Lupus-Associated Immune Complexes Activate Human Neutrophils in an FcγRIIA-Dependent but TLR-Independent Response

Abstract

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 FcγRIIA and FcγRIIIB. However, neutrophil activation induced by RNA- and DNA-containing ICs requires FcγRIIA, as blocking FcγRIIA 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 FcγRIIA-dependent and TLR7- and TLR9-independent manner that likely contributes to local tissue inflammation and damage.

Neutrophils in the Pathogenesis of Rheumatoid Arthritis and Systemic Lupus Erythematosus: Same Foe Different M.O.

“…Hydroxychloroquine, an anti-malarial already widely used to treat both RA and SLE, is a potent modulator of neutrophil function. It has been shown to inhibit neutrophilic inflammation into inflamed kidneys (297), inhibit NET production via inhibition of TLR9 (298), and block ROS and IL-8 production in response to RNA-containing immune complexes (152). Methotrexate, commonly used in both SLE and RA, inhibits cytokine-delayed neutrophil apoptosis, ROS production and leukotriene B4 synthesis (299)(300)(301).…”

Association of FcγRIIA‐R/H131 polymorphism and systemic lupus erythematosus lupus nephritis risk: A meta‐analysis

“…However, the study conducted by Zhu et al did not trophil activation in SLE is a FcγRIIA dependent pathway. 56 In our meta-analysis, allele R or genotype RR was found to be related to Some limitations should be paid attention to in the present study. First, potential gene-environment interaction and gene susceptibility haplotypes were not discussed because of insufficient data.…”

“…SLE is characterized by multiple autoantibodies production, such as antibodies against nucleic acids. Neutrophils isolated from lupus patients stimulated with SLE patient's serum having anti‐Sm/RNP antibody can release reactive oxygen species (ROS), and promote interleukin (IL)‐8 production . Blocking FcγRIIA to neutrophils down‐regulated binding, phagocytosis of RNA‐containing immune complex, and neutrophils stimulated with nucleic acid‐containing immune complex under anti‐FcγRIIA antibody showed reduced ROS, IL‐8 generation, indicating that neutrophil activation in SLE is a FcγRIIA dependent pathway .…”

IgG‐aggregates rapidly upregulate FcgRI expression at the surface of human neutrophils in a FcgRII‐dependent fashion: A crucial role for FcgRI in the generation of reactive oxygen species

“…The FcgRIIIb-specific 11.5 blocking antibody, actually enhanced FcgRI upregulation, as did PI-PLC, a FcgRIIIb-specific shedding enzyme. Moreover, the 3G8 blocking antibody, 57 which does not discriminate between the two FcgRIII isoforms, did not affect FcgRI upregulation, supporting the concept of a decoy role for FcgRIIIb 12,58,59 in this process. Results leave the possibility of a role for FcgRIIIa.…”