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01-04-2018 | Original Article

Carbon monoxide-releasing molecule, CORM-3, modulates alveolar macrophage M1/M2 phenotype in vitro

Authors: Hiroko Yamamoto-Oka, Shinjiro Mizuguchi, Michihito Toda, Yukiko Minamiyama, Shigekazu Takemura, Toshihiko Shibata, Gediminas Cepinskas, Noritoshi Nishiyama

Published in: Inflammopharmacology | Issue 2/2018

Abstract

Alveolar macrophages are key contributors to both the promotion and resolution of inflammation in the lung and are categorized into pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes. The change in M1/M2 balance has been reported in various pulmonary diseases and is a target for therapeutic intervention. The aim of this study was to assess the modulation of M1/M2 phenotype in alveolar macrophages by water-soluble carbon monoxide-releasing molecule-3 (CORM-3). Rat alveolar macrophages (AM) (NR8383) in culture were stimulated with LPS (5 ng/ml)/IFN-γ (10 U/ml) or IL-4 (10 ng/ml)/IL-13 (10 ng/ml) to induce M1 and M2 phenotypes, respectively. Expression of M1 phenotype markers, iNOS and TNF-α, and M2 phenotype markers, CD206 and Ym-1, was assessed by western blotting after 1, 3, 6, or 24 h in the absence or presence of CORM-3 (0.15 mM) treatment. Inactive CORM-3 (iCORM-3) was used as a control. Treatment of naïve (unstimulated) AM with CORM-3 promoted progression of the M2 phenotype as evidenced by the increased expression of CD206 (at 1 h; 1.8-fold) and Ym-1 (at 3 h; 1.9-fold), respectively. Surprisingly, CORM-3 treatment also upregulated the expression of iNOS protein as assessed 6 h following stimulation of AM with CORM-3 (2.6-fold). On the contrary, CORM-3 effectively reduced LPS/IFN-γ-induced expression of iNOS protein (0.6-fold); however, it had no effect on TNF-α expression. Finally, CORM-3 acutely (1–3 h) upregulated CD206 (1.4-fold) and Ym-1 (1.6-fold) levels in IL-4-/IL-13-treated (M2-stimulus) macrophages. These findings indicate that CORM-3 modulates macrophage M1 and M2 phenotypes in vitro with respect to continuous suppression of iNOS expression in M1-polarized macrophages and transient (early-phase) upregulation of CD206 and Ym-1 proteins in M2-polarized macrophages.

Aggarwal NR, King LS, D’Alessio FR (2014) Diverse macrophage populations mediate acute lung inflammation and resolution. Am J Physiol Lung Cell Mol Physiol 306(8):L709–L725. doi:10.1152/ajplung.00341.2013 CrossRefPubMedPubMedCentral

Boczkowski J, Poderoso JJ, Motterlini R (2006) CO-metal interaction: vital signaling from a lethal gas. Trends Biochem Sci 31(11):614–621. doi:10.1016/j.tibs.2006.09.001 CrossRefPubMed

Boorsma CE, Draijer C, Melgert BN (2013) Macrophage heterogeneity in respiratory diseases. Mediat Inflamm 2013:769214. doi:10.1155/2013/769214 CrossRef

Cepinskas G, Katada K, Bihari A, Potter RF (2008) Carbon monoxide liberated from carbon monoxide-releasing molecule CORM-2 attenuates inflammation in the liver of septic mice. Am J Physiol Gastrointest Liver Physiol 294(1):G184–G191. doi:10.1152/ajpgi.00348.2007 CrossRefPubMed

Dobashi K, Aihara M, Araki T, Shimizu Y, Utsugi M, Iizuka K, Murata Y, Hamuro J, Nakazawa T, Mori M (2001) Regulation of LPS induced IL-12 production by IFN-gamma and IL-4 through intracellular glutathione status in human alveolar macrophages. Clin Exp Immunol 124(2):290–296CrossRefPubMedPubMedCentral

Foresti R, Bani-Hani MG, Motterlini R (2008) Use of carbon monoxide as a therapeutic agent: promises and challenges. Intensive Care Med 34(4):649–658. doi:10.1007/s00134-008-1011-1 CrossRefPubMed

Gazi U, Martinez-Pomares L (2009) Influence of the mannose receptor in host immune responses. Immunobiology 214(7):554–561. doi:10.1016/j.imbio.2008.11.004 CrossRefPubMed

Helmke RJ, Boyd RL, German VF, Mangos JA (1987) From growth factor dependence to growth factor responsiveness: the genesis of an alveolar macrophage cell line. In Vitro Cell Dev Biol 23(8):567–574CrossRefPubMed

Helmke RJ, German VF, Mangos JA (1989) A continuous alveolar macrophage cell line: comparisons with freshly derived alveolar macrophages. In Vitro Cell Dev Biol 25(1):44–48CrossRefPubMed

Herold S, Mayer K, Lohmeyer J (2011) Acute lung injury: how macrophages orchestrate resolution of inflammation and tissue repair. Front Immunol 2:65. doi:10.3389/fimmu.2011.00065 CrossRefPubMedPubMedCentral

