Arhalofenate acid inhibits monosodium urate crystal-induced inflammatory responses through activation of AMP-activated protein kinase (AMPK) signaling
Tóm tắt
Arhalofenate 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. We 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. Oral 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. Arhalofenate 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.
Tài liệu tham khảo
Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population: the National Health and nutrition examination survey 2007–2008. Arthritis Rheum. 2011;63:3136–41.
Keenan RT, O’Brien WR, Lee KH, Crittenden DB, Fisher MC, et al. Prevalence of contraindications and prescription of pharmacologic therapies for gout. Am J Med. 2011;124:155–63.
Gregoire FM, Zhang F, Clarke HJ, Gustafson TA, Sears DD, et al. MBX-102/JNJ39659100, a novel peroxisome proliferator-activated receptor-ligand with weak transactivation activity retains antidiabetic properties in the absence of weight gain and edema. Mol Endocrinol. 2009;23:975–88.
Lavan BE, McWherter C, Choi YJ. Arhalofenate, a novel uricosuric agent, is an inhibitor of human uric acid transporters [abstract]. Ann Rheum Dis. 2013;71(Suppl 3):450–1.
Poiley J, Steinberg AS, Choi YJ, Davis CS, Martin RL, et al. Arhalofenate flare study investigators. A randomized, double-blind, active- and placebo-controlled efficacy and safety study of arhalofenate for reducing flare in patients with gout. Arthritis Rheum. 2016;68:2027–34.
Busso N, So A. Mechanisms of inflammation in gout. Arthritis Res Ther. 2010;12:206.
Cronstein BN, Sunkureddi P. Mechanistic aspects of inflammation and clinical management of inflammation in acute gouty arthritis. J Clin Rheumatol. 2013;19:19–29.
Cleophas MC, Crişan TO, Joosten LA. Factors modulating the inflammatory response in acute gouty arthritis. Curr Opin Rheumatol. 2017;29:163–70.
Terkeltaub R. What makes gouty inflammation so variable? BMC Med. 2017;15:158.
Yu JW, Lee MS. Mitochondria and the NLRP3 inflammasome: physiological and pathological relevance. Arch Pharm Res. 2016;39:1503–18.
Gurung P, Lukens JR, Kanneganti TD. Mitochondria: diversity in the regulation of the NLRP3 inflammasome. Trends Mol Med. 2015;21:193–201.
Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2011;469:221–5.
Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat Immunol. 2010;11:136–40.
Yoshihara E, Masaki S, Matsuo Y, Chen Z, Tian H, et al. Thioredoxin/TXNIP: redoxisome as a redox switch for the pathogenesis of diseases. Front Immunol. 2014;4:514.
Jin HS, Suh HW, Kim SJ, Jo EK. Mitochondrial control of innate immunity and inflammation. Immune Netw. 2017;17:77–88.
Okamoto K, Kondo-Okamoto N. Mitochondria and autophagy: critical interplay between the two homeostats. Biochim Biophys Acta. 2012;1820:595–600.
Rodgers MA, Bowman JW, Liang Q, Jung JU. Regulation where autophagy intersects the inflammasome. Antioxid Redox Signal. 2014;20:495–506.
Choe JY, Jung HY, Park KY, Kim SK. Enhanced p62 expression through impaired proteasomal degradation is involved in caspase-1 activation in monosodium urate crystal-induced interleukin-1b expression. Rheumatology (Oxford). 2014;53:1043–53.
Carling D. AMPK signalling in health and disease. Curr Opin Cell Biol. 2017;45:31–7.
Salminen A, Kaarniranta K. AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing Res Rev. 2012;11:230–41.
Salminen A, Hyttinen JM, Kaarniranta K. AMP-activated protein kinase inhibits NF-κB signaling and inflammation: impact on healthspan and lifespan. J Mol Med (Berl). 2011;89:667–76.
Wang Y, Viollet B, Terkeltaub R, Liu-Bryan R. AMP-activated protein kinase suppresses urate crystal-induced inflammation and transduces colchicine effects in macrophages. Ann Rheum Dis. 2016;75:286–94.
