2.4 Necroptosis related signaling pathway
The different kinds of RCD can be regard as an individual, concerted
cell death system, in which the single pathways are closely interrelated
and mutual coordinate for each other. These interaction describes a
complicated molecular signal network can be consider as a homeostatic
mechanism for the organism (Galluzzi et al. 2017) (show in Fig 4).
Therefore, it is not difficult to understand that necroptosis signal
pathway is closely related with several other forms of RCD containing
apoptosis, autophagy and ferroptosis. It has mentioned above, casepase 8
is seems like a key switch between apoptosis and necroptosis, due to its
cleaving capacity of RIPK1 and RIPK3. In addition, apoptosis and
necroptosis share the upstream TNFR pathway, mainly including
FADD,
cellular FLICE-inhibitory protein
(cFLIP),
caspase 8, cylindroma protein (CYLD)
and various inhibitor of apoptosis protein (IAP) family members that
interact with TNFR1(Oberst et al. 2011, Dillon et al. 2012). Moreover,
caspase
6 is the downstream regulator of apoptosis and cathepsins can leading to
lysosomal injury by accelerates permeation of mitochondrial outer
membrane (Galluzzi, Bravo-San Pedro and Kroemer 2014). Both caspase 6
and cathepsins can proteolytic inactivate RIPK1 to exert
necroptosis-inhibitory effects (van Raam et al. 2013, McComb et al.
2014b). Researches have shown that, in transformed cells, autophagy can
promote necroptosis by ROS accumulation (Chen et al. 2011). In addition,
autophagy-related protein 16-1 can interdicts necroptosis in the
intestinal epithelium (Matsuzawa-Ishimoto et al. 2017). Moreover, it is
reported that glutathione peroxidase 4, the primary endogenous inhibitor
of ferroptosis, can mediates powerful necroptosis inhibition effects in
erythroid precursor cells (Canli et al. 2016). Besides different forms
of RCD mentioned above, necroptosis also intimately connected with
inflammation, oxidative stress and many other physiopathological
processes (Galluzzi et al. 2017). Ca(2+)-calmodulin-dependent protein
kinase is a RIPK3 substrate mediating ischemia- and oxidative
stress-induced myocardial necroptosis (Zhang et al. 2016b). Recent
literature indicated that necroptosis is a primary mechanism of retinal
pigment epithelial (RPE) cell death in response to oxidative stress
(Hanus, Anderson and Wang 2015). It is well known that reactive oxygen
species (ROS) can be regarded as a driving force of necroptosis. ROS can
trigger RIPK1 autophosphorylation on S161 by modify three crucial
cysteine residues which is necessary for RIP3 recruitment into necrosome
complex of necroptosis (Zhang et al. 2017). In addition, studies show
that TNFα-mediated necroptosis accelerates increased transcription of
inflammatory cytokine gene by a cell-autonomous mechanism involving
NF-κB and p38 (Zhu et al. 2018a). In a word, it has been demonstrated
that necroptosis participate in cell death in diverse disease
conditions, including organ fibrosis, viral infection, acute kidney
injury, and cardiac I/R (Galluzzi et al. 2017, Schwabe and Luedde 2018).
In this review, we aim to focus on the relationship between the
pathological process of necroptosis and tissue fibrosis, as well as
potential drug targets of necroptosis for the clinical treatment of
fibrotic diseases.