One of the bodies many partners in the immune system is the macrophage cell. A macrophage cell can literally detect dead cells through smell.
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- Unplanned Cell Death
- What Happens When Human Body Cells Die?
- What Happens When Human Body Cells Die? | Education - Seattle PI
Specialized enzymes called caspases also aid in the breakdown process, helping to disassemble the cell in a controlled way. When cells do not reliably undergo apoptosis, problems such as cancer can result. Cancer is a process of uncontrolled growth of certain cells in the body of affected individuals. According to Siva Kumar Kolluri of Oregon State University, certain proteins regulate apoptosis, but when they fail to function as they should, cells do not die.
If, however, researchers can learn to trigger apoptosis in cancer cells but allow normal cells to continue growing, they might be able to fight it more effectively. Sarah Moore has been a writer, editor and blogger since She holds a master's degree in journalism. Unplanned Cell Death Cells die in an unplanned manner when exposed to a variety of harmful environmental agents.
Cell Apoptosis Apoptosis is the opposite of unplanned cell death: To resolve this issue it will be necessary to identify and evaluate the contribution of the various potential mediators in different cell types, e. In addition to cellular components with intrinsic proinflammatory activity, other kinds of cellular molecules that potentially contribute to the death-induced inflammatory response are ones that are not themselves proinflammatory, but instead work indirectly by activating extracellular inflammatory mediators. Several extracellular proinflammatory pathways have been postulated to play potential roles in this process Table II.
In most of the cases, more is known about the extracellular mediators than of the cellular components that trigger them. One extracellular proinflammatory pathway that is thought to contribute to sterile inflammation to tissue injury is the complement system. Intrinsic enzymatic activity to cleave C3 fragment was first identified in lysates of rat myocardium It was subsequently found that complement components were deposited on dead cells in ischemic infarcts Since complement was not found on adjacent viable cells, this observation indicated that dead cells were triggering the complement pathway.
One of the well known consequences of activating the complement cascade is the generation of complement fragments that are proinflammatory see section Molecular basis of inflammation to infection.
Therefore, the complement pathway is triggered by dead cells and this process contributes to the ensuing sterile inflammatory response. Dead cells may be triggering the complement system through a number of different mechanisms. There is limited evidence that some cellular components can directly activate the complement cascade. Thus, lysates of myocardium were found to cleave the C3 component into active form Presumably, cellular proteases were responsible for this activity but their identity is unknown.
In addition, isolated mitochondrial membranes were also shown to activate complement via the C1q component Again the underlying molecular basis for this activity is not known. More recently it was discovered that certain cellular components could also activate the complement pathway by an indirect mechanism Non-muscle myosin heavy chains type IIA and C are released after ischemia-reperfusion injury of the intestine, myocardium and skeletal muscle. By themselves, the myosin molecules are not intrinsically proinflammatory.
The bound autoantibody activates complement that then initiates the inflammatory response see section Molecular basis of inflammation to infection. Immunodeficient mice that lack antibody fail to develop inflammatory responses in these models However, when an anti-myosin monoclonal antibody is injected into these animals it is sufficient to initiate inflammation at sites of ischemia reperfusion injury Moreover, in normal mice antibody sufficient inhibiting the endogenous anti-myosin antibodies by infusion of myosin peptides, reduces the inflammatory response to ischemic injury Therefore, these data identify myosin heavy chain as a cellular trigger of sterile inflammation in vivo and elucidates a novel mechanism by which it generates this response.
It is not yet know whether this mechanism plays a role in generating the inflammatory response to cell death in other settings. Another set of potential extracellular mediators that might be generated by components released from dead cells are ones derived from components of the extracellular matrix Table II. One set of such matrix components are the glycosaminoglycans, hyaluronic acid and heparin sulfate. Hyaluronic acid fragments have been shown to stimulate the production of proinflammatory mediators from endothelial and dendritic cells in vitro and to stimulate the production of chemokines when injected in vivo Heparan sulfate has also been shown in vitro to activate macrophages and dendritic cells and stimulate the production of proinflammatory cytokines 68 - There is also limited data that collagen and elastin-derived peptides, laminin and fibronectin fragments can have proinflammatory activites 71 72 , 73 74 - The importance of these mediators to the death-induced inflammatory response in vivo is not known.
