
- Immunology
- Biochemistry
Background:
- Monocytes and macrophages exhibit significant resistance to peroxynitrite, a reactive nitrogen species implicated in inflammatory conditions.
- This resistance is not due to direct scavenging but involves a specific intracellular signaling cascade that prevents cell death.
- Understanding this survival mechanism is crucial for addressing inflammation-related pathologies.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying peroxynitrite resistance in monocyte/macrophage lineage cells.
- To identify the key signaling molecules and pathways involved in preventing peroxynitrite-induced cell death.
- To explore the therapeutic potential of targeting this survival pathway for anti-inflammatory strategies.
Main Methods:
- Investigated peroxynitrite resistance in monocyte/macrophage cells.
- Analyzed the role of cytosolic phospholipase A2, arachidonic acid, 5-lipoxygenase (5-LO), and protein kinase C alpha in the survival signaling pathway.
- Examined the impact of inhibiting 5-LO on mitochondrial protein accumulation (Bad and Bax) and cell toxicity.
- Assessed the role of mitochondrial permeability transition (MPT) in cell death.
Main Results:
- Peroxynitrite resistance is mediated by a survival signaling pathway initiated by cytosolic phospholipase A2-released arachidonic acid.
- This pathway sequentially activates 5-lipoxygenase (5-LO) and protein kinase C alpha, leading to cytosolic Bad accumulation and preventing MPT-dependent necrosis.
- Inhibition of 5-LO (or other pathway components) resulted in mitochondrial Bad and Bax accumulation and rapid MPT-dependent cell death.
- The findings highlight a critical role for this signaling cascade in monocyte/macrophage survival during inflammation.
Conclusions:
- Monocytes/macrophages survive peroxynitrite exposure through a defined signaling cascade that prevents mitochondrial dysfunction and necrosis.
- The pathway involves arachidonic acid, 5-LO, and protein kinase C alpha, culminating in the regulation of pro-apoptotic proteins like Bad.
- Targeting this survival pathway offers a potential therapeutic strategy for developing novel anti-inflammatory treatments by suppressing inflammatory cell survival.
