Session Type: ACR Concurrent Abstract Session
Session Time: 4:30PM-6:00PM
Results: Both FcgRIIA- and TLR8-engagement were required for induction of NETosis by RNA-ICs, as demonstrated by FcgR blocking antibodies as well as RNase treatment. While degradation of RNA inhibited NETosis as expected, surprisingly, removal of the TLR ligand by RNase markedly increased the phagocytosis of RNA-ICs by neutrophils (p<0.0001), suggesting that TLR activation suppressed phagocytosis. Consistent with this hypothesis, addition of TLR8 agonist (R848) inhibited phagocytosis of ICs (p<0.0001), but not of latex beads, by neutrophils. Mechanistically, TLR8 activation mediated furin-dependent proteolytic cleavage of the most N-terminal part of FcgRIIA, reducing the phagocytic capacity, while promoting progression into NETosis. Interestingly, the opposite was also true, namely that phagocytic stimuli (beads) could suppress IC-mediated NETosis (p<0.01) while promoting phagocytosis (p<0.05), suggesting plasticity of the neutrophils in adapting into specific effector cell functions. Importantly, ex vivo isolated neutrophils from SLE patients demonstrated increased shedding of FcgRIIA (p<0.0001), which correlated with neutrophil activation (r=-0.73, p=0.003) and the presence of anti-Sm/RNP antibodies (p<0.001), consistent with the in vitro data.
To cite this abstract in AMA style:Lood C, Arve S, Durcan L, Ledbetter J, Elkon KB. Immune Complex-Mediated TLR8 Activation Shifts Neutrophils from Phagocytosis to Netosis through Furin-Dependent Shedding of Fcgriia [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/immune-complex-mediated-tlr8-activation-shifts-neutrophils-from-phagocytosis-to-netosis-through-furin-dependent-shedding-of-fcgriia/. Accessed November 25, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/immune-complex-mediated-tlr8-activation-shifts-neutrophils-from-phagocytosis-to-netosis-through-furin-dependent-shedding-of-fcgriia/