When cell death goes wrong: inflammatory outcomes of failed apoptosis and mitotic cell death

Abstract

Apoptosis is a regulated cellular pathway that ensures that a cell dies in a structured fashion to prevent negative consequences for the tissue or the organism. Dysfunctional apoptosis is a hallmark of numerous pathologies, and treatments for various diseases are successful based on the induction of apoptosis. Under homeostatic conditions, apoptosis is a non-inflammatory event, as the activation of caspases ensures that inflammatory pathways are disabled. However, there is an increasing understanding that under specific conditions, such as caspase inhibition, apoptosis and the apoptotic machinery can be re-wired into a process which is inflammatory. In this review we discuss how the death receptor and mitochondrial pathways of apoptosis can activate inflammation. Furthermore, we will highlight how cell death due to mitotic stress might be a special case when it comes to cell death and the induction of inflammation.

Fig. 1. Overview of the death receptor and mitochondrial pathways of apoptosis.

Ligation of the TRAIL or Fas death receptor stimulates its trimerisation. FADD binds to the cytoplasmic death domain (DD) portion of the death receptor, which in turn recruits death effector domain-containing proteins such as caspase-8, cFLIP, and caspase-10 to form the death-inducing signalling complex (DISC). Activation of caspase-8 at the DISC forms a catalytically active dimer, which can cleave a limited number of substrates, but crucially including caspases −3 and −7 and BID. Cleavage and activation of the executioner caspases −3 and −7 drives cellular demolition.

Fig. 2. Death receptor apoptotic machinery can be proinflammatory.

Ligation of the TRAIL receptor stimulates the formation of the death-inducing signalling complex (DISC). FADD is the first to be recruited, which allows the recruitment of multiple copies of caspase-8 through death-effector domain (DED) interactions. RIPK1 is also recruited, and can be modified with ubiquitin chains by cIAP1/2. This complex can then dissociate from the plasma membrane, forming the FADDosome which can activate NF-κB-dependent gene transcription and cytokine and chemokine production.

Fig. 3. Mitochondrial apoptosis is pro-inflammatory via BAX/BAK pores.

Permeabilisation of the mitochondrial outer membrane by BAX/BAK can trigger inflammation in a number of different ways. Firstly, following MOMP, the inner membrane herniates and permeabilises, allowing the efflux of mtDNA into the cytoplasm where it activates cGAS-STING-dependent inflammatory responses, such as activation of type I interferon responses and NF-κB. SMAC release during MOMP triggers IAP degradation and NIK activation, leading to NF-κB activation. During infection with viruses, such as SFTSV, BAX/BAK pores facilitate the release of oxidized mtDNA, which can bind and activate the NLRP3 inflammasome, triggering NF-κB responses. Finally, mitochondrial RNA can be released via BAX/BAK pores, which are detected by MDA5 and MAVS in the cytoplasm, triggering a type I interferon response.

Fig. 4. Stress during mitosis activates apoptosis and inflammation.

DNA damage or other mitotic stresses can lead to defects in mitosis, including chromosomal instability and micronuclei. These issues are detected by various surveillance mechanisms to prevent the propagation of potentially mutated or otherwise harmful cells. Micronuclei or cytoplasmic chromatin fragments are detected by the cGAS-STING pathway, leading to the activation of type I interferon, NF-κB signaling, and subsequently inflammation, but also metastasis or cell death. Supernumerary centrosomes promote the activation of the PIDDosome, which cleaves and inhibits MDM2. Therefore, p53 is stabilized and can promote apoptosis, cell cycle arrest or senescence. Mitotic stress also shifts the balance of pro-survival BCL-2 proteins and proapoptotic BH3-only proteins to promote apoptosis.