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

ABSTRACT

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-1ß, 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.