Abstract
Macrophages are key effector cells in obesity-associated inflammation. G protein-coupled receptor kinase 2 (GRK2) is highly expressed in different immune cell types. Using LysM-GRK2+/− mice, we uncover that a reduction of GRK2 levels in myeloid cells prevents the development of glucose intolerance and hyperglycemia after a high fat diet (HFD) through modulation of the macrophage pro-inflammatory profile. Low levels of myeloid GRK2 confer protection against hepatic insulin resistance, steatosis and inflammation. In adipose tissue, pro-inflammatory cytokines are reduced and insulin signaling is preserved. Macrophages from LysM-GRK2+/− mice secrete less pro-inflammatory cytokines when stimulated with lipopolysaccharide (LPS) and their conditioned media has a reduced pathological influence in cultured adipocytes or naïve bone marrow-derived macrophages. Our data indicate that reducing GRK2 levels in myeloid cells, by attenuating pro-inflammatory features of macrophages, has a relevant impact in adipose-liver crosstalk, thus preventing high fat diet-induced metabolic alterations.
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Abbreviations
- BMDM:
-
Bone marrow-derived macrophages
- CM:
-
Conditioned media
- COX-2:
-
Cyclooxygenase-2
- FA:
-
Fatty acids
- GRK2:
-
G protein-coupled receptor kinase 2
- GTT:
-
Glucose tolerance test
- HFD:
-
High fat diet
- HO-1:
-
Heme oxygenase-1
- iNOS:
-
Inducible nitric oxide synthase
- IR:
-
Insulin resistance
- ITT:
-
Insulin tolerance test
- LPS:
-
Lipopolysaccharide
- NAFLD:
-
Non-alcoholic fatty liver disease
- NASH:
-
Non-alcoholic steatohepatitis
- PTT:
-
Pyruvate tolerance test
- TEPMs:
-
Thioglycollate -elicited peritoneal macrophages
- TG:
-
Triglycerides
- TLR:
-
Toll-like receptor
- WAT:
-
White adipose tissue
References
Younossi Z, Tacke F, Arrese M, Sharma BC, Mostafa I, Bugianesi E, Wong VW, Yilmaz Y, George J, Fan J, Vos MB (2018) Global perspectives on non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Hepatology. https://doi.org/10.1002/hep.30251
Rosen ED, Spiegelman BM (2014) What we talk about when we talk about fat. Cell 156(1–2):20–44. https://doi.org/10.1016/j.cell.2013.12.012
Donath MY, Shoelson SE (2011) Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 11(2):98–107. https://doi.org/10.1038/nri2925
Lumeng CN, Bodzin JL, Saltiel AR (2007) Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Investig 117(1):175–184. https://doi.org/10.1172/JCI29881
Lumeng CN, DelProposto JB, Westcott DJ, Saltiel AR (2008) Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes. Diabetes 57(12):3239–3246. https://doi.org/10.2337/db08-0872
Olefsky JM, Glass CK (2010) Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 72:219–246. https://doi.org/10.1146/annurev-physiol-021909-135846
Odegaard JI, Chawla A (2008) Mechanisms of macrophage activation in obesity-induced insulin resistance. Nat Clin Pract Endocrinol Metab 4(11):619–626. https://doi.org/10.1038/ncpendmet0976
Cusi K (2012) Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology 142(4):711–725. https://doi.org/10.1053/j.gastro.2012.02.003
