Key Role of Group V Secreted Phospholipase A(2) in Th2 Cytokine and Dendritic Cell-Driven Airway Hyperresponsiveness and Remodeling

BACKGROUND: Previous work has shown that disruption of the gene for group X secreted phospholipase A(2) (sPLA(2)-X) markedly diminishes airway hyperresponsiveness and remodeling in a mouse asthma model. With the large number of additional sPLA(2)s in the mammalian genome, the involvement of other sPLA(2)s in the asthma model is possible – in particular, the group V sPLA(2) (sPLA(2)-V) that like sPLA(2)-X is highly active at hydrolyzing membranes of mammalian cells. METHODOLOGY AND PRINCIPAL FINDINGS: The allergen-driven asthma phenotype was significantly reduced in sPLA(2)-V-deficient mice but to a lesser extent than observed previously in sPLA(2)-X-deficient mice. The most striking difference observed between the sPLA(2)-V and sPLA(2)-X knockouts was the significant impairment of the primary immune response to the allergen ovalbumin (OVA) in the sPLA(2)-V(−/−) mice. The impairment in eicosanoid generation and dendritic cell activation in sPLA2-V(−/−) mice diminishes Th2 cytokine responses in the airways. CONCLUSIONS: This paper illustrates the diverse roles of sPLA(2)s in the immunopathogenesis of the asthma phenotype and directs attention to developing specific inhibitors of sPLA(2)-V as a potential new therapy to treat asthma and other allergic disorders.