Initially, cell death was believed to be either programmed, called “apoptosis”, or passive, called “necrosis”. Apoptosis was considered instrumental to development and other physiological functions, while necrosis was seen as a response to unfavorable conditions. Now, necrosis is known to have programmed aspects, with “necroptosis” describing regulated necrotic cell death.
Features of Necrosis
Apoptosis and necrosis are characterized by different mechanisms leading to cell death. Apoptosis is associated with nuclear disintegration, followed by removal of the cell by macrophages. In necrosis, the nucleus stays intact and instead the membrane becomes balloon-like, resulting in leakage of cellular components. Apoptosis mainly occurs during embryogenesis, while necrosis is more common during disease states. Necroptosis falls somewhere in the middle, with several molecules and processes that can trigger, modulate, and effect necroptosis in cells.
In 1988, Laster and colleagues exposed two cell lines to TNF to investigate whether TNF (tumor necrosis factor) targets underwent DNA fragmentation. They found that TNF induced both apoptotic and necrotic cell death. This result sparked further interest in how necrotic cell death occurs.
Mechanism of Action
Studies show that necrotic death is induced by a ligand binding to a receptor, such as when apoptosis is initiated. The “death receptors”, which typically cause cell death by apoptosis, can be activated by ligands, such as TNF. However, apoptosis can be blocked by caspase inhibitors resulting in a “ballooning cell membrane”, typical of necrosis. Necroptosis can therefore start in an apoptosis-like manner, but result in necrotic-like cell death.
The signaling cascade following ligand binding is also important in deciding cell fate and potentially initiating necroptosis. The formation of necrosome, a multiprotein complex that stimulates necroptosis, is tightly regulated by proteins downstream of the receptor and can be the deciding factor in inducing necroptosis.
Necroptosis is associated with a range of pathological conditions. Excitotoxicity, oxidative stress and mitochondrial dysfunction can contribute to necroptosis, and are implicated in conditions, such as stroke, Alzheimer’s, Huntington’s, and Parkinson’s disease. Cell death by necroptosis involves membrane breakage, which leaks intracellular molecules such as heat shock proteins. These can trigger inflammation and an immune response.
Viral infections can induce different kinds of cell death. For example, HIV-1 induce necroptosis in T cells. The induced necrotic cell death by virial agents is important for virus-induced inflammation, and blockage of necroptosis is a primary concern for controlling certain viral diseases. Necroptosis can also be beneficial during infection. Cell death before the viral replication cycle is complete can limit disease progression. For example, MCMV (murine cytomegalovirus) replication can be prevented by necroptosis. Necroptosis can therefore be both beneficial and deleterious during infection.
Cancer, characterized by uncontrolled cell proliferation, is treated by chemotherapy and radiotherapy to induce apoptosis and kill cancerous cells. Resistance to these treatments are due to the cells resisting apoptotic death. In such cases, alternate mechanisms of cell death, such as necroptosis can be successfully induced.