PARP1 and inflammatory disease
PARP1 activation is observed in both infectious and non-infectious
diseases, simultaneous to inflammatory responses. Hyper-activation of
PARP1 in response to DNA damage causes NAD and ATP depletion and
consequently necrosis (Rajawat et al., 2007) , leading to inflammatory
state in many diseases. PARP1 also plays an important role in regulating
pro-inflammatory gene expression and subsequently cell death in the
damaged tissues (Beneke & Burkle, 2007; Jagtap & Szabo, 2005). Several
evidences reflect the role of PARP1 in activation of transcription
factors like NFкB, AP-1, heat shock proteins, adhesion molecules in
promoting inflammation. PARP1 is known to be a coactivator of AP-1 and
NFкB and hence regulates their expression during chronic inflammation.
PARP1- NFкB interaction then induces downstream signalling by inducing
the expression of pro-inflammatory cytokines including IL-1, TNF-α, IFNγ
and iNOS activation (Ba & Garg, 2011). Implication of PARP1 was also
observed in renin-angiotensin system (RAS) that responds to inflammation
(Reinemund et al., 2009). RAS signalling promotes viral entry and
simultaneously inhibits or regulates severe lung injury and inflammation
(Fung & Liu, 2019). PARP1 deletion or inhibition was beneficial in
lipopolysaccharides (LPS) induced pulmonary inflammation (Liaudet et
al., 2002; Zerfaoui et al., 2009). Similarly, PARP1 inhibition delayed
the gut inflammation during enterocolitis caused by Salmonella
typhimurium (Altmeyer et al., 2010). Additionally, massive DNA damage
induced PARP activation aggravates inflammatory response in ventilator
induced lung injury (Kim et al., 2008; Vaschetto et al., 2008). Thus,
PARP inhibition is anti-inflammatory and can control hyper-inflammation
induced during several pathologies. Moreover, PARP1 also controls the
immune function by destabilizing the Foxp3 in regulatory T cells (Treg)
(Hori et al., 2017). PARP1 is known to destabilize Foxp3 by
ADP-ribosylation, while, PARP inhibition stabilizes Foxp3 and
subsequently downstream gene expression involved in Treg immune
suppressive function (Luo et al., 2015).
Cytokine storm, which is represented by a dysregulated
cytokine/chemokine response, has been shown to be one of the key
biological manifestation during the SARS-CoV pandemic (Channappanavar &
Perlman, 2017). While the cell types infected by the SARS-CoV-2 are
still under investigation, the cytokine storm they may entail may be
more varied and detrimental for the healthy cells, apart from the viral
infection itself. Cytokine storm leads to hyper-inflammation that could
be a major cause for mortality (Mehta et al., 2020). Hyper-inflammation
can be curbed by inhibiting PARP with nicotinamide, as this might lead
to inhibition of iNOS and downstream pro-inflammatory gene response.
Furthermore, NAD and niacin supplementation could also prove to be
beneficial in suppressing inflammation and oxidative stress induced cell
death (Gharote, 2020). There are reports of the association of
senescence with chronic obstructive pulmonary disorder (COPD). These
senescent cells are also known to secrete pro-inflammatory cytokines
such as IL-6, IL-8 and plasminogen activator inhibitor-I (PAI) (Kumar et
al., 2014). Thus, senescence and senescence associated secretory
phenotype (SASP) during viral infection cannot be neglected.
Table 1: PARP inhibitors in inflammatory diseases: