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Haptoglobin Acts As a TLR4 Ligand to Suppress Osteoclastogenesis Via the TLR4− IFN-Β Axis

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Haptoglobin Acts As a TLR4 Ligand to Suppress Osteoclastogenesis Via the TLR4− IFN-Β Axis Haptoglobin Acts as a TLR4 Ligand to Suppress Osteoclastogenesis via the TLR4− IFN-β Axis This information is current as Jun-Oh Kwon, Won Jong Jin, Bongjun Kim, Hyunil Ha, of September 29, 2021. Hong-Hee Kim and Zang Hee Lee J Immunol published online 10 May 2019 http://www.jimmunol.org/content/early/2019/05/09/jimmun ol.1800661 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2019/05/10/jimmunol.180066 Material 1.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 29, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2019 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published May 10, 2019, doi:10.4049/jimmunol.1800661 The Journal of Immunology Haptoglobin Acts as a TLR4 Ligand to Suppress Osteoclastogenesis via the TLR4–IFN-b Axis Jun-Oh Kwon,*,1 Won Jong Jin,†,1 Bongjun Kim,* Hyunil Ha,‡ Hong-Hee Kim,* and Zang Hee Lee* Haptoglobin (Hp), a type of acute-phase protein, is known to have a systemic anti-inflammatory function and to modulate inflam- mation by directly affecting immune cells, such as T cells, dendritic cells, and macrophages. However, the effects of Hp on osteoclast differentiation are not well studied, even though osteoclast precursor cells belong to a macrophage-monocyte lineage. In this study, we found that the bone volume was reduced, and the number of osteoclasts was increased in Hp-deficient mice compared with wild- type mice. Moreover, our in vitro studies showed that Hp inhibits osteoclastogenesis by reducing the protein level of c-Fos at the early phase of osteoclast differentiation. We revealed that Hp-induced suppression of c-Fos was mediated by increased IFN-b levels. Furthermore, Hp stimulated IFN-b via a TLR4-dependent mechanism. These results demonstrate that Hp plays a protective role Downloaded from against excessive osteoclastogenesis via the Hp–TLR4–IFN-b axis. The Journal of Immunology, 2019, 202: 000–000. aptoglobin (Hp) belongs to a class of acute-phase pro- scavenging free Hb (2, 3). In addition to a systemic anti- teins that are rapidly upregulated upon stimulation inflammatory function, recent studies have shown that Hp is in- H by cytokines such as TNF-a, IL-6, and IL-1 (1). Hp is volved in the proliferation, function, and cytokine secretion of expressed in most tissues and is mainly produced by stromal cells immune cells. The binding of Hp to CD11b/CD18, which is http://www.jimmunol.org/ and hepatocytes. The primary function of Hp is to combine with expressed in various immune cells, including dendritic cells (DCs), the free hemoglobin (Hb) that is released during hemolysis monocytes, and macrophages, suppresses the effector functions of or healthy RBC turnover, which leads to the elimination of the macrophages and DCs, such as Ag presentation and phagocytosis Hb–Hp complex by macrophages. Free Hb reacts with H2O2 to and, at the same time, reduces the secretion of proinflammatory form reactive oxygen species, such as reactive hydroxyl radicals, cytokines, such as IL-6 (4–6). In the case of T cells, Hp directly which cause damage to tissues. Hp prevents oxidative stress by binds to activated or resting CD4+ and CD8+ T cells, thereby inhibiting proliferation (7). These results imply that Hp does not only suppress the inflammatory response but physiologically plays *Department of Cell and Developmental Biology, Dental Research Institute, School by guest on September 29, 2021 of Dentistry, Seoul National University, Seoul 110-749, Republic of Korea; an important role in the biological processes of immune cells. †Department of Human Oncology, University of Wisconsin School of Medicine An osteoclast is a multinuclear giant cell that is formed by the ‡ and Public Health, Madison, WI 53705; and Clinical Research Division, Korea fusion of mononuclear precursor cells of a macrophage-monocyte Institute of Oriental Medicine, 483 Expo-Ro, Yuseong-Gu, Daejeon 305-811, Repub- lic of Korea lineage. Osteoclasts have a unique ability to resorb the bone di- 1J.-O.K. and W.J.J. contributed equally to this work. rectly. Two factors are essential for the differentiation from pro- genitor cells to osteoclasts: M-CSF and the receptor activator ORCIDs: 0000-0001-5454-3391 (J.-O.K.); 0000-0003-4147-9735 (W.J.J.); 0000- 0001-7198-0411 (B.K.); 0000-0001-5947-9982 (H.H.). of NF-kB ligand (RANKL) (8, 9). These factors induce the ex- Received for publication May 9, 2018. Accepted for publication April 12, 2019. pression and activation of c-Fos, a key regulator of osteoclast This work was supported by the Basic Science Research Program through the differentiation. c-Fos raises the level of RANK, the receptor of National Research Foundation of Korea funded by the Ministry of Science, RANKL, and increases the expression of NF of activated T cells 1 ICT and Future Planning (NRF-2017R1A2B2002312) and by grants from the (NFATc1), which is another key transcription factor for osteo- National Research Foundation of Korea (NRF-2017R1A2A1A17069648 and NRF-2018R1A5A2024418 to H.