Eosinophil Cysteinyl Leukotriene Synthesis Mediated by Exogenous Secreted Phospholipase A2 Group X

Regulation and Function of Epithelial Secreted Phospholipase A2 Group X in Asthma

“…Despite the effect of PLa2g10 deficiency on AA release, the synthesis of prostaglandin E 2 (PGE 2 ) was not altered in PLa2g10 2/2 mice; however, TNF plus IL-1b increased PGE 2 synthesis in both mouse strains, and the cPLA 2 inhibitor Pyr-2 was effective in blocking PGE 2 synthesis ( Figure 6D). These results further support the novel finding that epithelial-derived sPLA 2 -X serves as a regulator of eicosanoid metabolism through the release of AA before secretion and by acting on target cells such as eosinophil after secretion (20); furthermore, sPLA 2 -X is selective and does not alter the formation of PGE 2 .…”

“…We have found that sPLA 2 group X (sPLA 2 -X) gene (PLA2G10) has the highest expression in the airways of patients with asthma (17,18) and is strongly expressed in the airway epithelium relative to the other sPLA 2 genes (18). The sPLA 2 with the strongest ability to initiate eicosanoid synthesis in mammalian cells is sPLA 2 -X (19), and sPLA 2 -X specifically initiates cysteinyl LT (CysLT) synthesis by eosinophils (20). An important in vivo role for sPLA 2 -X has been demonstrated with protection from ovalbumin-induced airway inflammation, eicosanoid production, and AHR in Pla2g10-deficient (Pla2g10 2/2 ) mice (21).…”

Secreted PLA2 group X orchestrates innate and adaptive immune responses to inhaled allergen

“…Because eosinophils in close proximity to the airways play a pathogenic role in the development of airway dysfunction in murine models (23)(24)(25)(26), we used image analysis on tissue sections immunostained for the eosinophil granule protein major basic protein (MBP). We have previously demonstrated that human sPLA 2 -X activates CysLT formation in human eosinophils (6) and that endogenous sPLA 2 -X in eosinophils regulates CysLT formation (7). Immunostaining for MBP was sparse in saline-exposed WT and Pla2g10 -/-mice ( Figure 4, A and C), but following HDM exposure, eosinophils were observed in the peribronchial space; further, the density of eosinophils surrounding the airways was substantially attenuated in Pla2g10 -/-mice ( Figure 4, B and D).…”

“…As sPLA 2 s hydrolyze membrane-bound phospholipids at the sn2 position, releasing free fatty acids including arachidonic acid (AA) and lysophospholipids (5), this step serves as the rate-limiting step in the formation of cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) derived prostaglandins and leukotrienes (LT). For example, we previously demonstrated that sPLA 2 -X serves as a key regulator of cysteinyl LT (CysLT) formation by human eosinophils (6,7). Additionally, sPLA 2 -X may also act independently of its enzymatic activity as a high-affinity ligand for the phospholipase A2 receptor, PLA2R1, a c-type lectin receptor expressed on human lung macrophages (8) and airway epithelial cells (9).…”

Blockade of Human Group X Secreted Phospholipase A2 (GX-sPLA2)-induced Airway Inflammation and Hyperresponsiveness in a Mouse Asthma Model by a Selective GX-sPLA2 Inhibitor

“…Levels of Th2 cytokines IL-4, IL-5, and IL-13 in the lungs were decreased in mGX-sPLA 2 Ϫ/Ϫ mice compared with wild-type controls after OVA treatment. Furthermore, the cyclooxygenase products prostaglandin E 2 and prostaglandin D 2 and the 5-lipoxygenase products leukotriene B 4 and cysteinyl leukotrienes C 4 , D 4 , and E 4 of arachidonic acid metabolism were significantly reduced in mGX-sPLA 2 Ϫ/Ϫ mice after OVA treatment compared with wild-type controls (3). These data indicated that mGX-sPLA 2 plays a key role in eicosanoid generation and that the decreased release of arachidonate metabolites secondary to mGX-sPLA 2 deficiency impairs the Th2 responses in this asthma model.…”