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THE PPARgamma ligand 15d-PGJ2 modulates macrophage activation after injury in a murine trauma model
M Alexandra Monroy1, Kay K Opperman, Margo Pucciarelli
1Department of Surgery, Temple University School of Medicine, 3400 North Broad Street, Philadelphia, PA 19140, USA. amonroy@temple.edu
Abstract:
In macrophages, peroxisome proliferator-activated receptor gamma (PPARgamma) has been shown to be important for differentiation, and it serves as a negative regulator of activation. Major trauma/injury causes a dramatic host response that disrupts cellular immune homeostasis and initiates an inflammatory cascade that predisposes the injured host to subsequent infections. In prior studies using a murine trauma model consisting of femur fracture and hemorrhage, splenic macrophages from traumatized mice had significantly enhanced LPS-induced cyclooxygenase enzyme (subtype 2) and iNOS production as well as elevated levels of inflammatory cytokines at 1 week after injury compared with uninjured controls. These up-regulated cellular responses corresponded to increased mortality when animals were challenged with LPS or Candida. In the current study, we used the injury model to determine the effect of treatment of injured mice with the endogenous PPARgamma ligand 15-deoxy-Delta(12-, 14)-PGJ2 (15d-PGJ2). It was found that in vivo 15d-PGJ2 treatment significantly reduced the levels of inflammatory mediators produced by splenic macrophages 7 days after injury. The mechanism of inhibition is dependent on PPARgamma because concomitant treatment of animals with the PPARgamma antagonist GW9662 reversed the inhibitory effect of 15d-PGJ2. Endogenous PPARgamma modulated activation of LPS-induced p38 mitogen-activated protein kinase. Furthermore, treatment of injured mice with 15d-PGJ2 conferred a significant survival advantage after infectious challenge induced by cecal ligation and puncture. Thus, this PPARgamma ligands significantly attenuate the postinjury inflammatory response and improve survival after infectious challenge.
Insights
Treatment with a PPARgamma ligand reduced inflammation and improved survival in injured mice. This suggests PPARgamma ligands can attenuate the post-injury inflammatory response and enhance survival after infection.
Area of Science:
- Immunology
- Cellular Biology
- Pharmacology
Background:
- Major trauma disrupts immune homeostasis, leading to inflammation and increased infection risk.
- Traumatized mice exhibit enhanced inflammatory responses in splenic macrophages, correlating with higher mortality.
- Peroxisome proliferator-activated receptor gamma (PPARgamma) is crucial for macrophage differentiation and regulates activation.
Purpose of the Study:
- To investigate the therapeutic potential of the endogenous PPARgamma ligand 15-deoxy-Delta(12-, 14)-PGJ2 (15d-PGJ2) in a murine trauma model.
- To determine if 15d-PGJ2 treatment can mitigate the exaggerated inflammatory response post-injury.
- To assess the impact of 15d-PGJ2 on survival following infectious challenge.
Main Methods:
- Utilized a murine model of femur fracture and hemorrhage to induce trauma.
- Administered 15d-PGJ2 in vivo to injured mice and assessed splenic macrophage inflammatory mediator production.
- Employed the PPARgamma antagonist GW9662 to confirm the mechanism of action.
- Evaluated the effect of 15d-PGJ2 on LPS-induced p38 mitogen-activated protein kinase activation.
- Challenged treated and untreated mice with cecal ligation and puncture to assess survival.
Main Results:
- In vivo 15d-PGJ2 treatment significantly reduced inflammatory mediators in splenic macrophages 7 days post-injury.
- The inhibitory effect of 15d-PGJ2 was dependent on PPARgamma, as reversed by GW9662.
- Endogenous PPARgamma activation modulated LPS-induced p38 mitogen-activated protein kinase.
- 15d-PGJ2 treatment conferred a significant survival advantage in mice challenged with infection.
Conclusions:
- PPARgamma ligands, specifically 15d-PGJ2, effectively attenuate the post-injury inflammatory response.
- Modulating PPARgamma activity presents a viable strategy to improve survival in injured individuals susceptible to infection.
- Targeting PPARgamma offers a promising therapeutic avenue for managing trauma-induced immune dysregulation.