Hishiki T, Yamamoto T, Morikawa T, Kubo A, Kajimura M, Suematsu M (2012) Carbon monoxide: impact on remethylation/transsulfuration metabolism and its pathophysiologic implications. J Mol Med (Berl) 90(3):245–254. doi:10.1007/s00109-012-0875-2 CrossRef

Hoetzel A, Dolinay T, Schmidt R, Choi AM, Ryter SW (2007) Carbon monoxide in sepsis. Antioxid Redox Signal 9(11):2013–2026. doi:10.1089/ars.2007.1762 CrossRefPubMed

Hussell T, Bell TJ (2014) Alveolar macrophages: plasticity in a tissue-specific context. Nat Rev Immunol 14(2):81–93. doi:10.1038/nri3600 CrossRefPubMed

Jordens R, Thompson A, Amons R, Koning F (1999) Human dendritic cells shed a functional, soluble form of the mannose receptor. Int Immunol 11(11):1775–1780CrossRefPubMed

Kadl A, Meher AK, Sharma PR, Lee MY, Doran AC, Johnstone SR, Elliott MR, Gruber F, Han J, Chen W, Kensler T, Ravichandran KS, Isakson BE, Wamhoff BR, Leitinger N (2010) Identification of a novel macrophage phenotype that develops in response to atherogenic phospholipids via Nrf2. Circ Res 107(6):737–746. doi:10.1161/CIRCRESAHA.109.215715 CrossRefPubMedPubMedCentral

Katada K, Bihari A, Mizuguchi S, Yoshida N, Yoshikawa T, Fraser DD, Potter RF, Cepinskas G (2010) Carbon monoxide liberated from CO-releasing molecule (CORM-2) attenuates ischemia/reperfusion (I/R)-induced inflammation in the small intestine. Inflammation 33(2):92–100. doi:10.1007/s10753-009-9162-y CrossRefPubMed

Kim HP, Ryter SW, Choi AM (2006) CO as a cellular signaling molecule. Annu Rev Pharmacol Toxicol 46:411–449. doi:10.1146/annurev.pharmtox.46.120604.141053 CrossRefPubMed

Lawendy AR, Bihari A, Sanders DW, Potter RF, Cepinskas G (2014) The severity of microvascular dysfunction due to compartment syndrome is diminished by the systemic application of CO-releasing molecule-3. J Orthop Trauma 28(11):e263–e268. doi:10.1097/BOT.0000000000000097 CrossRefPubMed

Lawrence Toby, Natoli Gioacchino (2011) Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat Rev Immunol 11(11):750–761CrossRefPubMed

Lee SJ, Evers S, Roeder D, Parlow AF, Risteli J, Risteli L, Lee YC, Feizi T, Langen H, Nussenzweig MC (2002) Mannose receptor-mediated regulation of serum glycoprotein homeostasis. Science 295(5561):1898–1901. doi:10.1126/science.1069540 CrossRefPubMed

Martinez-Pomares L (2012) The mannose receptor. J Leukoc Biol 92(6):1177–1186. doi:10.1189/jlb.0512231 CrossRefPubMed

Martínez-Pomares L, Mahoney JA, Káposzta R, Linehan SA, Stahl PD, Gordon S (1998) A functional soluble form of the murine mannose receptor is produced by macrophages in vitro and is present in mouse serum. J Biol Chem 273(36):23376–23380CrossRefPubMed

Mizuguchi S, Stephen J, Bihari R, Markovic N, Suehiro S, Capretta A, Potter RF, Cepinskas G (2009) CORM-3-derived CO modulates polymorphonuclear leukocyte migration across the vascular endothelium by reducing levels of cell surface-bound elastase. Am J Physiol Heart Circ Physiol 297(3):H920–H929. doi:10.1152/ajpheart.00305.2009 CrossRefPubMed

Mizuguchi S, Capretta A, Suehiro S, Nishiyama N, Luke P, Potter RF, Fraser DD, Cepinskas G (2010) Carbon monoxide-releasing molecule CORM-3 suppresses vascular endothelial cell SOD-1/SOD-2 activity while up-regulating the cell surface levels of SOD-3 in a heparin-dependent manner. Free Radic Biol Med 49(10):1534–1541. doi:10.1016/j.freeradbiomed.2010.08.017 CrossRefPubMed

Motterlini R, Otterbein LE (2010) The therapeutic potential of carbon monoxide. Nat Rev Drug Discov 9(9):728–743. doi:10.1038/nrd3228 CrossRefPubMed

Motterlini R, Clark JE, Foresti R, Sarathchandra P, Mann BE, Green CJ (2002) Carbon monoxide-releasing molecules: characterization of biochemical and vascular activities. Circ Res 90(2):E17–E24CrossRefPubMed

Murray PJ, Wynn TA (2011) Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 11(11):723–737. doi:10.1038/nri3073 CrossRefPubMedPubMedCentral

