Expression and detrimental role of hematopoietic prostaglandin D synthase in spinal cord contusion injury


Adriana Redensek, Khizr I. Rathore, Jennifer L. Berard, Rubèn López-Vales, Leigh Anne Swayne, Steffany A.L. Bennett, Ikuko Mohri, Masako Taniike, Yoshihiro Urade, Samuel David


Prostaglandin D2 (PGD2) is a potent inflammatory mediator, which is implicated in both the initiation and resolution of inflammation in peripheral non-neural tissues. Its role in the central nervous system has not been fully elucidated. Spinal cord injury (SCI) is associated with an acute inflammatory response, which contributes to secondary tissue damage that worsens functional loss. We show here, with the use of hematopoietic prostaglandin D synthase (HPGDS) deficient mice and a HPGDS selective inhibitor (HQL-79), that PGD2 plays a detrimental role after SCI. We also show that HPGDS is expressed in macrophages in the injured mouse spinal cord and contributes to the increase in PGD2 in the contused spinal cord. HPGDS−/− mice also show reduced secondary tissue damage and reduced expression of the proinflammatory chemokine CXCL10 as well as an increase in IL-6 and TGFβ-1 expression in the injured spinal cord. This was accompanied by a reduction in the expression of the microglia/macrophage activation marker Mac-2 and an increase in the antioxidant metallothionein III. Importantly, HPGDS deficient mice exhibit significantly better locomotor recovery after spinal cord contusion injury than wild-type (Wt) mice. In addition, systemically administered HPGDS inhibitor (HQL-79) also enhanced locomotor recovery after SCI in Wt mice. These data suggest that PGD2 generated via HPGDS has detrimental effects after SCI and that blocking the activity of this enzyme can be beneficial.