APE1/Ref-1 Role in Inflammation and Immune Response

Abstract

Apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1) is a multifunctional enzyme that is essential for maintaining cellular homeostasis. APE1 is the major apurinic/apyrimidinic endonuclease in the base excision repair pathway and acts as a redox-dependent regulator of several transcription factors, including NF-κB, AP-1, HIF-1α, and STAT3. These functions render APE1 vital to regulating cell signaling, senescence, and inflammatory pathways. In addition to regulating cytokine and chemokine expression through activation of redox sensitive transcription factors, APE1 participates in other critical processes in the immune response, including production of reactive oxygen species and class switch recombination. Furthermore, through participation in active chromatin demethylation, the repair function of APE1 also regulates transcription of some genes, including cytokines such as TNFα. The multiple functions of APE1 make it an essential regulator of the pathogenesis of several diseases, including cancer and neurological disorders. Therefore, APE1 inhibitors have therapeutic potential. APE1 is highly expressed in the central nervous system (CNS) and participates in tissue homeostasis, and its roles in neurodegenerative and neuroinflammatory diseases have been elucidated. This review discusses known roles of APE1 in innate and adaptive immunity, especially in the CNS, recent evidence of a role in the extracellular environment, and the therapeutic potential of APE1 inhibitors in infectious/immune diseases.

Keywords: DNA repair; NF-κB; biomarker; cytokines; inflammation; innate immunity; oxidized DNA damage; reactive oxygen species.

Figure 1

Representative scheme of the functional domains of Apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1). The N-terminal domain (amino acids 1 to 127) contains redox activity and the nuclear localization signal. The C-terminal domain (amino acids 161 to 318) contains apurinic/apyrimidinic endonuclease activity. Both domains may be involved in the transcriptional regulation of some genes, such as VEGF.

Figure 2

Involvement of APE1 in expression of cytokines and chemokines and reactive oxygen species (ROS) regulation. (A) The stimulation of Toll-like receptors promotes NF-κB activation and its translocation to the nucleus. APE1 redox function reduces transcription factors, such as NF-κB and AP-1, and increases expression of cytokines. APE1 also inhibits Rac1 and ROS production by NADPH oxidase. Inhibition of APE1 redox function decreases the expression of NOX1, P65, and ELK1 (represented in red color). (B) The DNA repair activity of APE1 also regulates expression of cytokines. 8-Oxoguanine DNA glycosylase and APE1 recruitment to damaged sites is essential for downstream recruitment of transcription factors. Additionally, inhibition of APE1 DNA repair activity decreases the expression of various genes/proteins (represented in red color).

Figure 3

Effect of APE1 redox and repair activities in adaptive immunity. Repair activity of APE1/Ref-1 participates in class switch recombination, while redox activity downregulates Th1 responses and regulates B cell activation.