PXR mediated cardiac protection after sepsis through TLR4 modulation pathway

Abstract

Cardiac dysfunction is a vital component of multi-organ failure during severe sepsis. The primary function of pregnane X receptor (PXR) is to sense the presence of foreign toxic substances and in response up regulate the expression of proteins involved in the detoxification and clearance of these substances from the body. Further, Toll-like receptor 4 (TLR4), the signal-transducing molecule of the LPS receptor complex, plays a fundamental role in the sensing of LPS from Gram-negative bacteria. Activation of TLR4 signaling pathways by LPS is a critical upstream event in the pathogenesis of Gram-negative sepsis, making TLR4 an attractive target for novel antisepsis therapy. TLR4 mutant (TLR4-/-) and wild type TLR4 (TLR4+/+) mice underwent a sterile (lipopolysaccharide; LPS) or infectious (Streptococcus pneumoniae or Klebsiella pneumoniae) septic challenge. Production of cytokines, TNF, IL-1β, IL-6 and IL-10, in the blood and from cardiomyocytes was exaggerated in the TLR4+/+ mice compared to responses measured in mutant TLR4-/- type mice given an identical septic challenge. This enhanced compartmentalized myocardial inflammation was associated with significantly decreased cardiac contraction and diminished relaxation in the TLR4+/+ mice. Furthermore, PXR expression has critical role in down-regulation of sepsis via TLR4 pathway, and more reduction in cytokines, improved myocardial function in PXR+/+suggesting that PXR was a major cause of the greater myocardial contractile improvement in TLR4-/- mice. Taken together, our results suggest that PXR plays a role in the down-regulation of myocardium during sepsis. Further studies are warranted to further define the precise mechanisms of PXR mediated cardiac protection.