Intrapulmonary Administration of Purified NEIL2 Abrogates Nf-κB-Mediated Inflammation

Authors

Nisha Tapryal
Shandy Shahabi
Anirban Chakraborty
Koa Hosoki
Maki Wakamiya
Gobinda Sarkar
Gulshan Sharma
Victor J Cardenas
Istvan Boldogh
Sanjiv Sur
Gourisankar Ghosh
Tapas K Hazra

Publication Date

1-1-2021

Journal

Journal of Biological Chemistry

DOI

10.1016/j.jbc.2021.100723

PMID

33932404

PMCID

PMC8164026

PubMedCentral® Posted Date

4-28-2021

PubMedCentral® Full Text Version

Post-print

Published Open-Access

no

Keywords

Animals, Cell Movement, DNA Glycosylases, Gene Expression Regulation, Inflammation, Lung, Mice, NF-kappa B, Signal Transduction

Abstract

Aberrant or constitutive activation of nuclear factor kappa B (NF-κB) 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-κB signaling has potential for therapeutic applications in cancer and inflammatory diseases. We reported previously that Nei-like DNA glycosylase 2 (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 tumor necrosis factor α (TNFα)- and lipopolysaccharide-induced inflammation. Both TNFα and lipopolysaccharide are potent activators of NF-κB. However, the underlying mechanism of NEIL2's role in the NF-κB-mediated inflammation remains elusive. Here, we have documented a noncanonical function of NEIL2 and demonstrated that the expression of genes, such as Cxcl1, Cxcl2, Cxcl10, Il6, and Tnfα, involved in inflammation and immune cell migration was significantly higher in both mock- and TNFα-treated Neil2-null mice compared with that in the WT mice. NEIL2 blocks NF-κB's binding to target gene promoters by directly interacting with the Rel homology region of RelA and represses proinflammatory gene expression as determined by co-immunoprecipitation, chromatin immunoprecipitation, and electrophoretic mobility-shift assays. Remarkably, intrapulmonary administration of purified NEIL2 via a noninvasive nasal route significantly abrogated binding of NF-κB to cognate DNA, leading to decreased expression of proinflammatory genes and neutrophil recruitment in Neil2-null as well as WT mouse lungs. Our findings thus highlight the potential of NEIL2 as a biologic for inflammation-associated human diseases.