van der Poorten D, Milner KL, Hui J, Hodge A, Trenell MI, Kench JG, London R, Peduto T, Chisholm DJ, George J (2008) Visceral fat: a key mediator of steatohepatitis in metabolic liver disease. Hepatology 48(2):449–457. https://doi.org/10.1002/hep.22350
Kazankov K, Jorgensen SMD, Thomsen KL, Moller HJ, Vilstrup H, George J, Schuppan D, Gronbaek H (2019) The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Nat Rev Gastroenterol Hepatol 16(3):145–159. https://doi.org/10.1038/s41575-018-0082-x
Gregor MF, Hotamisligil GS (2011) Inflammatory mechanisms in obesity. Annu Rev Immunol 29:415–445. https://doi.org/10.1146/annurev-immunol-031210-101322
Ouchi N, Parker JL, Lugus JJ, Walsh K (2011) Adipokines in inflammation and metabolic disease. Nat Rev Immunol 11(2):85–97. https://doi.org/10.1038/nri2921
Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Investig 112(12):1796–1808. https://doi.org/10.1172/JCI19246
Cani PD, Everard A, Duparc T (2013) Gut microbiota, enteroendocrine functions and metabolism. Curr Opin Pharmacol 13(6):935–940. https://doi.org/10.1016/j.coph.2013.09.008
Shen J, Obin MS, Zhao L (2013) The gut microbiota, obesity and insulin resistance. Mol Aspects Med 34(1):39–58. https://doi.org/10.1016/j.mam.2012.11.001
Musso G, Gambino R, Cassader M (2011) Interactions between gut microbiota and host metabolism predisposing to obesity and diabetes. Annu Rev Med 62:361–380. https://doi.org/10.1146/annurev-med-012510-175505
Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C, Waget A, Delmee E, Cousin B, Sulpice T, Chamontin B, Ferrieres J, Tanti JF, Gibson GR, Casteilla L, Delzenne NM, Alessi MC, Burcelin R (2007) Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56(7):1761–1772. https://doi.org/10.2337/db06-1491
Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS (2006) TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Investig 116(11):3015–3025. https://doi.org/10.1172/JCI28898
Nguyen MT, Favelyukis S, Nguyen AK, Reichart D, Scott PA, Jenn A, Liu-Bryan R, Glass CK, Neels JG, Olefsky JM (2007) A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways. J Biolog Chem 282(48):35279–35292. https://doi.org/10.1074/jbc.M706762200
Biswas SK, Mantovani A (2012) Orchestration of metabolism by macrophages. Cell Metab 15(4):432–437. https://doi.org/10.1016/j.cmet.2011.11.013
Ribas C, Penela P, Murga C, Salcedo A, Garcia-Hoz C, Jurado-Pueyo M, Aymerich I, Mayor F Jr (2007) The G protein-coupled receptor kinase (GRK) interactome: role of GRKs in GPCR regulation and signaling. Biochem Biophys Acta 1768(4):913–922. https://doi.org/10.1016/j.bbamem.2006.09.019
Hullmann J, Traynham CJ, Coleman RC, Koch WJ (2016) The expanding GRK interactome: Implications in cardiovascular disease and potential for therapeutic development. Pharmacol Res 110:52–64. https://doi.org/10.1016/j.phrs.2016.05.008
Penela P, Lafarga V, Tapia O, Rivas V, Nogues L, Lucas E, Vila-Bedmar R, Murga C, Mayor F Jr (2012) Roles of GRK2 in cell signaling beyond GPCR desensitization GRK2HDAC6 interaction modulates cell spreading and motility. Sci Signal 5(224):9–10. https://doi.org/10.1126/scisignal.2003098
Penela P, Murga C, Ribas C, Lafarga V, Mayor F Jr (2010) The complex G protein-coupled receptor kinase 2 (GRK2) interactome unveils new physiopathological targets. Br J Pharmacol 160(4):821–832. https://doi.org/10.1111/j.1476-5381.2010.00727.x
Anis Y, Leshem O, Reuveni H, Wexler I, Ben Sasson R, Yahalom B, Laster M, Raz I, Ben Sasson S, Shafrir E, Ziv E (2004) Antidiabetic effect of novel modulating peptides of G-protein-coupled kinase in experimental models of diabetes. Diabetologia 47(7):1232–1244. https://doi.org/10.1007/s00125-004-1444-1
Mayor F Jr, Lucas E, Jurado-Pueyo M, Garcia-Guerra L, Nieto-Vazquez I, Vila-Bedmar R, Fernandez-Veledo S, Murga C (2011) G Protein-coupled receptor kinase 2 (GRK2): a novel modulator of insulin resistance. Arch Physiol Biochem 117(3):125–130. https://doi.org/10.3109/13813455.2011.584693
Ciccarelli M, Cipolletta E, Iaccarino G (2012) GRK2 at the control shaft of cellular metabolism. Curr Pharm Des 18(2):121–127
Fan J, Malik AB (2003) Toll-like receptor-4 (TLR4) signaling augments chemokine-induced neutrophil migration by modulating cell surface expression of chemokine receptors. Nat Med 9(3):315–321. https://doi.org/10.1038/nm832
Loniewski K, Shi Y, Pestka J, Parameswaran N (2008) Toll-like receptors differentially regulate GPCR kinases and arrestins in primary macrophages. Mol Immunol 45(8):2312–2322. https://doi.org/10.1016/j.molimm.2007.11.012
Lombardi MS, Kavelaars A, Penela P, Scholtens EJ, Roccio M, Schmidt RE, Schedlowski M, Mayor F Jr, Heijnen CJ (2002) Oxidative stress decreases G protein-coupled receptor kinase 2 in lymphocytes via a calpain-dependent mechanism. Mol Pharmacol 62(2):379–388
Vroon A, Heijnen CJ, Kavelaars A (2006) GRKs and arrestins: regulators of migration and inflammation. J Leukoc Biol 80(6):1214–1221. https://doi.org/10.1189/jlb.0606373
Clausen BE, Burkhardt C, Reith W, Renkawitz R, Forster I (1999) Conditional gene targeting in macrophages and granulocytes using LysMcre mice. Transgen Res 8(4):265–277
Willemen HL, Eijkelkamp N, Wang H, Dantzer R, Dorn GW 2nd, Kelley KW, Heijnen CJ, Kavelaars A (2010) Microglial/macrophage GRK2 determines duration of peripheral IL-1beta-induced hyperalgesia: contribution of spinal cord CX3CR1, p38 and IL-1 signaling. Pain 150(3):550–560. https://doi.org/10.1016/j.pain.2010.06.015
Rivas V, Carmona R, Munoz-Chapuli R, Mendiola M, Nogues L, Reglero C, Miguel-Martin M, Garcia-Escudero R, Dorn GW 2nd, Hardisson D, Mayor F Jr, Penela P (2013) Developmental and tumoral vascularization is regulated by G protein-coupled receptor kinase 2. J Clin Investig 123(11):4714–4730. https://doi.org/10.1172/JCI67333
Vila-Bedmar R, Cruces-Sande M, Lucas E, Willemen HL, Heijnen CJ, Kavelaars A, Mayor F, Murga C (2015) Reversal of diet-induced obesity and insulin resistance by inducible genetic ablation of GRK2. Science Signal 8(386):9–10. https://doi.org/10.1126/scisignal.aaa4374
Cruces-Sande M, Vila-Bedmar R, Arcones AC, Gonzalez-Rodriguez A, Rada P, Gutierrez-de-Juan V, Vargas-Castrillon J, Iruzubieta P, Sanchez-Gonzalez C, Formentini L, Crespo J, Garcia-Monzon C, Martinez-Chantar ML, Valverde AM, Mayor F Jr (1864) Murga C (2018) Involvement of G protein-coupled receptor kinase 2 (GRK2) in the development of non-alcoholic steatosis and steatohepatitis in mice and humans. Biochim Biophys Acta Mol Basis Dis 12:3655–3667. https://doi.org/10.1016/j.bbadis.2018.09.027
