Ascaris suum-Derived Products Induce Human Neutrophil Activation via a G Protein-Coupled Receptor That Interacts with the Interleukin-8 Receptor Pathway

Abstract

Infection with tissue-migrating helminths is frequently associated with intense granulocyte infiltrations. Several host-derived factors are known to mediate granulocyte recruitment to the tissues, but less attention has been paid to how parasite-derived products trigger this process. Parasite-derived chemotactic factors which selectively recruit granulocytes have been described, but nothing is known about which cellular receptors respond to these agents. The effect of products from the nematodesAscaris suum, Toxocara canis, andAnisakis simplexon human neutrophils were studied. We monitored four parameters of activation: chemotaxis, cell polarization, intracellular Ca²⁺transients, and priming of superoxide anion production. Body fluids ofA. suum(ABF) andT. canis(TcBF) induced strong directional migration, shape change, and intracellular Ca²⁺transients. ABF also primed neutrophils for production of superoxide anions. Calcium mobilization in response toA. suum-derived products was completely abrogated by pretreatment with pertussis toxin, implicating a classical G protein-coupled receptor mechanism in the response to ABF. Moreover, pretreatment with interleukin-8 (IL-8) completely abrogated the response to ABF, demonstrating desensitization of a common pathway. However, ABF was unable to fully desensitize the response to IL-8, and binding to CXCR1 or CXCR2 was excluded in experiments using RBL-2H3 cells transfected with the two human IL-8 receptors. Our results provide the first evidence for a direct interaction between a parasite-derived chemotactic factor and the host's chemotactic network, via a novel G protein-coupled receptor which interacts with the IL-8 receptor pathway.