Autophagic cell death and innate immunity
Different experimental evidences have revealed the presence of
autophagosomes and the rearrangement of the cytoskeleton in dying cells,
but wherever this is a strategy of cell survival rather than an active
death mechanism, has been a controversy. Conclusive data, using
apoptosis inhibitors and Bax/Bak-deficient mouse embryonic fibroblasts
have showed that autophagic cell death is an alternative to apoptosis in
which cell dies in response to chemical stressors or cytotoxic
substances like staurosporine or etoposide, through a process that
involve the formation of multiple vesicular organelles and can be
reversed using classical autophagy inhibitors such as
3-methyladenine(3-MA) or silencing ATG genes (reviewed in
(Tsujimoto & Shimizu, 2005)). It seems
that like regulated necrosis, autophagic death is activated under
certain stimulus including infection when apoptosis is blocked or
inhibited, playing a protective role in host defense. In line with this,
different in vivo studies have demonstrated the importance of theATG genes against bacterial and viral infections such asListeria monocytogenes, Toxoplasma gondii , herpes simplex virus 1
and Sindbis virus in mice (Orvedahl et
al., 2007; Orvedahl et al., 2010;
Zhao et al., 2008).
As occurs with apoptosis and regulated necrosis, autophagic cell death
can be activated by PRRs as result of direct contact with pathogens,
inducing an alternative defense that helps cells to deal with viruses or
intracellular microorganisms, a key element of innate immune response.
The activation of the autophagic death by TLRs such as TLR1/2, TLR3,
TLR4 and TLR7 has been corroborated in mice-derived macrophages and
dendritic cells, in response to agonists like bacterial
lipopolysaccharide (LPS) or under Mycobacterium tuberculosisinfection. In the same way, peptidoglycan has demonstrated to induce
autophagy through NOD proteins, mainly Nod1 and Nod2 in murine myeloid
and epithelial cells (reviewed in (Sumpter
Jr & Levine, 2010)). Interestingly, muramyldipeptide a peptidoglycan
derived product, also activates autophagy in human dendritic cells, in a
process that requires NOD2, RIP2 , and the ATG genes,ATG5, ATG7 , and ATG16L1 , increasing MHC Class II antigen
expression and CD4+ T lymphocytes proliferation
(Cooney et al., 2010). Not only bacterial
but viral infections also induce an autophagic defensive response in
host cells. Viral single strand RNAs (ssRNAs) are recognized by TLR7 and
NOD2 stimulating antiviral defense in RAW 264.7 macrophages and type I
IFN production in dendritic cells. The ssRNAs can additionally activate
other intracellular sensors like RNA-dependent protein kinase (PKR)
which activate autophagy via Beclin-1 in mouse embryonic fibroblasts and
primary neurons infected with herpes simplex virus 1
(Gu, Wang, & Yang, 2014).
The process of autophagy by itself is intrinsically connected to innate
immune clearance of intracellular pathogens. Thus, when a pathogen
interacts with a host cell it triggers an autophagic process that could
lead to its own phagocytosis or eventually to the death of the infected
cell, exposing this microbe to other effector cells of the immune
system. Experimental results with intracellular Salmonella ,
enteropathogenic Echerichia coli , Streptococcus pyogenesand L. monocytogenes show that engulfed bacteria are targeted to
autophagosomes and subsequently to autolysosomes by a coat of ubiquitin
that interacts with the cytoskeleton protein LC3. This was corroborated
by colocalization and confocal microscopy studies, together with the use
of Atg5 or p62 deficient cells and genetically modified
microbial strains insensitive to ubiquitin recognition
(Sumpter Jr & Levine, 2010). In the
context of infection, different autophagic signalling proteins such as
p62, CALCOCO 2 (calcium binding and coiled-coil domain containing
protein 2) and optineurin can act as adaptor proteins in the
inflammatory pathway ultimately activating NF-κB and cytokine secretion.
Additionally, p62 is also involved in the recruitment of cytosolic
proteins such as ubiquitin or ribosomal proteins to autolysosomes, to be
converted by internal proteolysis in antimicrobial peptides, highly
effective to intracellular pathogens like M. tuberculosis(reviewed in (Deretic, 2012).
The processes of autophagy and autophagic cell death have been also
revised due to its controversial role in cancer. Some studies reveal
that autophagy actually contribute with survival, metabolic
reprogramming and tumor development. Interestingly, the same process can
lead to the elimination of cancer cells by autophagic cell death
(Yang et al., 2015). Autophagy is also
required for immune cell activation, antigen presentation, thymus
selection and cytokine release in different cell types such as NK cells,
Dendritic cells (DC) and T lymphocytes, but represents a “double edge
sword” that can also regulate these cell populations by autophagic cell
death. Current research is focus on the understanding of this dual role
and its potential application in cancer immunotherapy
(Jiang et al., 2019).