Callahan BJ, McMurdie PJ, Rosen MJ, Han AW, Johnson AJA, Holmes SP (2016) DADA2: high resolution sample inference from Illumina amplicon data. Nat Methods 13(7):581–583. https://doi.org/10.1038/nmeth.3869
Bolyen ERJ, Dillon MR, Bokulich NA, Abnet C, Al-Ghalith GA, Alexander H, Alm EJ, Arumugam M, Asnicar F, Bai Y, Bisanz JE, Bittinger K, Brejnrod A, Brislawn CJ, Brown CT, Callahan BJ, Caraballo-Rodríguez AM, Chase J, Cope E, Da Silva R, Dorrestein PC, Douglas GM, Durall DM, Duvallet C, Edwardson CF, Ernst M, Estaki M, Fouquier J, Gauglitz JM, Gibson DL, Gonzalez A, Gorlick K, Guo J, Hillmann B, Holmes S, Holste H, Huttenhower C, Huttley G, Janssen S, Jarmusch AK, Jiang L, Kaehler B, Kang KB, Keefe CR, Keim P, Kelley ST, Knights D, Koester I, Kosciolek T, Kreps J, Langille MG, Lee J, Ley R, Liu Y, Loftfield E, Lozupone C, Maher M, Marotz C, Martin BD, McDonald D, McIver LJ, Melnik AV, Metcalf JL, Morgan SC, Morton J, Naimey AT, Navas-Molina JA, Nothias LF, Orchanian SB, Pearson T, Peoples SL, Petras D, Preuss ML, Pruesse E, Rasmussen LB, Rivers A, Robeson MS II, Rosenthal P, Segata N, Shaffer M, Shiffer A, Sinha R, Song SJ, Spear JR, Swafford AD, Thompson LR, Torres PJ, Trinh P, Tripathi A, Turnbaugh PJ, Ul-Hasan S, van der Hooft JJ, Vargas F, Vázquez-Baeza Y, Vogtmann E, von Hippel M, Walters W, Wan Y, Wang M, Warren J, Weber KC, Williamson CH, Willis AD, Xu ZZ, Zaneveld JR, Zhang Y, Zhu Q, Knight R, Caporaso JG (2018) QIIME 2: Reproducible, interactive, scalable, and extensible microbiome data science. PeerJ Prepr 6:27292–27295. https://doi.org/10.7287/peerj.preprints.27295v2
Rognes T, Flouri T, Nichols B, Quince C, Mahé F (2016) VSEARCH: a versatile open source tool for metagenomics. PeerJ 4:e2584. https://doi.org/10.7717/peerj.2584
Mandal S, Van Treuren W, White RA, Eggesbø M, Knight R, Peddada SD (2015) Analysis of composition of microbiomes: a novel method for studying microbial composition. Microb Ecol Health Dis 26(1):27663. https://doi.org/10.3402/mehd.v26.27663
Maganto-Garcia E, Punzon C, Terhorst C, Fresno M (2008) Rab5 activation by Toll-like receptor 2 is required for Trypanosoma cruzi internalization and replication in macrophages. Traffic 9(8):1299–1315. https://doi.org/10.1111/j.1600-0854.2008.00760.x
Vila-Bedmar R, Garcia-Guerra L, Nieto-Vazquez I, Mayor F Jr, Lorenzo M, Murga C, Fernandez-Veledo S (2012) GRK2 contribution to the regulation of energy expenditure and brown fat function. FASEB J 26(8):3503–3514. https://doi.org/10.1096/fj.11-202267
Vila-Bedmar R, Lorenzo M, Fernandez-Veledo S (2010) Adenosine 5'-monophosphate-activated protein kinase-mammalian target of rapamycin cross talk regulates brown adipocyte differentiation. Endocrinology 151(3):980–992. https://doi.org/10.1210/en.2009-0810
Hatting M, Tavares CDJ, Sharabi K, Rines AK, Puigserver P (2018) Insulin regulation of gluconeogenesis. Ann N Y Acad Sci 1411(1):21–35. https://doi.org/10.1111/nyas.13435
Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, Shoelson SE (2005) Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med 11(2):183–190. https://doi.org/10.1038/nm1166
