Pharmacologic inhibition of PARP5, but not that of PARP1 or 2, promotes cytokine production and osteoclastogenesis through different pathways

Objectives: PARPs, part of the poly(ADP-ribose) polymerase superfamily, are implicated in tumorigenesis and tumor-associated inflammation, making them important therapeutic targets in various cancers. This study aims to explore the mechanistic roles of PARPs in inflammation.

Methods: Primary murine macrophages were cultured with or without the PARP5 inhibitor NVP-TNKS656 to investigate the role of PARP5 in cytokine production.

Results: Contrary to the roles of other PARPs in promoting inflammation, our findings indicate that pharmacological inhibition of PARP5 actually enhances the production of inflammatory cytokines in primary murine macrophages. Treatment with NVP-TNKS656 increased both steady-state and LPS-induced cytokine production by degrading IκBα, leading to the nuclear translocation of NF-κB. Additionally, we observed that inhibiting PARP5 stabilizes the adaptor protein 3BP2, a substrate of PARP5. The heightened cytokine production resulting from PARP5 inhibition was diminished in macrophages lacking 3BP2. Furthermore, LPS treatment increased the expression of 3BP2 and AXIN1, a negative regulator of β-catenin, by suppressing PARP5 transcripts in macrophages. This process further activated cytokine production while inhibiting β-catenin-mediated cell proliferation. Lastly, we found that PARP5 inhibition promotes osteoclastogenesis in macrophages by stabilizing 3BP2 and AXIN1, which activates SRC and suppresses β-catenin.

Conclusions: Our results reveal that pharmacological inhibition of PARP5, unlike the inhibition of other PARPs, unexpectedly triggers adverse autoinflammatory responses through the activation of innate immunity.