Cell Death-Associated Molecular-Pattern Molecules: Inflammatory Signaling and Control
Figure 5
Inflammatory response to the cell death-associated factors release by apoptotic and necrotic cells and their control by the redox inflammatory microenvironment. Dying and dead cells release a wide array of molecules, including ATP, CTR, HMGB1, nuclear DNA, and IL-1α that exert multiple functions in the innate immune response. IL-1α is most potent danger factor. These cells also release nonprotein thiols and thiol-regulating enzymes and highly diffusible prooxidant reactive oxygen and nitrogen species, which create an oxidizing and reducing gradient in the in extracellular milieu. The pro- and anti-inflammatory activity of DAMPs, alarmins, cytokines, and lipid mediators are affected by oxidation/reduction reactions in certain components of their structures. For instance, if all cysteines in the HMGB1 protein are reduced, it binds to CXCR4 and acts as chemoattractant. HMGB1 linked with disulfide binds to TLR-4 and induces proinflammatory cytokines, whereas further cysteine oxidation to sulfonates by ROS abrogates both activities. The constitutively higher ROS levels in macrophages were shown to inhibit procaspase-1 activation by reversible oxidation of cysteine residues on the zymogen. Similarly, IL-1β and IL-18 are prone of oxidation, causing their inactivation. Thus, the outcome of inflammatory response depends on the balance of oxidizing and reducing factors confined within injured cells that are released in the extracellular milieu. Inflammation resolution occurs with efficient macrophage clearance of the apoptotic cells. Apoptotic cells emit a small number of DAMPs, alarmins, and cytokines as well as proteases, as compared with apoptotic cells. Thus, necrotic cells sustain a long inflammatory response throughout the process of cellular resolution. Futures studies focusing on molecular targets involved in the critical steps of necrotic cell death program may help us to find new therapeutics to control the deleterious inflammatory response.