Wan X, Xu C, Yu C, Li Y (2016) Role of NLRP3 Inflammasome in the Progression of NAFLD to NASH. Can J Gastroenterol Hepatol 2016:6489012. https://doi.org/10.1155/2016/6489012
Hersoug LG, Moller P, Loft S (2016) Gut microbiota-derived lipopolysaccharide uptake and trafficking to adipose tissue: implications for inflammation and obesity. Obesity Rev 17(4):297–312. https://doi.org/10.1111/obr.12370
Ley RE, Backhed F, Turnbaugh P, Lozupone CA, Knight RD, Gordon JI (2005) Obesity alters gut microbial ecology. Proc Natl Acad Sci USA 102(31):11070–11075. https://doi.org/10.1073/pnas.0504978102
Moran-Salvador E, Lopez-Parra M, Garcia-Alonso V, Titos E, Martinez-Clemente M, Gonzalez-Periz A, Lopez-Vicario C, Barak Y, Arroyo V, Claria J (2011) Role for PPARgamma in obesity-induced hepatic steatosis as determined by hepatocyte- and macrophage-specific conditional knockouts. FASEB J 25(8):2538–2550. https://doi.org/10.1096/fj.10-173716
Poggi M, Bastelica D, Gual P, Iglesias MA, Gremeaux T, Knauf C, Peiretti F, Verdier M, Juhan-Vague I, Tanti JF, Burcelin R, Alessi MC (2007) C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet. Diabetologia 50(6):1267–1276. https://doi.org/10.1007/s00125-007-0654-8
Bronsart LL, Contag CH (2016) A role of the adaptive immune system in glucose homeostasis. BMJ Open Diabetes Res Care 4(1):e000136. https://doi.org/10.1136/bmjdrc-2015-000136
Bruun JM, Helge JW, Richelsen B, Stallknecht B (2006) Diet and exercise reduce low-grade inflammation and macrophage infiltration in adipose tissue but not in skeletal muscle in severely obese subjects. Am J Physiol Endocrinol Metab 290(5):E961–967. https://doi.org/10.1152/ajpendo.00506.2005
Norris AW, Chen L, Fisher SJ, Szanto I, Ristow M, Jozsi AC, Hirshman MF, Rosen ED, Goodyear LJ, Gonzalez FJ, Spiegelman BM, Kahn CR (2003) Muscle-specific PPARgamma-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones. J Clin Investig 112(4):608–618. https://doi.org/10.1172/JCI17305
Stanton MC, Chen SC, Jackson JV, Rojas-Triana A, Kinsley D, Cui L, Fine JS, Greenfeder S, Bober LA, Jenh CH (2011) Inflammatory Signals shift from adipose to liver during high fat feeding and influence the development of steatohepatitis in mice. J Inflamm (Lond) 8:8. https://doi.org/10.1186/1476-9255-8-8
Lefere S, Tacke F (2019) Macrophages in obesity and non-alcoholic fatty liver disease: crosstalk with metabolism. JHEP Rep 1(1):30–43. https://doi.org/10.1016/j.jhepr.2019.02.004
Bijnen M, Josefs T, Cuijpers I, Maalsen CJ, van de Gaar J, Vroomen M, Wijnands E, Rensen SS, Greve JWM, Hofker MH, Biessen EAL, Stehouwer CDA, Schalkwijk CG, Wouters K (2018) Adipose tissue macrophages induce hepatic neutrophil recruitment and macrophage accumulation in mice. Gut 67(7):1317–1327. https://doi.org/10.1136/gutjnl-2016-313654
Rytka JM, Wueest S, Schoenle EJ, Konrad D (2011) The portal theory supported by venous drainage-selective fat transplantation. Diabetes 60(1):56–63. https://doi.org/10.2337/db10-0697
Sabio G, Das M, Mora A, Zhang Z, Jun JY, Ko HJ, Barrett T, Kim JK, Davis RJ (2008) A stress signaling pathway in adipose tissue regulates hepatic insulin resistance. Science 322(5907):1539–1543. https://doi.org/10.1126/science.1160794