The release of cellular proteases have also been suggested to trigger other extracellular pathways that generate proinflammatory mediators. These pathways include the clotting, fibrinolytic and kinin cascades The proinflammatory signals that are released from dying cells or extracellular matrix are for the most part not ones that had been previously identified to be biologically active mediators.
So how do these signals actually stimulate inflammation? This is an issue that is not well understood. This would be similar to the process by which the host generates inflammation to extracellular microbes. In fact, there is emerging evidence that sometimes, the exact same mechanisms may be used to sense infection and cell death: As we will review next, this appears to be the case for several of the proinflammatory molecules from dead cells Table I and the extracellular matrix Table II.
Interestingly, a number of other cellular and extracellular components have also reported to mediate their proinflammatory effects through these same TLR e. HSP 88 and hyaluronic acid Other TLR might also play a role in recognizing released cellular components.
For example, although TLR9 has specificity for unmethylated C and G-rich DNA sequences that are abundant in prokaryotic DNA, it can also recognize some similar sequences present more rarely in mammalian DNA and this is thought to account for the stimulatory activity of autologous chromatin-DNA complexes Since TLR are stimulated by microbial components, the possibility that microbial contaminants might account for some examples of endogenous molecules stimulating TLR, especially TLR4, needs to be kept in mind.
Uric acid was originally reported to stimulate inflammation through TLR2 and 4 91 , however a subsequent study failed to find any role for TLR2 or 4 in both genetic loss and gain of function experiments Similarly, the stimulatory activity of some HSP has been attributed to microbial contaminants Therefore, while TLRs may indeed recognize some host components, caution is warranted in evaluating such findings.
Insight into this issue has come from studies that have injected dead cells into mice that genetically lack various TLR Chen et al. In this situation, inflammation was reduced in mice that were doubly-deficient in TLR2 and TLR4, confirming that these receptors do indeed play a role in the sterile inflammatory response. However, in the absence of these two TLR, the reduction in the inflammatory response was quite modest. This indicates that there must be other receptors involved in this process.
It remains possible that TLR not examined TLR5 or 8 play a role in this process or that multiple TLRs are involved and function in a redundant manner so loss of individual receptors has little impact. Therefore, there are almost certainly other as yet unidentified receptors involved in this process. This raises the interesting possibility that the major receptors and pathways that stimulate inflammation to dying cells and microbes could be different. If this is true, it would have important implications for the potential development of therapeutics that might selectively block the sterile inflammatory response.
The other receptors that sense the release of cellular components and trigger inflammation are not yet clear. NALP3 is a component of a molecular complex called the inflammasome that cleaves the IL-1 precursor into its mature form. In some situations, NALP3 is known to function downstream of a surface receptor e. After the initial recognition of a dead cell or microbe, the ensuing inflammatory response that evolves is largely orchestrated and amplified by mediators generated by host cells. These factors include cytokines, chemokines, vasoactive amines, and phospholipids metabolites.
There are large numbers of such mediators and many have overlapping functions. While many of these mediators are likely to contribute to the inflammatory response to dead cells, the extent of their contributions to this process and whether there are differences in the principal ones that drive inflammation to dying cells versus microbes is not well understood.
Recently, the proinflammatory cytokine IL-1 was unexpectedly found to have a key role in the acute neutrophilic inflammatory response to dead cells Chen et al. When sterile dead cells were injected into mice, wild type animals developed a strong neutrophilic inflammatory response. Similarly, neutrophilic inflammation to hepatocyte death induced by injection of a hepatotoxic drug was markedly reduced in mice lacking the IL-1R-MyD88 pathway Chen et al. Therefore, IL-1 is a particularly important host mediator in the acute neutrophilic inflammatory response to dead cells.
