Stroma Cell-Derived Factor 1 alpha Mediates Desensitization of Human Neutrophil Respiratory Burst in Synovial Fluid from Rheumatoid Arthritic Patients

摘要

Classical chemoattractants such as fMLP or the complement factor C5a use G protein(Gi)-coupled receptors to stimulate both chemotaxis and production of reactive oxygen species(respiratory burst,RB)by polymorphonuclear leukocytes(PMN).The chemokine stroma cell-derived factor la(SDFlalpha)and its Gi-coupled receptor,CXCR4,regulate leukocyte trafficking and recruitment to the synovial fluid of rheumatoid arthritic patients(RA-SF).However,the role of SDFla in the RB is unknown and was studied in this work in vitro with healthy PMN in the absence and presence of RA-SF.In healthy PMN,SDFla failed to stimulate the RB,even though the p38 mitogen-activated protein kinase was activated to a similar level as in fMLP-stimulated PMN.In contrast,the SDFlalpha-mediated calcium transients and activation of phosphatidylinositol 3-kinase/Akt were partially deficient,while p44/42 mitogen-activated protein kinases were not activated.SDFlalpha actually desensitized weakly the fMLP-mediated RB of healthy PMN.This cross-inhibitory effect was amplified in PMN treated with RA-SF,providing a protection against the exacerbation of RB induced by C5a or fMLP.This SDFlalpha beneficial effect,which was prevented by the CXCR4 antagonist AMD3100,was associated with impairment of C5alpha- and fMLP-mediated early signaling events.Thus,although SDFlalpha promotes leukocyte emigration into rheumatoid synovium,our data suggest it cross-desensitizes the production of oxidant by primed PMN,a property that may be beneficial in the context of arthritis.