Zhang J, Zhang Y, Xiao F, Liu Y, Wang J, et al. The peroxisome proliferator-activated receptor γ agonist pioglitazone prevents NF-κB activation in cisplatin nephrotoxicity through the reduction of p65 acetylation via the AMPK-SIRT1/p300 pathway. Biochem Pharmacol. 2016;101:100–11.
Osman I, Segar L. Pioglitazone, a PPARγ agonist, attenuates PDGF-induced vascular smooth muscle cell proliferation through AMPK-dependent and AMPK-independent inhibition of mTOR/p70S6K and ERK signaling. Biochem Pharmacol. 2016;101:54–70.
Morrison A, Yan X, Tong C, Li J. Acute rosiglitazone treatment is cardioprotective against ischemia-reperfusion injury by modulating AMPK, Akt, and JNK signaling in nondiabetic mice. Am J Physiol Heart Circ Physiol. 2011;301:H895–902.
Fernandez-Marcos PJ, Auwerx J. Regulation of PGC-1alpha, a nodal regulator of mitochondrial biogenesis. Am J Clin Nutr. 2011;93:884S–90.
Pasqua T, Mahata S, Bandyopadhyay GK, Biswas A, Perkins GA, et al. Impact of chromogranin A on catecholamine storage, catecholamine granule morphology, and chromaffin cell energy metabolism in vivo. Cell Tissue Res. 2016;363:693–712.
Shaked M, Ketzinel-Gilad M, Cerasi E, Kaiser N, Leibowitz G. AMP-activated protein kinase (AMPK) mediates nutrient regulation of thioredoxin-interacting protein (TXNIP) in pancreatic beta-cells. PLoS One. 2011;6:e28804.
Gao K, Chi Y, Sun W, Takeda M, Yao J. 5'-AMP-activated protein kinase attenuates adriamycin-induced oxidative podocyte injury through thioredoxin-mediated suppression of the apoptosis signal-regulating kinase 1-P38 signaling pathway. Mol Pharmacol. 2014;85:460–71.
Lee WH, Kim SG. AMPK-dependent metabolic regulation by PPAR agonists. PPAR Res. 2010;2010. https://doi.org/10.1155/2010/549101.
Huang LS, Cobessi D, Tung EY, Berry EA. Binding of the respiratory chain inhibitor antimycin to the mitochondrial BC1 complex: a new crystal structure reveals an altered intramolecular hydrogen-bonding pattern. J Mol Biol. 2005;351:573–97.
Li N, Ragheb K, Lawler G, Sturgis J, Rajwa B, et al. Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production. J Biol Chem. 2003;278:8516–25.
Hou X, Song J, Li XN, Zhang L, Wang X, et al. Metformin reduces intracellular reactive oxygen species levels by upregulating expression of the antioxidant thioredoxin via the AMPK-FOXO3 pathway. Biochem Biophys Res Commun. 2010;396:199–205.
Chai TF, Hong SY, He H, Zheng L, Hagen T, et al. A potential mechanism of metformin-mediated regulation of glucose homeostasis: inhibition of thioredoxin-interacting protein (TXNIP) gene expression. Cell Signal. 2012;24:1700–5.
Kim MJ, Yoon JH, Ryu JH. Mitophagy: a balance regulator of NLRP3 inflammasome activation. BMB Rep. 2016;49:529–35.
Lazarou M. Keeping the immune system in check: a role for mitophagy. Immunol Cell Biol. 2015;93:3–10.
Zhong Z, Umemura A, Sanchez-Lopez E, Liang S, Shalapour S, et al. NF-κB restricts inflammasome activation via elimination of damaged mitochondria. Cell. 2016;164:896–910.
Zhong Z, Sanchez-Lopez E, Karin M. Autophagy, NLRP3 inflammasome and auto-inflammatory/immune diseases. Clin Exp Rheumatol. 2016;34:12–6.