Interestingly, in bone marrow-transplanted chimeric mice, the sterile neutrophilic inflammatory response to dead cells required the IL-1R on parenchymal radioresistant cells but not ones of bone marrow origin radiosensitive Chen et al. Therefore, for this response IL-1 must be principally acting in on cells resident in the tissues rather than on neutrophils or other leukocytes. These data suggest that IL-1 functions to orchestrate the neutrophilic response into tissues at sites of cell death.
Whether this is true in all tissues and with all types of dying cells remains to be determined. Surprisingly, the recruitment of monocytes into sites of cell death was either not reduced or only modestly decreased in IL-1R or MyDdeficient mice Chen et al. This indicates that after cell death triggers the inflammatory response, the recruitment of monocytes and neutrophils are controlled by different mechanisms. Also surprisingly, neurophilic inflammation to a microbial stimulus, yeast zymosan, was not reduced in mice lacking the IL-1R Chen et al. This indicated that in some situations, the acute inflammatory response to microbial components and dead cells can be controlled by different mediators.
In addition to IL-1, it is likely that other proinflammatory cytokines play important roles in the inflammatory response to dead cells. These and many other cytokines and mediators could well play major roles in death-induced inflammation. However, the role of these various factors in responses to dead cells has not been specifically examined or quantified. While the inflammatory response plays important roles in protecting the host and repairing tissues, it can also damage normal tissues.
Molecules generated to kill microbes, such as reactive oxygen species and proteases, leak from live and dying leukocytes and kill normal cells. These and other mediators that are generated can also cause the host significant pain and disability. In an infection, the collateral damage to normal tissues may be a small price to pay to contain a potentially dangerous microorganism as rapidly as possible.
However, in situations where there is sterile tissue injury, inflammation is more costly to the host and in some settings may actually do more harm than good. This is illustrated in experimental models of acute myocardial infarctions and in toxic damage to the liver where tissue damage is substantially reduced by the depletion of neutrophils 97 , 98 or blocking the mediators that lead to their accumulation 31 , There is similar evidence that wound healing is actually prolonged by neutrophilic inflammation Thus, in a number of acute settings, the neutrophil component of sterile inflammation may be particularly detrimental.
However, tissue damage from inflammation is not only limited to acute responses and neutrophils. Macrophage rich chronic inflammatory infiltrates can also damage normal tissues and this is thought to underlie the pathogenesis of many chronic diseases, e. There are a number of sterile processes that can stimulate such chronic responses including ones, such as sunburn in SLE or cigarette smoke in COPD , in which cell death causes or contributes to the inflammatory response.
Thus the ongoing inflammatory response to sterile cell death may cause disease. In those settings where inflammation to dying cells does more harm than good it would potentially be useful to block these responses therapeutically. This might be achieved if it were possible to selectively inhibit inflammation to sterile dead cells. Such selective inhibition might be achieved by neutralizing the cellular triggers of inflammation that are released from dead cells or inhibiting the receptors that sense them. Another potential therapeutic strategy might be to inhibit only the neutrophilic component of this response, ideally without blocking effective responses to microbes.
This might be achieved by blocking the inflammatory mediators that are needed to recruit neutrophils to the site of injury. That this might be possible and beneficial is shown in experiments where liver damage was induced and the IL-1 receptor pathway was blocked Chen et al. In this situation, neutrophilic inflammation was inhibited and the ensuing liver damage was markedly reduced.
Under these same conditions, monocyte recruitment was much less affected and neutrophil recruitment to at lease one microbial stimulus was normal Chen et al. Moreover, blocking IL-1R function in humans has not been associated with infectious complications Thus, it might actually be possible to selectively block neutrophilic inflammation to tissue damage under conditions that preserves host defense functions to microbes.