Naito Y, Takagi T, Higashimura Y (2014) Heme oxygenase-1 and anti-inflammatory M2 macrophages. Arch Biochem Biophys 564:83–88. doi:10.1016/j.abb.2014.09.005 CrossRefPubMed

Ndisang JF, Tabien HE, Wang R (2004) Carbon monoxide and hypertension. J Hypertens 22(6):1057–1074CrossRefPubMed

Otterbein LE, Bach FH, Alam J, Soares M, Tao Lu H, Wysk M, Davis RJ, Flavell RA, Choi AM (2000) Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nat Med 6(4):422–428. doi:10.1038/74680 CrossRefPubMed

Patterson EK, Fraser DD, Capretta A, Potter RF, Cepinskas G (2014) Carbon monoxide-releasing molecule 3 inhibits myeloperoxidase (MPO) and protects against MPO-induced vascular endothelial cell activation/dysfunction. Free Radic Biol Med 70:167–173. doi:10.1016/j.freeradbiomed.2014.02.020 CrossRefPubMed

Piantadosi CA (2008) Carbon monoxide, reactive oxygen signaling, and oxidative stress. Free Radic Biol Med 45(5):562–569. doi:10.1016/j.freeradbiomed.2008.05.013 CrossRefPubMedPubMedCentral

Qin S, Du R, Yin S, Liu X, Xu G, Cao W (2015) Nrf2 is essential for the anti-inflammatory effect of carbon monoxide in LPS-induced inflammation. Inflamm Res 64(7):537–548. doi:10.1007/s00011-015-0834-9 CrossRefPubMed

Rőszer T (2015) Understanding the mysterious M2 macrophage through activation markers and effector mechanisms. Mediat Inflamm 2015:816460. doi:10.1155/2015/816460

Ryter SW, Alam J, Choi AM (2006) Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiol Rev 86(2):583–650. doi:10.1152/physrev.00011.2005 CrossRefPubMed

Sarady JK, Otterbein SL, Liu F, Otterbein LE, Choi AM (2002) Carbon monoxide modulates endotoxin-induced production of granulocyte macrophage colony-stimulating factor in macrophages. Am J Respir Cell Mol Biol 27(6):739–745. doi:10.1165/rcmb.4816 CrossRefPubMed

Sarady JK, Zuckerbraun BS, Bilban M, Wagner O, Usheva A, Liu F, Ifedigbo E, Zamora R, Choi AM, Otterbein LE (2004) Carbon monoxide protection against endotoxic shock involves reciprocal effects on iNOS in the lung and liver. FASEB J 18(7):854–856. doi:10.1096/fj.03-0643fje CrossRefPubMed

Sawle P, Foresti R, Mann BE, Johnson TR, Green CJ, Motterlini R (2005) Carbon monoxide-releasing molecules (CO-RMs) attenuate the inflammatory response elicited by lipopolysaccharide in RAW264.7 murine macrophages. Br J Pharmacol 145(6):800–810. doi:10.1038/sj.bjp.0706241 CrossRefPubMedPubMedCentral

Serizawa F, Patterson E, Potter RF, Fraser DD, Cepinskas G (2015) Pretreatment of human cerebrovascular endothelial cells with CO-releasing molecule-3 interferes with JNK/AP-1 signaling and suppresses LPS-induced proadhesive phenotype. Microcirculation 22(1):28–36. doi:10.1111/micc.12161 CrossRefPubMed

Sierra-Filardi E, Vega MA, Sanchez-Mateos P, Corbi AL, Puig-Kroger A (2010) Heme Oxygenase-1 expression in M-CSF-polarized M2 macrophages contributes to LPS-induced IL-10 release. Immunobiology 215(9–10):788–795. doi:10.1016/j.imbio.2010.05.020 CrossRefPubMed

Taylor PR, Gordon S, Martinez-Pomares L (2005) The mannose receptor: linking homeostasis and immunity through sugar recognition. Trends Immunol 26(2):104–110. doi:10.1016/j.it.2004.12.001 CrossRefPubMed

Tsoyi K, Ha YM, Kim YM, Lee YS, 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. doi:10.1007/s10753-009-9144-0 CrossRefPubMed

Zobi F (2013) CO and CO-releasing molecules in medicinal chemistry. Future Med Chem 5(2):175–188. doi:10.4155/fmc.12.196 CrossRefPubMed

Title: Carbon monoxide-releasing molecule, CORM-3, modulates alveolar macrophage M1/M2 phenotype in vitro
Authors: Hiroko Yamamoto-Oka
Shinjiro Mizuguchi
Michihito Toda
Yukiko Minamiyama
Shigekazu Takemura
Toshihiko Shibata
Gediminas Cepinskas
Noritoshi Nishiyama
Publication date: 01-04-2018
Publisher: Springer International Publishing
Published in: Inflammopharmacology / Issue 2/2018
Print ISSN: 0925-4692
Electronic ISSN: 1568-5608
DOI: https://doi.org/10.1007/s10787-017-0371-y

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Carbon monoxide-releasing molecule, CORM-3, modulates alveolar macrophage M1/M2 phenotype in vitro

Abstract

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Abstract

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