A Perspective on Mammalian Caspases as Positive and Negative Regulators of Inflammation

Abstract

Members of the caspase family of cysteine proteases coordinate the morphological and biochemical events that typify apoptosis. However, neutralization of caspase activity in mammals fails to block death in response to most proapoptotic stimuli. This is because many cell death triggers provoke mitochondrial dysfunction upstream of caspase activation as a consequence of BAX/BAK channel opening. Although genetic or pharmacological inactivation of caspases fails to block cell death in most instances, it does convert the phenotype from apoptosis to necrosis. This has important implications for how the immune system responds to such cells, as necrotic cells provoke inflammation whereas apoptotic cells typically do not. Here, we propose an alternative perspective on apoptosis-associated caspase function by suggesting that these proteases are activated, not to kill, but to extinguish the proinflammatory properties of dying cells. This perspective unifies the mammalian caspase family as either positive or negative regulators of inflammation.

Die another way – non-apoptotic mechanisms of cell death

“…In the absence of being phagocytosed, apoptotic cells undergo secondary necrosis and lyse; however, even in this situation they might fail to stimulate an inflammatory response. This has led to the proposal that rather than being required for cell death, caspases serve to inactivate DAMPs (Martin et al, 2012). Various data support this idea, in that caspases -either by direct cleavage or indirectly -have been shown to inactivate various DAMPs, including HMGB1 and IL-33 (Kazama et al, 2008;Lüthi et al, 2009).…”

Cell death offers exceptional cellular and molecular windows for pharmacological interventions in protozoan parasites

“…A landmark study has implicated necrotic cells are sensed by the NLRP3 inflammasome resulting in the subsequent pro-inflammatory cytokine IL-1ß release ( Figure 10) [100]. Early examples of research reported that caspases served to inactivate DAMPs ( [101][102][103], thereby caspases could be viewed as cell death effectors and regulators of inflammation [103].…”

GSK-3 – at the crossroads of cell death and survival

“…Caspase-9 undergoes auto-processing and then cleaves the effector caspase-3 and caspase-7, resulting in their activation. Caspase-3 (and caspase-7) activity mediates all the hallmarks of apoptosis, such as nuclear condensation, oligonucleosomal DNA cleavage, phosphatidylserine exposure and the shut-off of respiration, resulting in cell death and immediate uptake of apoptotic cells by phagocytes, in general without triggering inflammation (Martin et al, 2012;Riedl and Salvesen, 2007) .…”