In addition to stimulating inflammation an innate immune response , dying cells may also provide signals that help mobilize adaptive lymphocyte immunity to antigens present in the affected tissue. This hypothesis proposed that the adaptive immune system evolved to recognize cell death as a potentially dangerous situation and that this recognition would promote immune responses to antigens associated with the site of injury.
To understand this idea, it is necessary to first discuss how T cell immune responses are initiated. The first step in the initiation of a T cell immune response occurs when dendritic cells acquire antigen from the local environment. These cells then hydrolyze the antigen into peptides some of which are displayed on their surface bound to MHC molecules The dendritic cells then migrate into secondary lymphoid organs when they interact with T cells T cells are then stimulated when they recognize their specific antigenic peptide bound to an MHC molecule on the dendritic cell.
However this recognition is insufficient to productively activate the T cell and by itself may actually tolerize inactivate the lymphocyte To become fully activated the T cell must also receive other co-stimulatory signals from the dendritic cell and these second signals are only provided if the dendritic cells have previously been stimulated in certain ways One of the important signals that can activate dendritic cells to become immunostimulatory are microbial molecules that engage receptors like the TLRs Through this mechanism, T cell responses will only be generated in response to a potential threat, such as an infection, and not to other innocuous situations.
Subsequent studies showed that dead cells could indeed activate dendritic cells and promote the generation of T cells response to associated antigens , Cells contain multiple danger signals that are released upon death and disintegration of the plasma membrane 7 , Whether these molecules are the same ones that stimulate inflammation is not clear but is certainly possible.
Unplanned Cell Death
Uric acid in the form of MSU was shown to be one of the endogenous cellular components capable of activating dendritic cells and promoting CD8 T cell responses to cell-associated antigens In addition, there is also evidence that HMGB1 can also function as a danger signal that could induce DC maturation in vitro and promote antitumor immunity in vivo HSP have also been postulated to have immune stimulating activities It is likely that there are other such molecules e.
These danger signals when released can help promote the generation of CD4 and CD8 T cell responses to immunogenic antigens that are present in or around the dying cells. This provides an additional surveillance mechanism to detect pathological processes and recruit specialized defenders to reinforce the initial innate defenses of the inflammatory response. Such adaptive responses are important for host defense against microbes and tumors.
However, this process also has potential downsides. As with inflammation, the adaptive immune response may cause collateral damage. Moreover, the release of both antigens and danger signals may lead to the initiation of autoimmune disease in those individuals that are not fully tolerant to self antigens , , Furthermore, this process may also contribute to the initiation of cellular rejection mechanisms against organ transplants , It is clear that when cells die they set in motion a number of important processes.
One is the rapid recruitment of innate immune components from the blood as part of a process we recognize as inflammation. Another parallel process is the mobilization of highly specific T and B cell defenses from more distal sites. In this manner this is a rapid but indiscriminate response followed more slowly by one that is much more highly specific.
This helps to ensure adequate host defense. These responses induced by cell injury are double-edged swords. On the one hand they protect and help heal injured tissues, while on the other hand they can cause significant damage and disease. The signals that drive these sterile inflammatory and adaptive immune response are normally concealed in the interior of cells and released when cells loses integrity of their plasma membrane. The host then recognizes the release of these normally hidden self molecules and initiates responses.
There has been progress in identifying some these signals and their potential modes of action. Nevertheless there still remains much to be learned about the role and mechanism of action of these factors as well as others that are almost certainly waiting to be discovered. We thank Tom Smith for help with photomicroscopy. National Center for Biotechnology Information , U. Author manuscript; available in PMC May Rock and Hajime Kono. The publisher's final edited version of this article is available at Annu Rev Pathol.
See other articles in PMC that cite the published article. Abstract When cells die in vivo they trigger an inflammatory response. Necrosis, danger, toll-like receptors, inflammation, cytokines. Introduction Everyone has experienced injuries and knows from common observation that the injured site becomes inflamed. Open in a separate window. Role of the inflammatory response In an infection, the role of the inflammatory response is clear.
