Partial Wwox Loss of Function Increases Severity of Murine Sepsis and Neuroinflammation

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Abstract Rationale WW domain-containing oxidoreductase ( WWOX ) is a gene associated implicated in both neurologic and inflammatory diseases and is susceptible to environmental stressors. We hypothesize partial loss of Wwox function will result in increased sepsis severity and neuroinflammation. Methods Wwox WT/P47T mice, generated by CRISPR/Cas9, and Wwox WT/WT mice were treated with intraperitoneal PBS vs LPS (10mg/kg) and euthanized 12 hours post-injection. Open Field Testing (OFT) and Murine Sepsis Severity Scores (MSS) were utilized to measure sickness behavior and sepsis severity, respectively. Brain tissue was analyzed using immunohistochemistry and PCR to measure neuroinflammation and apoptosis. Results Wwox WT/P47T LPS mice demonstrated a more significant response to sepsis with an increase in sickness behavior, sepsis severity, gliosis, and apoptosis compared to Wwow WT/WT LPS littermates. Conclusions Partial loss of Wwox function increases risk for severe sepsis and neuroinflammation. Given the susceptibility of WWOX to environmental stressors, this may be a target for future therapeutic interventions.

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