Αρχειοθήκη ιστολογίου

Τρίτη 22 Ιανουαρίου 2019

Lupus-Associated Immune Complexes Activate Human Neutrophils in an Fc{gamma}RIIA-Dependent but TLR-Independent Response [AUTOIMMUNITY]

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of autoantibodies against nucleic acids and nucleoproteins. Anti-dsDNA Abs are considered a hallmark of SLE, and previous studies have indicated that nucleic acid–containing immune complexes (ICs) induce B cell and dendritic cell activation in a TLR-dependent process. How ICs containing nucleic acids affect neutrophil function has not been well investigated. In this study, we report that nucleic acid–containing ICs derived from the sera of SLE patients induce human and mouse neutrophil activation through TLR-independent mechanisms. Soluble ICs containing Sm/RNP, an RNA Ag, activate human neutrophils to produce reactive oxygen species (ROS) and IL-8. In contrast, ICs containing DNA have to be immobilized to efficiently activate neutrophils. We found that deleting TLR7 or TLR9, the receptors for RNA and DNA, had no effect on mouse neutrophil activation induced by RNA-containing and immobilized DNA–containing ICs. Binding of ICs are mediated through FcRIIA and FcRIIIB. However, neutrophil activation induced by RNA- and DNA-containing ICs requires FcRIIA, as blocking FcRIIA inhibited ROS release from neutrophils. RNA-containing ICs induce calcium flux, whereas TLR7/8 ligand R848 do not. Surprisingly, chloroquine inhibits calcium flux induced by RNA-containing ICs, suggesting that this lesser known function of chloroquine is involved in the neutrophil activation induced by ICs. These data indicate the SLE-derived ICs activate neutrophils to release ROS and chemokines in an FcRIIA-dependent and TLR7- and TLR9-independent manner that likely contributes to local tissue inflammation and damage.



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