Poly (ADP-ribose) polymerase 14 and its enzyme activity regulates TH2 differentiation and allergic airway disease

Abstract

Background Interleukin-4 (IL-4) and STAT6 play an important role in progression of allergic airway disease (AAD) or asthma. IL-4 and STAT6 mediate T helper 2 (Th2) responses in T cells, and immunoglobulin class switching to IgE in B cells. Both, Th2 responses and IgE promote the asthmatic condition. We have previously demonstrated that PARP-14, a member of the poly ADP-ribose polymerase (PARP) family of proteins regulates the transcription function of STAT6. However, the role of PARP-14 in AAD is not known. Objective Here we investigate the role of PARP-14 and the enzyme activity associated with it in AAD dependent on airway hyper-responsiveness (AHR) and lung inflammation. We also elucidate the mechanism by which PARP-14 regulates AAD. Methods The role of PARP-14 and its enzyme activity in AAD and Th2 differentiation were examined using a mouse model of AAD and in vitro T helper cell differentiation. Results PARP-14 deficient animals when compared to controls show reduced lung pathology and IgE. Treating mice with a pharmacological inhibitor for PARP activity reduced the severity of AHR and lung inflammation. Mechanistically, our data indicate that PARP-14 and its enzyme activity aid in the differentiation of T cells towards a Th2 phenotype by regulating the binding of STAT6 to the Gata3 promoter. Conclusion PARP-14 and the catalytic activity associated with it promote Th2 differentiation and AAD in a murine model, and targeting PARP-14 may be a potential new therapy for allergic asthma.

B Cell–Intrinsic and –Extrinsic Regulation of Antibody Responses by PARP14, an Intracellular (ADP-Ribosyl)Transferase

“…Recent work has provided parallel evidence that PARP14 impacts a primary immune response leading to allergic lung inflammation and IgE anti-ovalbumin (61). Intriguingly, our data revealed no reduction in pulmonary inflammation after the primary exposure, yet upon recall challenge major markers of Th2 inflammation (eosinophil recruitment; IL-4) were halved.…”

PARP9 and PARP14 cross-regulate macrophage activation via STAT1 ADP-ribosylation

“…PARP14 −/− mice were backcrossed into the C57BL/6 genetic background over 10 generations2554. Male PARP14 −/− mice and age-matched PARP14 +/+ mice were used for a vascular injury model or as donors for BMT.…”

The Immunologic Mechanisms of Eosinophilic Esophagitis

“…The CCL26 promoter is hypomethylated, and CCL26 expression is highly induced, in patients with EoE [45, 56]. Additionally, PARP14, a transcriptional cofactor from the poly(ADP-ribose) polymerase (PARP) family that facilitates CCL26 transcription via STAT6, is also dysregulated in EoE [83–85]. PARP14 expression is increased in biopsies of children with EoE compared to controls, and CCL26 expression strongly correlates with PARP14 expression [85].…”