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).