Page 218 - Clinical Immunology_ Principles and Practice ( PDFDrive )

13

Regulated Necrosis and Its Immunogenicity

Wulf Tonnus, Andreas Linkermann

For more than a century and a half, we have known that the KEY CONCEPTS
process of regulated cell death (RCD) is an integral part of life.
The first insights into the mechanisms underlying RCD came Necroinflammation—An Autoamplificatory
1
from the identification of apoptotic pathways in 1972. For almost Feed-Forward Loop
40 years, the apoptotic process of RCD was viewed as the opposite • Induced by cells dying by necrosis (e.g., in hypoxia)
of necrosis, which was considered accidental (and therefore • Associated proinflammatory damage-associated molecular pattern
unregulated). In 2008, however, it was realized that necrosis (DAMP) release
could be antagonized under certain conditions. This led to the • Immune cell infiltration
appreciation that necrosis could also be a genetically determined, • Regulated necrosis (RN) in parenchymal and endothelial cells induced
regulated process. by immune cells
The current challenge is to elucidate the various genes and • RN in inflammatory cells (e.g., macrophages undergoing pyroptosis)
• More necrotically dying cells
pathways that take part in regulated physiological and pathophysi- • DAMP transfer to remote organs
ological cell death and to better understand why there are multiple • Remote organ injury
pathways. It has become clear from these studies that the various
pathways create differences in the immunogenicity of the byprod-
ucts of necrosis. As tissue injury and inflammation are tightly Briefly, this model proposes that cellular stress activates the
linked, these discoveries fuel the need to better understand how innate immune system, thus leading to an inflammatory response
necrosis influences pathologies, including autoimmune diseases, that can, under certain circumstances, then induce a specific
transplant rejection, and cancer. This chapter focuses on the most adaptive response.
clearly identified regulated necrosis (RN) pathways. Our “selection” Key to this is the concept are DAMPs (Chapter 3). DAMPs
of the RN pathways discussed is based on the current appreciation include a wide array of different stimuli, including exogenous
of the importance of these pathways, either physiologically or stimuli (e.g., LPS) and intracellular contents (e.g., uremic acid
5,6
pathophysiologically, to differences in the immunogenicity of and high-mobility group box-1 [HMGB1]). These are sensed
these RN pathways and their role in diseases (Fig. 13.1). by either “classic” PRRs or “nonclassic” receptors found on the
surface or within cells of innate immunity. When cells die by
RN, these DAMPs become accessible to the immune system in
CELL DEATH AND DAMAGE-ASSOCIATED the extracellular space. They are sensed especially by cells of the
MOLECULAR PATTERNS—THE CONCEPT innate immune system. Dendritic cells (DCs) (Chapter 6) are
OF NECROINFLAMMATION activated by directly sensing DAMPs via surface receptors (e.g.,
calreticulin [CALR]–CD91, adenosine triphosphate [ATP]–P2X7R,
Pattern recognition receptors (PRRs) bind a wide range of or HMGB1–Toll-like receptor 4 [TLR4]). Sensing of DAMPs by
damage-associated molecular patterns (DAMPs). These include monocytes leads to activation of inflammasomes, which then
exogenous stimuli such as lipopolysaccharides (LPS) as well as promote expression of mature inflammatory cytokines (e.g.,
an array of intracellular content. interleukin-1β [IL-1β] and IL-18) (Chapter 9). Natural killer
It is now understood that necrosis triggers inflammation and (NK) cells (Chapter 17) also directly interact with injured cells.
that inflammation can, in turn, lead to further RN. This observa- However both monocytes and NK cells give rise to inflammation
tion gave rise to the concept of necroinflammation. Necroinflam- and thus support the maturation of immature DCs.
mation can create an autoamplificatory feedback loop that results The infiltration of innate immune cells into the inflamed
in DAMP release between organs. For example, ischemic or tissues and their subsequent inflammatory response is thought
traumatic tissue in the lung can initiate a positive feedback loop to account for a significant part of the overall damage to the
2,3
that leads to acute respiratory distress syndrome (ARDS). Recent organ, above and beyond initial necrosis itself. Mechanisms that
observations have indicated that the DAMPs released by this mediate this deterioration may include the edema that arises
type of feedback after renal transplantation can lead to RN in following capillary leakage, induction of cell death by innate
the lung as well. 4 immune cells with the effect of decreased organ function, and
For years, immunology focused on the issue of self versus dysregulated partial oxygen pressure within the area of
nonself recognition. However, within the past two decades, the inflammation/necrosis. Also, mature DCs interact with CD8 T
danger/injury model has become more and more prominent. cells (Chapter 17) via major histocompatibility complex (MHC)

197