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Involvement of eNAMPT/TLR4 signaling in murine radiation pneumonitis: protection by eNAMPT neutralization
Alexander N Garcia1, Nancy G Casanova2, Daniel G Valera1
1Department of Radiation Oncology, University of Arizona Health Sciences, Tucson, Arizona.
Abstract:
Therapeutic strategies to prevent or reduce the severity of radiation pneumonitis are a serious unmet need. We evaluated extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a damage-associated molecular pattern protein (DAMP) and Toll-Like Receptor 4 (TLR4) ligand, as a therapeutic target in murine radiation pneumonitis. Radiation-induced murine and human NAMPT expression was assessed in vitro, in tissues (IHC, biochemistry, imaging), and in plasma. Wild type C57Bl6 mice (WT) and Nampt+/- heterozygous mice were exposed to 20Gy whole thoracic lung irradiation (WTLI) with or without weekly IP injection of IgG1 (control) or an eNAMPT-neutralizing polyclonal (pAb) or monoclonal antibody (mAb). BAL protein/cells and H&E staining were used to generate a WTLI severity score. Differentially-expressed genes (DEGs)/pathways were identified by RNA sequencing and bioinformatic analyses. Radiation exposure increases in vitro NAMPT expression in lung epithelium (NAMPT promoter activity) and NAMPT lung tissue expression in WTLI-exposed mice. Nampt+/- mice and eNAMPT pAb/mAb-treated mice exhibited significant histologic attenuation of WTLI-mediated lung injury with reduced levels of BAL protein and cells, and plasma levels of eNAMPT, IL-6, and IL-1β. Genomic and biochemical studies from WTLI-exposed lung tissues highlighted dysregulation of NFkB/cytokine and MAP kinase signaling pathways which were rectified by eNAMPT mAb treatment. The eNAMPT/TLR4 pathway is essentially involved in radiation pathobiology with eNAMPT neutralization an effective therapeutic strategy to reduce the severity of radiation pneumonitis.
Insights
Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) neutralization effectively reduces radiation pneumonitis severity. Targeting the eNAMPT/Toll-Like Receptor 4 pathway offers a promising therapeutic strategy for lung injury.
Area of Science:
- Immunology
- Molecular Biology
- Radiology
Background:
- Radiation pneumonitis is a significant clinical challenge with limited therapeutic options.
- Extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a damage-associated molecular pattern protein and Toll-Like Receptor 4 (TLR4) ligand, is implicated in inflammatory responses.
Purpose of the Study:
- To investigate eNAMPT as a therapeutic target for radiation-induced lung injury.
- To assess the efficacy of eNAMPT neutralization in a murine model of radiation pneumonitis.
Main Methods:
- Radiation pneumonitis was induced in mice using whole thoracic lung irradiation (WTLI).
- eNAMPT expression was analyzed in vitro and in vivo.
- Mice were treated with eNAMPT-neutralizing antibodies (polyclonal and monoclonal).
- Lung injury was assessed via histology, bronchoalveolar lavage (BAL) analysis, and plasma cytokine profiling.
- RNA sequencing identified differentially expressed genes and pathways.
Main Results:
- Radiation exposure increased NAMPT expression in lung epithelial cells and tissues.
- Treatment with eNAMPT antibodies significantly attenuated lung injury, reducing BAL protein/cells and plasma inflammatory markers (IL-6, IL-1β).
- eNAMPT neutralization rectified dysregulated NFkB/cytokine and MAP kinase signaling pathways in irradiated lungs.
Conclusions:
- The eNAMPT/TLR4 pathway plays a critical role in radiation pneumonitis pathogenesis.
- Neutralizing eNAMPT represents a viable therapeutic strategy to mitigate radiation-induced lung damage.
