Necrosis is a very bad thing. I used to think that all cell death was bad, but that was before I began to understand the difference between apoptosis and necrosis. In its most basic form: Apoptosis = good cell death and Necrosis = bad cell death. That may be a little too simple, but it was the beginning of my understanding of some of the intricacies of cellular response to damage, disease or stress.
There has been a lot of research over the last 10 years focusing on cell stress and cell death and the molecular pathway differences between the two types of cell death. In apoptosis, the programmed death of a cell, cells naturally expire and produce apoptotic bodies which can be properly engulfed by phagocytes and removed before they can cause damage. The process of apoptosis is critical in embryonic development for processes like separating our fingers into individual digits and the overexpression or underexpression of apoptosis can cause problems like atrophy or cancer.
Necrosis, on the other hand, is the completely unplanned death of a cell, or at least unplanned by the cell. There are lots of causes for necrosis; including physical injury, infection, or toxicity. Cells that undergo necrosis do not elicit the proper signal pathways for the phagocytes. Instead, they uncontrollably release their contents into the intracellular space, causing inflammation or spreading the cause for the necrosis into surrounding cells. The result is a cascading effect of cell death that results in things like gangrene.
As scientists have begun to understand this process, one of the things they discovered was a wide array of damage associated molecular pattern molecules, or more easily called DAMPs. DAMP molecules are commonly released in the process of necrosis, but are prevented from release during apoptosis. IL1A is one such DAMP molecule that is responsible for activating an immunity response. The immunity response from DAMPs causes sterile inflammatory response which has been shown to be a factor in many diseases including atherosclerosis, ischemia reperfusion injury and Alzheimer's. Increased IL1 activity has also been associated with diabetes, rheumatoid arthritis, gout, and psoriasis.
Since IL1A is universally expressed, it is believed to act as a universal DAMP molecule, but the actual process has still be unclear. While it was known that the pro-IL1A (p33) is processed to the mature IL1A (p17) by calpain, it was not known what the consequences were for that cleavage. Yue Zheng et al. describe in a recent paper that the cleavage of p33 is essential for IL1A and increases its affinity for IL1R1 (Receptor 1). What they found was that IL1A is primarily bound by IL1R2 (Receptor 2), which protects it from cleavage and prevents its activity. In fact, without IL1R2, the most significant DAMP in necrotic cells is IL1A. They showed that IL1R1 rich tissue (e.g. liver) activated the immune response regardless of IL1A cleavage, whereas IL1R1 deficient tissue (e.g. kidney) that cannot cleave p33 did not respond to IL1A at all.
There are other DAMP molecules, of course, and IL1A isn’t the only molecule that can drive inflammation, but Zheng points out that the additional activation of IL1A might just act as the tipping point of the inflammatory response that drives it toward adaptive immunity. Zheng has found that IL1R2 controls the release of Il1A through the activation of caspase-1, which processes IL1R2 and releases IL1A for binding to IL1R1 and cleavage by calpain.
Fundementally, this paper presents a small, but meaningful step toward understanding the roles of these molecules play in situations like graft rejection or chronic diseases like Alzheimer's and atherosclerosis. And ultimately, we can hope that this knowledge will help doctors work around these types of problems in the future.
Zheng, Y., Humphry, M., Maguire, J. J., Bennett, M. R., & Clarke, M. C. (2013). Intracellular Interleukin-1 Receptor 2 Binding Prevents Cleavage and Activity of Interleukin-1α, Controlling Necrosis-Induced Sterile Inflammation. Immunity. 38, 285–295
Category Code: 88221 79101