Wueest S, Rapold RA, Schumann DM, Rytka JM, Schildknecht A, Nov O, Chervonsky AV, Rudich A, Schoenle EJ, Donath MY, Konrad D (2010) Deletion of Fas in adipocytes relieves adipose tissue inflammation and hepatic manifestations of obesity in mice. J Clin Investig 120(1):191–202. https://doi.org/10.1172/JCI38388
Rosso C, Kazankov K, Younes R, Esmaili S, Marietti M, Sacco M, Carli F, Gaggini M, Salomone F, Moller HJ, Abate ML, Vilstrup H, Gastaldelli A, George J, Gronbaek H, Bugianesi E (2019) Crosstalk between adipose tissue insulin resistance and liver macrophages in non-alcoholic fatty liver disease. J Hepatol 71(5):1012–1021. https://doi.org/10.1016/j.jhep.2019.06.031
Andersson CX, Gustafson B, Hammarstedt A, Hedjazifar S, Smith U (2008) Inflamed adipose tissue, insulin resistance and vascular injury. Diabetes Metab Res Rev 24(8):595–603. https://doi.org/10.1002/dmrr.889
Fruhbeck G, Catalan V, Rodriguez A, Gomez-Ambrosi J (2018) Adiponectin-leptin ratio: a promising index to estimate adipose tissue dysfunction. Relation with obesity-associated cardiometabolic risk. Adipocyte 7(1):57–62. https://doi.org/10.1080/21623945.2017.1402151
Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K (2006) Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Investig 116(7):1784–1792. https://doi.org/10.1172/JCI29126
Combs TP, Marliss EB (2014) Adiponectin signaling in the liver. Rev Endocr Metab Disord 15(2):137–147. https://doi.org/10.1007/s11154-013-9280-6
Gustafson B, Hammarstedt A, Andersson CX, Smith U (2007) Inflamed adipose tissue: a culprit underlying the metabolic syndrome and atherosclerosis. Arterioscler Thromb Vasc Biol 27(11):2276–2283. https://doi.org/10.1161/ATVBAHA.107.147835
Gustafson B (2010) Adipose tissue, inflammation and atherosclerosis. J Atheroscler Thromb 17(4):332–341
Liu Z, Jiang Y, Li Y, Wang J, Fan L, Scott MJ, Xiao G, Li S, Billiar TR, Wilson MA, Fan J (2013) TLR4 Signaling augments monocyte chemotaxis by regulating G protein-coupled receptor kinase 2 translocation. J Immunol 191(2):857–864. https://doi.org/10.4049/jimmunol.1300790
Arnon TI, Xu Y, Lo C, Pham T, An J, Coughlin S, Dorn GW, Cyster JG (2011) GRK2-dependent S1PR1 desensitization is required for lymphocytes to overcome their attraction to blood. Science 333(6051):1898–1903. https://doi.org/10.1126/science.1208248
Penela P, Ribas C, Aymerich I, Eijkelkamp N, Barreiro O, Heijnen CJ, Kavelaars A, Sanchez-Madrid F, Mayor F Jr (2008) G protein-coupled receptor kinase 2 positively regulates epithelial cell migration. EMBO J 27(8):1206–1218. https://doi.org/10.1038/emboj.2008.55
Grisanti LA, Traynham CJ, Repas AA, Gao E, Koch WJ, Tilley DG (2016) beta2-Adrenergic receptor-dependent chemokine receptor 2 expression regulates leukocyte recruitment to the heart following acute injury. Proc Natl Acad Sci USA 113(52):15126–15131. https://doi.org/10.1073/pnas.1611023114
Parker R, Weston CJ, Miao Z, Corbett C, Armstrong MJ, Ertl L, Ebsworth K, Walters MJ, Baumart T, Newland D, McMahon J, Zhang P, Singh R, Campbell J, Newsome PN, Charo I, Schall TJ, Adams DH (2018) CC chemokine receptor 2 promotes recruitment of myeloid cells associated with insulin resistance in nonalcoholic fatty liver disease. Am J Physiol Gastrointest Liver Physiol 314(4):G483–G493. https://doi.org/10.1152/ajpgi.00213.2017
