Differential Effects of GM-CSF and G-CSF on Infiltration of Dendritic Cells during Early Left Ventricular Remodeling after Myocardial Infarction This information is current as of September 26, 2021. Kotaro Naito, Toshihisa Anzai, Yasuo Sugano, Yuichiro Maekawa, Takashi Kohno, Tsutomu Yoshikawa, Kenjiro Matsuno and Satoshi Ogawa J Immunol 2008; 181:5691-5701; ; doi: 10.4049/jimmunol.181.8.5691 Downloaded from http://www.jimmunol.org/content/181/8/5691 References This article cites 68 articles, 28 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/181/8/5691.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! 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The Journal of Immunology Differential Effects of GM-CSF and G-CSF on Infiltration of Dendritic Cells during Early Left Ventricular Remodeling after Myocardial Infarction1 Kotaro Naito,* Toshihisa Anzai,2* Yasuo Sugano,* Yuichiro Maekawa,* Takashi Kohno,* Tsutomu Yoshikawa,* Kenjiro Matsuno,† and Satoshi Ogawa* Several lines of evidence suggest that the immune activation after myocardial infarction (MI) induces secondary myocardial injury. Although dendritic cells (DC) are potent regulators of immunity, their role in MI is still undetermined. We investigated the effect of DC modulation by CSF on left ventricular (LV) remodeling after MI. MI was induced by ligation of the left coronary ؍ a GM-CSF inducer (romurtide, 200 ␮g/kg/day, MI-GM, n ,(33 ؍ artery in male Wistar rats. G-CSF (20 ␮g/kg/day, MI-G, n was administered for 7 days. On day 14, MI-G animals had higher LV max dP/dt and smaller LV Downloaded from (55 ؍ or saline (MI-C, n ,(28 dimensions, whereas MI-GM animals had lower LV max dP/dt and larger LV dimensions than did MI-C animals, despite similar infarct size. In MI-C, OX62؉ DC infiltrated the infarcted and border areas, peaking on day 7. Bromodeoxyuridine-positive DC were observed in the border area during convalescence. Infiltration by DC was decreased in MI-G animals and increased in MI-GM animals compared with MI-C (p < 0.05). In the infarcted area, the heat shock protein 70, TLR2 and TLR4, and IFN-␥ expression were reduced in MI-G, but increased in MI-GM in comparison with those in MI-C animals. IL-10 expression was higher in MI-G and lower in MI-GM than in MI-C animals. In conclusion, G-CSF improves and GM-CSF exacerbates early http://www.jimmunol.org/ postinfarction LV remodeling in association with modulation of DC infiltration. Suppression of DC-mediated immunity could be a new strategy for the treatment of LV remodeling after MI. The Journal of Immunology, 2008, 181: 5691–5701. eft ventricular (LV)3 remodeling, an important structural role during infarct healing and ventricular remodeling. Although event after myocardial infarction (MI), is characterized by an excessive inflammatory response after MI is associated with a L myocardial necrosis, wall thinning, infarct expansion, col- poor clinical outcome (2), antiinflammatory therapy using cortico- lagen accumulation, and noninfarcted myocardial hypertrophy, steroids (7, 8) or nonsteroidal antiinflammatory drugs (9, 10) leads and contributes significantly to a worse clinical outcome. These to catastrophic results such as a higher incidence of infarct expan- by guest on September 26, 2021 alterations are caused not only by significant loss of myocardium, sion and cardiac rupture. These findings suggest that an inflam- but also by myocardial injury secondary to local and systemic matory reaction is a prerequisite for the healing process. As the factors such as neurohumoral activation, oxidative stress, and in- cause of inappropriate activation of the inflammatory response af- flammatory response. The inflammatory response after MI is inte- ter MI, an autoimmune reaction is a possible mechanism relating gral to the healing process and contributes to LV remodeling (1–3). to LV remodeling (11–13). Abbate et al. reported infiltration of However, no effective therapeutic strategy against inflammation activated T cells into both infarcted and remote areas of the myo- has been established. cardium in patients with recent MI (1). Moreover, the presence of We previously reported that elevated concentrations of serum autoimmunity to cardiac myosin (12), actin (14), and troponin (15) C-reactive protein (4), plasma IL-6 (5), and peripheral monocyto- is associated with an adverse clinical outcome after MI. These sis (6) predict a worse clinical outcome after acute MI, suggesting findings suggest that autoimmunity may contribute to secondary that an immune-mediated inflammatory response may have some myocardial injury after MI. For the activation of autoimmune responses, myocardial Ag pre- sentation is required. Dendritic cells (DC) are potent regulators of *Division of Cardiology, Department of Medicine, Keio University School of Med- icine, Tokyo, Japan; and †Department of Anatomy (Macro) and Solution-Oriented immunity by presenting Ag, activating T cells, and by causing Research for Science and Technology (SORST), Dokkyo University School of Med- differentiation T cells into Th1 and Th2 cells (16–18). After tissue icine, Tochigi, Japan injury, heat shock proteins (HSP) released from necrotic cells can Received for publication January 19, 2007. Accepted for publication August 11, 2008. promote activation and maturation of DC through stimulation of The costs of publication of this article were defrayed in part by the payment of page TLRs (19, 20). Additionally, Cheng et al. demonstrated that Th1/ charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Th2 imbalance participated in ventricular remodeling after MI 1 This work was supported in part by a Keio University Medical School Faculty and (21). However, the role of DC during the healing process after MI Alumni Grant (to T.A.) and by grants for scientific research 18790511 (to K.N.) and has not been determined. 16790433 (to Y.S.) from the Japan Ministry of Education, Culture, Sports, Science and Technology. The development of DC from hematopoietic progenitor cells is 2 Address correspondence and reprint requests to Dr. Toshihisa Anzai, Division of Car- differentially regulated by various cytokines such as GM-CSF and diology, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, G-CSF. We previously reported that G-CSF treatment improved Shinjuku-ku, Tokyo 160-8582, Japan. E-mail address: [email protected] (22) and GM-CSF induction aggravated (23) early LV remodeling 3 Abbreviations used in this paper: LV, left ventricle; ALP, alkaline phosphatase; DC, after MI through modification of the infarct healing process. GM- dendritic cells; HSP, heat shock protein; MI, myocardial infarction. CSF induces differentiation from immature DC to myeloid DC, Copyright © 2008 by The American Association of Immunologists, Inc. 0022-1767/08/$2.00 with a subsequent increase in Th1 cells, whereas G-CSF induces www.jimmunol.org 5692 DENDRITIC CELLS IN POST-MI LV REMODELING Table I. Heart weight, echocardiographic, and hemodynamic data on day 14a Sham (n ϭ 9) MI-C (n ϭ 10) MI-G (n ϭ 10) MI-GM (n ϭ 10) BW, g 252 Ϯ 13 254 Ϯ 14 242 Ϯ 11 242 Ϯ 14 RVW/BW, g/kg 0.5 Ϯ 0.03 0.8 Ϯ 0.06* 0.8 Ϯ 0.05* 0.9 Ϯ 0.06* LVW/BW, g/kg 2.0 Ϯ 0.04 2.1 Ϯ 0.08 2.1 Ϯ 0.08 2.1 Ϯ 0.12 LVEDD, mm 6.2 Ϯ 0.2 8.5 Ϯ 0.2* 8.1 Ϯ 0.1*† 9.0 Ϯ 0.1*† LVESD, mm 3.7 Ϯ 0.1 6.9 Ϯ 0.1* 6.1 Ϯ 0.2*† 7.6 Ϯ 0.1*† FS, % 41 Ϯ 1.9 19 Ϯ 1.5* 24 Ϯ 1.1*† 15 Ϯ 0.7*† LVSP, mmHg 123 Ϯ 3 101 Ϯ 4* 102 Ϯ 2* 110 Ϯ 5* LVEDP, mmHg 3.4 Ϯ 0.4 9.7 Ϯ 0.6* 8.0 Ϯ 0.5*† 12.3 Ϯ 1.1*† ϩ Ϯ Ϯ Ϯ Ϯ LV dP/dtmax, mmHg/s 9415 441 4530 195* 5828 227*† 3608 356*† Ϫ Ϫ Ϯ Ϫ Ϯ Ϫ Ϯ Ϫ Ϯ LV dP/dtmin, mmHg/s 7280 830 3536 242* 3595 159* 3675 220* a BW, body weight; RVW, right ventricular weight; LVW, left ventricular weight; LVEDD, left ventricular end-diastolic dimension; LVESD, left ventricular end-systolic dimension; FS, fractional shortening; LVSP, left ventricular systolic pressure; ϩ LVEDP, left ventricular end-diastolic pressure; LV dP/dtmax, left ventricular maximum rate of isovolumic pressure develop- Ͻ ء Ϫ Ϯ ment; LV dP/dtmin, left ventricular minimum rate of isovolumic pressure decay. Values are means SEM. , p 0.05 vs. sham; †, p Ͻ 0.05 vs. MI-C. plasmacytoid DC followed by proliferation of Th2 cells (24–26). ance during infarct healing and affect postinfarction LV remodel- Downloaded from Therefore, we hypothesized that G-CSF and GM-CSF diversely ing. To test this hypothesis, we examined the dynamics of DC in regulate DC maturation through modulation of the Th1/Th2 bal- a rat MI model using OX62 Ab, which is a reliable marker for the http://www.jimmunol.org/ by guest on September 26, 2021 FIGURE 1.