GPR105-Targeted Therapy Promotes Gout Resolution as a Switch Between NETosis and Apoptosis of Neutrophils

Abstract

The fate of infiltrating neutrophils in inflamed joints determines the development of acute gouty arthritis (AGA). GPR105 highly expressed in human neutrophils is sensitive to monosodium urate crystals (MSU); nevertheless, the roles of GPR105 in AGA remain unclear. Here, we show that GPR105 is significantly upregulated in peripheral polymorphonuclear neutrophils of AGA patients. GPR105 knockout (GPR105−/−) prevented NETosis and induced apoptosis of neutrophils under MSU exposure, as well as attenuating inflammatory cascades in AGA. Mechanistically, GPR105 deletion activated cAMP-PKA signals, thereby disrupting Raf-Mek1/2-Erk1/2 pathway-mediated NADPH oxidase activation, contributing to inhibition of NETosis. Whereas, cAMP-PKA activation resulting in GPR105 deficiency modulated PI3K-Akt pathway to regulate apoptosis. More importantly, suppression of cAMP-PKA pathway by SQ22536 and H-89 restored NETosis instead of apoptosis in GPR105−/− neutrophils, promoting MSU-induced gout flares. Interestingly, lobetyolin was screened out as a potent GPR105 antagonist using molecular docking-based virtual screening and in vitro activity test, which efficiently attenuated MSU-induced inflammatory response interacting with GPR105. Taken together, our study implicated that modulating cell death patterns between NETosis and apoptosis through targeting GPR105 could be a potential therapeutic strategy for the treatment of AGA.

Molecular mechanisms and therapeutic target of NETosis in diseases

“…Therefore, targeting GPR105 might be a possible therapy for acute gouty arthritis. 149 To cure multiple NET-associated diseases, further research on NETosis is needed.…”

“…Moreover, a recent study indicated that a decrease in GPR105, which is highly expressed in neutrophils and sensitive to MSU, can prevent NETosis and induce apoptosis. Therefore, targeting GPR105 might be a possible therapy for acute gouty arthritis 149 …”

Alicyclic Ring Size Variation of 4-Phenyl-2-naphthoic Acid Derivatives as P2Y14 Receptor Antagonists

“…The resulting mixture was bubbled with H 2 at rt for 5 h. The Pd/C was filtered. (12). A solution of 11 (0.012 mmol, crude reaction residue without HPLC purification) in TFA (2 mL) was refluxed in a 90 °C oil bath for 2 h. Volatiles were evaporated, and the residue was purified by RP-HPLC (C18, A: ACN, B: 10 mM TEAA, 45% → 60% A in 40 min, flow rate = 5 mL/min, t R = 21 min) to give 12 as a white powder (1.9 mg, 33% overall yield from 31): (14).…”

Amplification of Inflammation by Lubricin Deficiency Implicated in Incident, Erosive Gout Independent of Hyperuricemia

“…NETosis is a major consequence of neutrophil activation by urate crystals (5), and it is increased in peripheral blood neutrophils of gout patients (47). NETosis increases tissue urate levels in a DNase‐suppressed manner, potentially mediated by extracellular neutrophil DNA accumulation (4), which colocalizes with lubricin‐degrading proteases (e.g., neutrophil elastase, CTSG released from granules) and LTF. Since NETosis is linked to formation of tophus‐like urate crystal aggregation in experimental gout (47,48), our findings could be mechanistically pertinent to gout.…”

“…Urate crystal ingestion by monocytes and macrophages stimulates NLRP3 inflammasome activation and release of interleukin‐1β (IL‐1β) (1,3). The consequent endothelial and phagocyte activation amplifies inflammatory arthritis (1,3) and promotes NETosis, which can augment tissue urate levels (4) and modulate urate crystal aggregation, tophus development, and chronicity of gouty arthritis (5).…”