Ashino T, Yamanaka R, Yamamoto M, Shimokawa H, Sekikawa K, Iwakura Y, Shioda S, Numazawa S, Yoshida T (2008) Negative feedback regulation of lipopolysaccharide-induced inducible nitric oxide synthase gene expression by heme oxygenase-1 induction in macrophages. Mol Immunol 45(7):2106–2115. https://doi.org/10.1016/j.molimm.2007.10.011
Tak PP, Firestein GS (2001) NF-kappaB: a key role in inflammatory diseases. J Clin Investig 107(1):7–11. https://doi.org/10.1172/JCI11830
Rajakariar R, Yaqoob MM, Gilroy DW (2006) COX-2 in inflammation and resolution. Mol Interv 6(4):199–207. https://doi.org/10.1124/mi.6.4.6
Gilroy DW, Colville-Nash PR, Willis D, Chivers J, Paul-Clark MJ, Willoughby DA (1999) Inducible cyclooxygenase may have anti-inflammatory properties. Nat Med 5(6):698–701. https://doi.org/10.1038/9550
Gao Y, Zhang H, Luo L, Lin J, Li D, Zheng S, Huang H, Yan S, Yang J, Hao Y, Li H, Gao Smith F, Jin S (2017) Resolvin D1 Improves the Resolution of Inflammation via Activating NF-kappaB p50/p50-Mediated Cyclooxygenase-2 Expression in Acute Respiratory Distress Syndrome. J Immunol. https://doi.org/10.4049/jimmunol.1700315
Scher JU, Pillinger MH (2005) 15d-PGJ2: the anti-inflammatory prostaglandin? Clin Immunol 114(2):100–109. https://doi.org/10.1016/j.clim.2004.09.008
Tsoyi K, Ha YM, Kim YM, Lee YS, Kim HJ, Kim HJ, Seo HG, Lee JH, Chang KC (2009) Activation of PPAR-gamma by carbon monoxide from CORM-2 leads to the inhibition of iNOS but not COX-2 expression in LPS-stimulated macrophages. Inflammation 32(6):364–371. https://doi.org/10.1007/s10753-009-9144-0
Han Z, Zhu T, Liu X, Li C, Yue S, Liu X, Yang L, Yang L, Li L (2012) 15-deoxy-Delta 12,14 -prostaglandin J2 reduces recruitment of bone marrow-derived monocyte/macrophages in chronic liver injury in mice. Hepatology 56(1):350–360. https://doi.org/10.1002/hep.25672
Takayama K, Garcia-Cardena G, Sukhova GK, Comander J, Gimbrone MA Jr, Libby P (2002) Prostaglandin E2 suppresses chemokine production in human macrophages through the EP4 receptor. J Biolog Chem 277(46):44147–44154. https://doi.org/10.1074/jbc.M204810200
Jia XY, Chang Y, Wei F, Dai X, Wu YJ, Sun XJ, Xu S, Wu HX, Wang C, Yang XZ, Wei W (2019) CP-25 reverses prostaglandin E4 receptor desensitization-induced fibroblast-like synoviocyte dysfunction via the G protein-coupled receptor kinase 2 in autoimmune arthritis. Acta Pharmacol Sin. https://doi.org/10.1038/s41401-018-0196-2
Bacou E, Haurogne K, Allard M, Mignot G, Bach JM, Herve J, Lieubeau B (2017) beta2-adrenoreceptor stimulation dampens the LPS-induced M1 polarization in pig macrophages. Dev Comp Immunol 76:169–176. https://doi.org/10.1016/j.dci.2017.06.007
Grailer JJ, Haggadone MD, Sarma JV, Zetoune FS, Ward PA (2014) Induction of M2 regulatory macrophages through the beta2-adrenergic receptor with protection during endotoxemia and acute lung injury. J Innate Immun 6(5):607–618. https://doi.org/10.1159/000358524
Keranen T, Hommo T, Moilanen E, Korhonen R (2017) beta2-receptor agonists salbutamol and terbutaline attenuated cytokine production by suppressing ERK pathway through cAMP in macrophages. Cytokine 94:1–7. https://doi.org/10.1016/j.cyto.2016.07.016
