An Oligodeoxynucleotide with AAAG Repeats Significantly Attenuates Burn-induced Systemic inflammatory Responses by inhibiting interferon Regulatory Factor 5 Pathway
Previously, we showed that an oligodeoxynucleotide (ODN) with AAAG repeats (AAAG ODN) rescued mice from fatal acute lung injury (ALI) induced by influenza virus and inhibited production of tumor necrosis factor-α (TNF-α) in the injured lungs. However, its underlying mechanisms remain to be elucidated. Upon the bioinformatic analysis revealing that the sequence of AAAG ODN is in consensus with the interferon regulatory factor 5 (IRF5) binding site in the cis-regulatory elements of proinflammatory cytokines, we tried to explore whether AAAG ODN could attenuate burn injury-induced systemic inflammatory responses by inhibiting the IRF5 pathway. Using a mouse model with sterile systemic inflammation induced by burn injury, we found that AAAG ODN prolonged the lifespan of the mice, decreased the expression of IRF5 in the injured skin, reduced the production of TNF-α and IL-6 in the blood and injured skin, and attenuated the ALI. These effects were correlated with AAAG ODN-mediated inhibition of nuclear translocation of IRF5. The data suggest that AAAG ODN could act as a cytoplasmic decoy capable of interfering the function of IRF5 and be developed as a drug candidate for the treatment of inflammatory diseases.
The authors would like to thank Leichao Zhang, Jiwei Liu and Xian Zhang for technical assistance, and acknowledge the contribution of Wei Sun, Xiuping Meng and Shu Nie for analysis strategies. This work was supported by the National Nature Scientific Foundation of China (81471888, 81570002 and 31670937).
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