Epilogue: The Horror of an Injury-Induced Avalanche of DAMPs

Abstract

The Epilogue of Part V deals with the innate immune events of stress responses and regulated cell death which serve an individual to survive stress and injury but, in case of severe systemic injury, may get out of control in the emission of an avalanche of DAMPs which may kill the individual. Usually, in situations of mild or moderate injury, cell-intrinsic stress responses operate successfully and end up with restoration of cellular homeostasis. In the case of severe injury, these stress responses may fail and result in the catastrophic event of regulated cell death that can be regarded as a desperate attempt of a dying cell to induce life-saving immunity in the organism where it is derived from. The existence of various subroutines of regulated cell death associated with different degrees of both immunogenicity and energy consumption during the dying process is interpreted as the option of an irreversibly dying cell to use that cell death pathway that seems to be most promising in coping with a given life-threatening injury. For example, in case of life-threatening infectious tissue injury caused by dangerous microbes, a cell may choose pyroptosis that guarantees maximal immunogenicity needed to get rid of the pathogen. By contrast, apoptosis is selected by a cell in a situation, where there is no urgent need for an immune defense response to mount.

In this context, the scenario is again stressed that, in a situation of severe systemic infectious or sterile tissue injury, stress response—and regulated cell death-induced uncontrolled emission of DAMPs—may lead to pathologies such as sepsis and multiple organ failure. This deadly scenario is compared with an avalanche of DAMPs initially precipitated by stress responses and then amplified and aggravated by repeatedly induced rounds of regulated cell death associated with the emission of both constitutive and inducible DAMPs.