Patial S, Saini Y, Parvataneni S, Appledorn DM, Dorn GW 2nd, Lapres JJ, Amalfitano A, Senagore P, Parameswaran N (2011) Myeloid-specific GPCR kinase-2 negatively regulates NF-kappaB1p105-ERK pathway and limits endotoxemic shock in mice. J Cell Physiol 226(3):627–637. https://doi.org/10.1002/jcp.22384
Peregrin S, Jurado-Pueyo M, Campos PM, Sanz-Moreno V, Ruiz-Gomez A, Crespo P, Mayor F Jr, Murga C (2018) Phosphorylation of p38 by GRK2 at the docking groove unveils a novel mechanism for inactivating p38MAPK. Curr Biol 28(15):2513. https://doi.org/10.1016/j.cub.2018.07.033
Willemen HL, Eijkelkamp N, Garza Carbajal A, Wang H, Mack M, Zijlstra J, Heijnen CJ, Kavelaars A (2014) Monocytes/macrophages control resolution of transient inflammatory pain. J Pain 15(5):496–506. https://doi.org/10.1016/j.jpain.2014.01.491
Patial S, Luo J, Porter KJ, Benovic JL, Parameswaran N (2009) G-protein-coupled-receptor kinases mediate TNFalpha-induced NFkappaB signalling via direct interaction with and phosphorylation of IkappaBalpha. Biochem J 425(1):169–178. https://doi.org/10.1042/BJ20090908
Palikhe S, Ohashi W, Sakamoto T, Hattori K, Kawakami M, Andoh T, Yamazaki H, Hattori Y (2019) Regulatory role of GRK2 in the TLR signaling-mediated iNOS induction pathway in microglial cells. Front Pharmacol 10:59. https://doi.org/10.3389/fphar.2019.00059
Kawakami M, Hattori M, Ohashi W, Fujimori T, Hattori K, Takebe M, Tomita K, Yokoo H, Matsuda N, Yamazaki M, Hattori Y (2018) Role of G protein-coupled receptor kinase 2 in oxidative and nitrosative stress-related neurohistopathological changes in a mouse model of sepsis-associated encephalopathy. J Neurochem 145(6):474–488. https://doi.org/10.1111/jnc.14329
Acknowledgements
We acknowledge support by Ministerio de Economía y Competitividad (MINECO/FEDER), Spain (grant SAF2017-84125-R to FM and CM and SAF2017-82436R to LB); CIBER de Enfermedades Cardiovasculares (CIBERCV). Instituto de Salud Carlos III, Spain (grant CB16/11/00278 to F.M., CB16/11/00222 to L.B., and, PI15/01114 to Francisco Tinaones (Universidad De Málaga, Spain), co-funded with European FEDER contribution); European Foundation for the Study of Diabetes (EFSD) Novo Nordisk Partnership for Diabetes Research in Europe Grant (to F.M.); and Programa de Actividades en Biomedicina de la Comunidad de Madrid-B2017/BMD-3671-INFLAMUNE to FM and MF.. I.M.-I. was supported by the “MS type I” program (CP16/00163). The authors thank the Metagenomic Platform of the Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición, CIBERobn, Instituto de Salud Carlos III (ISCIII), Spain. We appreciate the help of the CBMSO Facilities, in particular Flow Cytometry, Genomics and Animal Care. We acknowledge Paula Ramos for technical support. We also acknowledge the institutional support to the CBMSO from Fundación Ramón Areces.
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Vila-Bedmar, R., Cruces-Sande, M., Arcones, A.C. et al. GRK2 levels in myeloid cells modulate adipose-liver crosstalk in high fat diet-induced obesity. Cell. Mol. Life Sci. 77, 4957–4976 (2020). https://doi.org/10.1007/s00018-019-03442-5
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DOI: https://doi.org/10.1007/s00018-019-03442-5