Inflammation to necrosic versus apoptotic cell death Cells can die through a number of different mechanisms. Molecular basis of inflammation to infection Over the last decade there have been major advances in our understanding of the molecular basis of the inflammatory response to microbes. The scent of death: Proinflammatory components from dead cells The fact that dead cells induce inflammation indicates that the cell corpse must expose or release some sort of proinflammatory signal s. Table 1 Cellular molecules with intrinsic proinflammatory activity.
Factor Cellular distribution Release from dead cells Proinflammatory in vitro Proinflammatory in vivo Putative receptor Purified molecule proinflammatory in vivo Neutralization reduces inflammation in vivo HMGB1 All cells Necrosis not apoptosis Chemotaxis Cytokine induction 51 Macrophage activation 51 DC activation Cellular molecules with intrinsic proinflammatory activity One interesting molecule that has been implicated in the triggering the inflammatory response to necrotic cells is HMGB1 Cellular molecules that activate extracellular proinflammatory mediators In addition to cellular components with intrinsic proinflammatory activity, other kinds of cellular molecules that potentially contribute to the death-induced inflammatory response are ones that are not themselves proinflammatory, but instead work indirectly by activating extracellular inflammatory mediators.
Table II Extracellular matrix with proinflammatory activity. Receptors that detect cell death and induce inflammation The proinflammatory signals that are released from dying cells or extracellular matrix are for the most part not ones that had been previously identified to be biologically active mediators. Host mediators that drive the inflammatory response to dying cells After the initial recognition of a dead cell or microbe, the ensuing inflammatory response that evolves is largely orchestrated and amplified by mediators generated by host cells.
The dark side of sterile inflammation: Conclusions It is clear that when cells die they set in motion a number of important processes. Do different cells have different intracellular proinflammatory molecules? Do different conditions lead to the release of different intracellular mediators? What are the pathways and receptors that are activated by the cellular proinflammatory molecules? What are the key mediators that ultimately drive the various components of the sterile inflammatory response?
What are the molecules and pathways that can be targeted for therapeutic intervention? Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. Pathways for bradykinin formation and inflammatory disease. J Allergy Clin Immunol. Anat Embryol Berl ; A clinical and experimental study of the function of neutrophils in the inflammatory response.
What Happens When Human Body Cells Die?
Cellular death and necrosis: Boxer L, Dale DC. Tolerance, danger, and the extended family. Interferons, immunity and cancer immunoediting. Majno G, Joris I. Apoptosis, oncosis, and necrosis.
- The inflammatory response to cell death?
- Stupider than Jupiter.
- Cell Suicide: An Essential Part of Life.
- Access Denied;
An overview of cell death. Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-beta1 secretion and the resolution of inflammation. Regulation of cytokine production during phagocytosis of apoptotic cells. As apoptosis destroys unwanted cells, mitosis cell division makes new cells. While they may seem to be at odds, apoptosis and mitosis work together to keep us healthy.
What Happens When Human Body Cells Die? | Education - Seattle PI
For example, our skin and hair cells are renewed via a continuous cycle of apoptosis and mitosis. So are the cells lining our intestines. Because new cells replace old, worn-out ones, our tissues remain healthy. As you can well imagine, loss of the balance between apoptosis and mitosis can have hazardous consequences. If apoptosis is triggered when it shouldn't be, our bodies squander perfectly good cells. Scientists believe that too much apoptosis is at least partly to blame for some neurodegenerative diseases, such as Alzheimer's, Parkinson's and Lou Gehrig's, and it may play a role in the fatal body-wide infection known as sepsis.
On the other hand, unchecked mitosis can lead to cancer. Live Science Health Cell Suicide: A mitochondrion blue undergoes the death throes of apoptosis. Two proteins, Reaper and Hid green , trigger the release of cytochrome c red , which in turn activates a fatal chain reaction. The yellow areas show a mix of Reaper-Hid and cytochrome c.