Submitted December 17, 2007
Accepted May 12, 2008
Sepsis-induced inhibition of neutrophil chemotaxis is mediated by activation of peroxisome proliferator-activated receptor-
Raju C Reddy*, Venkata R Narala, Venkateshwar G Keshamouni, Jami E Milam, Michael W Newstead, and Theodore J Standiford
Pulmonary and Critical Care Medicine/Internal Medicine, University of Michigan, Ann Arbor, MI, United States
* Corresponding author; email: rajuc{at}umich.edu.
Neutrophils (polymorphonuclear leukocytes [PMNs]) are critical to the immune response, including clearance of infectious pathogens. Sepsis is associated with impaired PMN function, including chemotaxis. PMNs express peroxisome proliferator-activated receptor-
(PPAR-), a ligand-activated nuclear transcription factor involved in immune and inflammatory regulation. The role of PPAR- in PMN responses, however, is not well characterized. We report that freshly isolated human PMNs constitutively express PPAR-, which is upregulated by the sepsis-induced cytokines TNF-
and IL-4. PMN chemotactic responses to formylmethionyl-leucyl-phenylalanine (fMLP) and IL-8 were dose-dependently inhibited by treatment with PPAR- ligands troglitazone and 15-deoxy-
12,14-prostaglandin J2 (15d-PGJ2) and by transfection of PMN-like HL-60 cells with a constitutively active PPAR- construct. Inhibition of chemotaxis by PPAR- ligands correlated with decreases in extracellular signal-regulated kinase-1 and -2 activation, actin polymerization, and adherence to a fibrinogen substrate. Furthermore, PMN expression of PPAR- was increased in sepsis patients and mice with either of two models of sepsis. Lastly, treatment with the PPAR- antagonist GW9662 significantly reversed the inhibition of PMN chemotaxis and increased peritoneal PMN recruitment in murine sepsis. This study indicates that PPAR- activation is involved in PMN chemotactic responses in vitro and may play a role in the migration of these cells in vivo
