Prostaglandin E2-Mediated Impairment of Innate Immune Response to A(H1N1)pdm09 Infection in Diet-Induced Obese Mice Could Be Restored by Paracetamol

Background Obesity is associated with increased severity of influenza infection. However, the underlying mechanism is largely unknown. Methods We employed a mouse model with diet-induced obesity (DIO) to study the innate immune responses induced by influenza virus. Results The lungs of DIO mice were heavily affected by obesity-associated chronic systemic inflammation with a significant increase in inflammatory cytokines/chemokines. Concurrently, lipid immune mediator prostaglandin E-2 (PGE(2)) was also significantly elevated in DIO mice. However, the DIO mice mounted a blunted and delayed upregulation of mRNA and protein concentrations of interferon- and inflammatory cytokines/chemokines upon A(H1N1)pdm09 virus (H1N1/415742Md) challenge compared with those of lean mice. PGE(2) concentrations were significantly higher in the lungs of DIO mice compared to that of lean mice postchallenge. Treatment with paracetamol in challenged DIO mice significantly enhanced the expression of interferon-/ and cytokine genes at days 1 and 3 postinfection compared with that of untreated DIO mice. Furthermore, paracetamol treatment alone started 3 days before virus challenge and continued until 6 days postchallenge ameliorated the severity of a lethal H1N1/415742Md infection in DIO mice with improved survival. Conclusions Impaired innate response to influenza in DIO mice is associated with elevated PGE(2), which could be restored to some degree by paracetamol treatment. Low-grade chronic inflammatory state in the respiratory tissue of diet-induced obese mice impairs innate immune response to A(H1N1)pdm09 infection. Treatment with paracetamol restores the interferon and cytokine responses, which supports that PGE(2) contributes to immune impairment.