| First Author | Tapryal N | Year | 2021 |
| Journal | J Biol Chem | Volume | 296 |
| Pages | 100723 | PubMed ID | 33932404 |
| Mgi Jnum | J:316229 | Mgi Id | MGI:6707449 |
| Doi | 10.1016/j.jbc.2021.100723 | Citation | Tapryal N, et al. (2021) Intrapulmonary administration of purified NEIL2 abrogates NF-kappaB-mediated inflammation. J Biol Chem :100723 |
| abstractText | Aberrant or constitutive activation of NF-kappaB contributes to various human inflammatory diseases and malignancies via the upregulation of genes involved in cell proliferation, survival, angiogenesis, inflammation, and metastasis. Thus, inhibition of NF-kappaB signaling has potential for therapeutic applications in cancer and inflammatory diseases. We reported previously that NEIL2, a mammalian DNA glycosylase, is involved in the preferential repair of oxidized DNA bases from the transcriptionally active sequences via the transcription-coupled base excision repair pathway. We have further shown that Neil2-null mice are highly sensitive to TNFalpha- and LPS-induced inflammation. Both TNFalpha and LPS are potent activators of NF-kappaB. However, the underlying mechanism of NEIL2's role in the NF-kappaB-mediated inflammation remains elusive. Here we have documented a non-canonical function of NEIL2, and demonstrated that the expression of genes involved in inflammation and immune cell migration, such as Cxcl1, Cxcl2, Cxcl10, Il6, and Tnfalpha was significantly higher in both mock- and TNFalpha-treated Neil2-null mice compared to that in the wild-type mice. NEIL2 blocks NF-kappaB's binding to target gene promoters by directly interacting with the Rel homology region of RelA and represses pro-inflammatory gene expression as determined by co-immunoprecipitation, chromatin immunoprecipitation and electrophoretic mobility-shift assays. Remarkably, intrapulmonary administration of purified NEIL2 via a non-invasive nasal route significantly abrogated binding of NF-kappaB to cognate DNA, leading to decreased expression of pro-inflammatory genes and neutrophil recruitment in Neil2-null as well as wild-type mouse lungs. Our findings thus highlight the potential of NEIL2 as a biologic for inflammation-associated human diseases. |
