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DOI: 10.1055/s-0032-1324111
IRF3 KO mice are protected from polymicrobial sepsis by an MIP-2 dependent mechanism
Introduction: Interferon regulatory factors (IRFs) play diverse roles in innate and adaptive immunity by promoting type I interferon production and regulating the function of interferon-induced genes that are implicated in chemokine or cytokine production. We have previously reported that IRF3 but not IRF7 deficiency protects mice from bacterial-induced sepsis.
Methods: In the present study, we aimed at investigating the underlying mechanisms protecting IRF3-/- mice using real-time PCR, ELISA, multiplexed flow cytometry chemokine detection and immunohistochemistry.
Results and discussion: Splenocytes from IRF3-/- mice showed greater, although not significantly higher, IFN-α4 and IFN-ß mRNA levels compared to the WT and IRF7-/- mice. In contrast, pro-inflammatory cytokines such as IL-1ß and IL-17a were significantly less expressed in protected IRF3-/- mice. Susceptible mice presented increased peritoneal levels of various chemokines (including MIP-1α, RANTES) whereas others (GM-CSF) were similar to those in IRF3-/- mice. An unexpected finding was that levels of the MIP-2, a chemokine implicated in neutrophils' recruitment, were significantly higher in the plasma of susceptible compared to protected IRF3-/- mice, yet the former had more bacteriemia and peripheral organ bacterial infiltration. Moreover, we found significantly higher levels of this chemokine in the peritoneal lavage of susceptible mice although neutrophils were recruited and activated to a lesser extent. The underlying mechanism may be that in IRF3-/- mice MIP-2 is used early after sepsis induction in a protective way thus avoiding its uncontrolled accumulation and unwanted pro-inflammatory effects. Hence, the skewed MIP-2 distribution, up to 4 times greater levels in the blood compared to peritoneal lavage, in susceptible mice may represent rather a consequence of a delayed recruitment and activation of neutrophils in the peritoneum followed by bacterial escape into the circulation and generalized cytokine and chemokine production leading to sepsis.
Conclusion: Our present findings suggest that the uncontrolled bacterial inflammation in experimental sepsis can be mediated by IRF3 through an MIP-2-dependent mechanism.
Keywords: animal sepsis model, IRF, MIP-2, neutrophils
The first and second author=equal contribution