-H.K.). clastogenesis (10–12). Hematopoietic progenitor cells derived J.-O.K. and W.J.J. designed the research and performed experiments. J.-O.K. drafted from c-Fos–deficient mice did not have a significant problem the manuscript. B.K. participated in the research. H.H. performed statistical analyses. differentiating into macrophages but could not differentiate into H.-H.K. provided insightful guidance to design experiments. Z.H.L. provided insight- osteoclasts (13). These results indicate that c-Fos plays an es- ful guidance and critical appraisal of the manuscript. All authors read and approved the final manuscripts. sential role in the triggering of osteoclast differentiation. Address correspondence and reprint requests to Prof. Zang Hee Lee and Prof. Hong- Diseases such as lupus, rheumatoid arthritis (RA), cancer, and Hee Kim, Department of Cell and Developmental Biology, Dental Research Institute, osteoarthritis have disease-specific features but commonly have a School of Dentistry, Seoul National University, 28 Yeongon-Dong, Jongno-Gu, Seoul chronic inflammatory response (1, 14, 15). Persistent and exces- 110-749, Republic of Korea. E-mail addresses: [email protected] (Z.H.L.) and [email protected] (H.-H.K.) sive inflammatory responses increase proinflammatory cytokines, The online version of this article contains supplemental material. such as TNF-a, IL-1, and IL-6, to more than necessary levels, accelerating the recruitment of osteoclast precursor cells and Abbreviations used in this article: BMM, bone marrow–derived macrophage; mCT, microcomputed tomography; Ct.Ar, cortical bone area; DC, dendritic cell; Hb, he- osteoclastogenesis (16–19). Moreover, inflammatory responses moglobin; Hp, haptoglobin; NFATc1, NF of activated T cell 1; N.Oc./BS, number of increase RANKL expression in fibroblast-like cells and immune osteoclasts per bone surface; OCN, osteocalcin; Oc.S/BS, osteoclast surface per bone surface; P1NP, procollagen type 1 N-terminal propeptide; RA, rheumatoid cells like T cells and DCs. Thus, in diseases that are accompanied arthritis; RANK, receptor activator of NF-kB; RANKL, receptor activator of NF-kB by an inflammatory response, bone loss due to abnormal osteo- ligand; TRAP, tartrate-resistant acid phosphatase; Tt.Ar, total cross-sectional area; clast differentiation occurs frequently (20–22). Therefore, various WT, wild-type. studies have been conducted on inflammation-related molecules Copyright Ó 2019 by The American Association of Immunologists, Inc. 0022-1767/19/$37.50 to prevent bone loss. Nevertheless, no therapeutic agent has been www.jimmunol.org/cgi/doi/10.4049/jimmunol.1800661 2 HAPTOGLOBIN INHIBITS OSTEOCLASTOGENESIS developed to inhibit bone loss entirely, and there is a continuing containing 10 mM b-glycerophosphate (Sigma-Aldrich), 50 mg/ml demand for therapeutic targets. Previous studies suggest that Hp ascorbate-2-phosphate (Sigma-Aldrich), and 100 ng/ml of BMP-2. The is involved in various physiological functions of immune cells, medium was replaced every 3 d. After culturing, the cells were fixed with 10% of formalin for 20 min. Osteoblast differentiation was measured by indicating that Hp may affect osteoclast differentiation. Results alkaline phosphatase or Alizarin Red S staining following manufacturer’s showing that Hp is significantly higher in patients with lupus instructions (Sigma-Aldrich). and RA than in healthy individuals emphasize the importance of ELISA studying the effect of Hp on osteoclast differentiation (1, 3). In the current study, we investigated the effect of Hp deficiency on os- To analyze the secreted Hp, osteocalcin (OCN), procollagen type 1 teoclast differentiation that affects bone phenotype and examined N-terminal propeptide (P1NP) and IFN-b levels, mouse serum, or culture supernatant medium were collected and assessed using IFN-b ELISA kit the direct effect of Hp on osteoclastogenesis. (PBL Assay Science), OCN ELISA kit (LSBio, Seattle), P1NP ELISA kit (IDS, Boldon, U.K.), or a Hp ELISA kit (Abnova, Taipei City, Taiwan) Materials and Methods according to the manufacturer’s instructions. Animal experiments FITC labeling and immunostaining All animal experiments were performed in accordance with the Animal FITC labeling of Hp was performed by using a FluoroTag FITC Conjugation Care Committee of the Institute of Laboratory Animal Resources of Seoul 2/2 Kit (Sigma-Aldrich) according to the manufacturer’s instruction.
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