Apoptosis and innate immunity
Apoptosis, the most classical and the best characterized form of PCD, represents a biological strategy that selectively eliminates infected cells to restrict the reproduction and propagation of viruses and intracellular pathogens (H. Chen et al., 2017). In this context, apoptosis seems to be stimulated by pathogen-cell interactions leading to Caspase 8 activation and initiation of the extrinsic apoptotic pathway (Yeretssian et al., 2011). This evolutionary mechanism is in fact highly effective and many intracellular pathogens have evolved to suppress apoptosis in a Caspase 8-dependent manner (Weng et al., 2014). In addition, apoptosis is an essential part of the cytotoxic mechanism displayed by innate immune cells like natural killer (NK) lymphocytes. It has been described that these effector cells induce apoptosis in microbe infected cells through specific serine proteases, called granzymes (Abbas, Lichtman, & Pillai, 2014). In the current model proposed to explain this process, perforins and granzymes released from cytoplasmic granules of NK cells are internalized by target cells during immune synapse, through endocytosis. Once in the endocytic compartment, membrane pore-forming proteins perforins facilitate the release of granzymes into the cytosol, where they induce apoptosis proteolyticaly activating executioner caspases (like Caspase 3) or members of the B-cell lymphoma 2 (Bcl-2) protein family, like Bid (BH3 interacting domain death agonist) (reviewed in (Prager & Watzl, 2019)). These lymphocytes also eliminate target cellsby apoptosis, expressing Fas and TRAIL receptors, which induce the apoptotic process by the intrinsic pathway via Caspase 8 activation (Prager & Watzl, 2019).
The molecular crosstalk between apoptosis and innate immunity is not limited to the executioner mechanisms and it also occurs during the regulation of cell response to infection. For example, the stimulator of the mitochondrial apoptotic pathway Bid is also involved in pathogen recognition receptor (PRR) signaling, inflammation and immunity. Bid seems to be recruited by nucleotide-binding and oligomerization domain (NOD) proteins after microbial DNA recognition, to form a complex with IκB kinase (IKK) and promote the activation of nuclear factor-κB (NF-κB) and extracellular signal-regulated kinase (ERK) pathways (Yeretssian et al., 2011). Through this dual role, Bid regulates how cells react to infection, either dying by an apoptotic process or surviving and displaying a pro-inflammatory and antimicrobial response (Yeretssian et al., 2011). In a similar way, TNF could stimulate pro-inflammatory and antimicrobial defensive pathways or induce apoptotic cell death, depending on the cellular conditions (Pasparakis & Vandenabeele, 2015). Additional examples of this interplay between apoptosis induction and innate immune response are related with the multifunctional role of other proteins that interconnect both processes, such as the Interferon-β promoter stimulator 1 (IPS-1) and heat shock proteins (HSPs). IPS-1 is involved in mitochondrial antiviral signaling and virus-induced Interferon-β (IFN-β) stimulation; however, it is also crucial to apoptosis and anoikis induction after cell detachment (Li et al., 2009). It has been experimentally demonstrated that IPS-1 once inserted in mitochondrial outer membrane, is able to recruit and activate Caspase 8 to induce anoikis by a distinct pathway that is independent of death receptor signaling or death associated protein 3 (DAP3) function (Li et al., 2009). On the other hand, HSPs which are apoptosis inhibitors and cytoprotective chaperones that promote cell survival to stress, can be translocated to plasma membrane or secreted to extracellular space to stimulate the immune system and enhance the immune response (Joly, Wettstein, Mignot, Ghiringhelli, & Garrido, 2010). HSP70 and HSP90 inhibit apoptosis interfering with death receptor signaling, restricting the mitochondrial permeabilization and cytochrome c release and preventing caspase activation, but in their extracellular form, they display a variety of immune functions including antigen presentation, cell recruitment and activation and a cytokine-like behavior (reviewed in (Joly et al., 2010)).
Apoptosis not only controls infected cells, but also transformed and malignant cells, an important function that is tightly related to immune surveillance and primary immune response to cancer (Su et al., 2015). The intrinsic apoptotic pathway is triggered by irreversible events such as irreparable DNA damage, disruption of cell division or cell cycle arrest, representing a crucial process to prevent genomic instability, increase in mutation rate and consequently, oncogenesis (Hanahan & Weinberg, 2011). Likewise, anoikis is a very effective mechanism to prevent metastasis, eliminating misplaced and detached cells (Zörnig, Hueber, Baum, & Evan, 2001). During tumor development, cancer cells must survive to pro-apoptotic conditions like hypoxia, growth factors deprivation, oxidative stress and metabolic deregulation, therefore apoptosis evasion is consider a hallmark of cancer (Hanahan & Weinberg, 2011; Su et al., 2015). Furthermore, as was described above, apoptotic cell death is crucial to NK cell-mediated cytotoxicity. This primary immune mechanism is critical to antitumor defense and innate immune response to cancer, particularly during carcinogenesis and early tumorigenesis (Pistritto, Trisciuoglio, Ceci, Garufi, & D’Orazi, 2016). Malignant cells have to avoid apoptosis in several stages to successfully become a tumor and colonize a distant organ. In this sense, this form of PCD acts as an intrinsic defense to suppress oncogenesis and neoplastic growth.
In addition to the above described functions, apoptosis also plays a key role in regulation and homeostatic balance after immune response. This is the biochemical program by which immune cells die while the infection is resolved, ensuring the decreasing of circling immune cells to the end of the response and avoiding an excessive damage to local tissues. Thus, the population of activated immune cells is regulated by the own infection, via dead receptors and Caspase 8 (Abbas et al., 2014; Feig & Peter, 2007). Apoptotic death of neutrophils during bacterial, fungal or protozoal infection is a clear example of this scenario. Engulfed microorganisms accelerate neutrophil apoptosis ensuring a secure disposal of the phagocyted materials and ultimately the termination of the response, limiting the release of reactive oxygen species and at the same time recruiting and activating resident macrophages (Geering & Simon, 2011).