Abstract
BackgroundArhalofenate acid, the active acid form of arhalofenate, is a non-agonist peroxisome proliferator-activated receptor γ (PPARγ) ligand, with uricosuric activity via URAT1 inhibition. Phase II studies revealed decreased acute arthritis flares in arhalofenate-treated gout compared with allopurinol alone. Hence, we investigated the anti-inflammatory effects and mechanisms of arhalofenate and its active acid form for responses to monosodium urate (MSU) crystals.MethodsWe assessed in-vivo responses to MSU crystals in murine subcutaneous air pouches and in-vitro responses in murine bone marrow-derived macrophages (BMDMs) by enzyme-linked immunosorbent assay (ELISA), SDS-PAGE/Western blot, immunostaining, and transmission electron microscopy analyses.ResultsOral administration of arhalofenate (250 mg/kg) blunted total leukocyte ingress, neutrophil influx, and air pouch fluid interleukin (IL)-1β, IL-6, and CXCL1 in response to MSU crystal injection (p < 0.05 for each). Arhalofenate acid (100 μM) attenuated MSU crystal-induced IL-1β production in BMDMs via inhibition of NLRP3 inflammasome activation. In addition, arhalofenate acid dose-dependently increased activation (as assessed by phosphorylation) of AMP-activated protein kinase (AMPK). Studying AMPKα1 knockout mice, we elucidated that AMPK mediated the anti-inflammatory effects of arhalofenate acid. Moreover, arhalofenate acid attenuated the capacity of MSU crystals to suppress AMPK activity, regulated expression of multiple downstream AMPK targets that modulate mitochondrial function and oxidative stress, preserved intact mitochondrial cristae and volume density, and promoted anti-inflammatory autophagy flux in BMDMs.ConclusionsArhalofenate acid is anti-inflammatory and acts via AMPK activation and its downstream signaling in macrophages. These effects likely contribute to a reduction of gout flares.
Highlights
Arhalofenate acid, the active acid form of arhalofenate, is a non-agonist peroxisome proliferatoractivated receptor γ (PPARγ) ligand, with uricosuric activity via URAT1 inhibition
Arhalofenate attenuated monosodium urate (MSU) crystal-induced inflammation in mice in vivo In the murine subcutaneous air pouch model of acute gouty inflammation, arhalofenate significantly inhibited leukocyte or neutrophil infiltration and production of IL-1β, IL-6, and CXCL1 induced by MSU crystals (Fig. 1)
This study demonstrated that the uricosuric arhalofenate has anti-inflammatory effects, and it characterized the molecular mechanism of action for these activities of MSU crystal-induced inflammation
Summary
Arhalofenate acid, the active acid form of arhalofenate, is a non-agonist peroxisome proliferatoractivated receptor γ (PPARγ) ligand, with uricosuric activity via URAT1 inhibition. Arhalofenate is a non-agonist ligand of peroxisome proliferator-activated receptor γ (PPARγ) with weak transactivation but robust transrepression activity [3]. It was first developed as an insulin sensitizer for type 2 diabetes mellitus [3]. In a recent phase II trial in gout patients, which assessed acute gout flare as the primary endpoint, arhalofenate significantly reduced the risk of acute gouty arthritis in comparison with allopurinol alone, whereas there was no significant difference compared with allopurinol in combination with prophylactic colchicine [5]. This study was performed to directly test and characterize the anti-inflammatory effects of arhalofenate pertinent to gout
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