Heterozygous Apex1 deficiency exacerbates lipopolysaccharide-induced systemic inflammation in a murine model.

The biological role of apurinic/apyrimidinic endonuclease 1/redox factor-1 (Apex1) in modulating systemic inflammation remains unclear. This study aimed to assess the impact of Apex1 deficiency on systemic inflammation triggered by lipopolysaccharide (LPS) in a murine model. The methods involved transcriptomic analysis and assessments of inflammatory responses in age-matched 8-week-old Apex1 and wild-type Apex1 mice, generated using the CRISPR/Cas9 system. Apex1 mice displayed no overt changes in body weight, however, Apex1 protein expressions in tissues were significantly reduced compared to wild-type mice. Furthermore, in Apex1 mice transcriptomic analysis showed that genes associated with antioxidant pathways were downregulated, and levels of superoxide production, 8-hydroxy-2'-deoxyguanosine (8-OHdG), and malondialdehyde (MDA) were increased. Moreover, hematological analysis showed increased neutrophil levels and a twofold increase in the count of splenic lymphocyte antigen 6 family member G (Ly6G) neutrophils in the Apex1 mice compared to those in Apex1 mice. Furthermore, following LPS treatment, the levels of cytokines and chemokines, including interleukin-1β, interleukin-10, tumor necrosis factor-α, and monocyte chemoattractant protein 1, increased in the Apex1 mice. The Kaplan-Meier curve showed a significant reduction in the survival rates of Apex1 mice treated with LPS compared to those of Apex1 mice. The hepatic and lung injury scores and Ly6G neutrophil infiltration levels also increased in Apex1 mice after LPS treatment. These results showed that Apex1 deficiency exacerbated the LPS-induced tissue damage in the lung and liver. These findings illustrate that in vivo Apex1 deficiency exacerbates LPS-induced systemic inflammation, tissue damage, and mortality in a murine model, highlighting the crucial role of Apex1 in mitigating inflammatory responses and maintaining a holistic physiological equilibrium.