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: