Background The inflammatory response plays a critical role in hypertension-induced cardiac remodeling. We aimed to study how interaction among inflammatory cells causes inflammatory responses in the process of hypertensive cardiac fibrosis. Methodology/Principal Findings Infusion of angiotensin II (Ang II, 1500 ng/kg/min) in mice rapidly induced the expression of interferon γ (IFN-γ) and leukocytes infiltration into the heart. To determine the role of IFN-γ on cardiac inflammation and remodeling, both wild-type (WT) and IFN-γ-knockout (KO) mice were infused Ang II for 7 days, and were found an equal blood pressure increase. However, knockout of IFN-γ prevented Ang II-induced: 1) infiltration of macrophages and T cells into cardiac tissue; 2) expression of tumor necrosis factor α and monocyte chemoattractant protein 1 (MCP-1), and 3) cardiac fibrosis, including the expression of α-smooth muscle actin and collagen I (all p<0.05). Cultured T cells or macrophages alone expressed very low level of IFN-γ, however, co-culture of T cells and macrophages increased IFN-γ expression by 19.8±0.95 folds (vs. WT macrophage, p<0.001) and 20.9 ± 2.09 folds (vs. WT T cells, p<0.001). In vitro co-culture studies using T cells and macrophages from WT or IFN-γ KO mice demonstrated that T cells were primary source for IFN-γ production. Co-culture of WT macrophages with WT T cells, but not with IFN-γ-knockout T cells, increased IFN-γ production (p<0.01). Moreover, IFN-γ produced by T cells amplified MCP-1 expression in macrophages and stimulated macrophage migration. Conclusions/Significance Reciprocal interaction between macrophages and T cells in heart stimulates IFN-γ expression, leading to increased MCP-1 expression in macrophages, which results a forward-feed recruitment of macrophages, thus contributing to Ang II-induced cardiac inflammation and fibrosis.
References
[1]
Wynn TA (2007) Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Invest 117: 524–529.
[2]
Marchesi C, Paradis P, Schiffrin EL (2008) Role of the renin-angiotensin system in vascular inflammation. Trends Pharmacol Sci 29: 367–374.
[3]
Huang XR, Chung AC, Yang F, Yue W, Deng C, et al. (2010) Smad3 mediates cardiac inflammation and fibrosis in angiotensin II-induced hypertensive cardiac remodeling. Hypertension 55: 1165–1171.
[4]
Muller DN, Dechend R, Mervaala EM, Park JK, Schmidt F, et al. (2000) NF-kappaB inhibition ameliorates angiotensin II-induced inflammatory damage in rats. Hypertension 35: 193–201.
[5]
Guzik TJ, Hoch NE, Brown KA, McCann LA, Rahman A, et al. (2007) Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J Exp Med 204: 2449–2460.
[6]
Vinh A, Chen W, Blinder Y, Weiss D, Taylor WR, et al. (2010) Inhibition and genetic ablation of the B7/CD28 T-cell costimulation axis prevents experimental hypertension. Circulation 122: 2529–2537.
[7]
Fauvel JP, M’Pio I, Quelin P, Rigaud JP, Laville M, et al. (2003) Neither perceived job stress nor individual cardiovascular reactivity predict high blood pressure. Hypertension 42: 1112–1116.
[8]
Tang PC, Yakimov AO, Teesdale MA, Coady MA, Dardik A, et al. (2005) Transmural inflammation by interferon-gamma-producing T cells correlates with outward vascular remodeling and intimal expansion of ascending thoracic aortic aneurysms. FASEB J 19: 1528–1530.
[9]
Billiau A, Matthys P (2009) Interferon-gamma: a historical perspective. Cytokine Growth Factor Rev 20: 97–113.
[10]
Hu X, Ivashkiv LB (2009) Cross-regulation of signaling pathways by interferon-gamma: implications for immune responses and autoimmune diseases. Immunity 31: 539–550.
[11]
Cheng M, Nguyen MH, Fantuzzi G, Koh TJ (2008) Endogenous interferon-gamma is required for efficient skeletal muscle regeneration. Am J Physiol Cell Physiol 294: C1183–1191.
[12]
Hayashi N, Yoshimoto T, Izuhara K, Matsui K, Tanaka T, et al. (2007) T helper 1 cells stimulated with ovalbumin and IL-18 induce airway hyperresponsiveness and lung fibrosis by IFN-gamma and IL-13 production. Proc Natl Acad Sci U S A 104: 14765–14770.
[13]
Mazzolai L, Duchosal MA, Korber M, Bouzourene K, Aubert JF, et al. (2004) Endogenous angiotensin II induces atherosclerotic plaque vulnerability and elicits a Th1 response in ApoE-/- mice. Hypertension 44: 277–282.
[14]
Haudek SB, Cheng J, Du J, Wang Y, Hermosillo-Rodriguez J, et al. (2010) Monocytic fibroblast precursors mediate fibrosis in angiotensin-II-induced cardiac hypertrophy. J Mol Cell Cardiol 49: 499–507.
[15]
Ren J, Yang M, Qi G, Zheng J, Jia L, et al. (2011) Proinflammatory Protein CARD9 Is Essential for Infiltration of Monocytic Fibroblast Precursors and Cardiac Fibrosis Caused by Angiotensin II Infusion. Am J Hypertens 24: 701–707.
[16]
Qi G, Jia L, Li Y, Bian Y, Cheng J, et al. (2011) Angiotensin II infusion-induced inflammation, monocytic fibroblast precursor infiltration, and cardiac fibrosis are pressure dependent. Cardiovasc Toxicol 11: 157–167.
[17]
Kawai C (1999) From myocarditis to cardiomyopathy: mechanisms of inflammation and cell death: learning from the past for the future. Circulation 99: 1091–1100.
[18]
Zheng Y, Gardner SE, Clarke MC (2011) Cell death, damage-associated molecular patterns, and sterile inflammation in cardiovascular disease. Arterioscler Thromb Vasc Biol 31: 2781–2786.
[19]
Coelho PS, Klein A, Talvani A, Coutinho SF, Takeuchi O, et al. (2002) Glycosylphosphatidylinositol-anchored mucin-like glycoproteins isolated from Trypanosoma cruzi trypomastigotes induce in vivo leukocyte recruitment dependent on MCP-1 production by IFN-gamma-primed-macrophages. J Leukoc Biol 71: 837–844.
[20]
Nahmod KA, Vermeulen ME, Raiden S, Salamone G, Gamberale R, et al. (2003) Control of dendritic cell differentiation by angiotensin II. FASEB J 17: 491–493.
[21]
Brands MW, Banes-Berceli AK, Inscho EW, Al-Azawi H, Allen AJ, et al. (2010) Interleukin 6 knockout prevents angiotensin II hypertension: role of renal vasoconstriction and janus kinase 2/signal transducer and activator of transcription 3 activation. Hypertension 56: 879–884.
[22]
Sturgis LC, Cannon JG, Schreihofer DA, Brands MW (2009) The role of aldosterone in mediating the dependence of angiotensin hypertension on IL-6. Am J Physiol Regul Integr Comp Physiol 297: R1742–1748.
[23]
Finckenberg P, Inkinen K, Ahonen J, Merasto S, Louhelainen M, et al. (2003) Angiotensin II induces connective tissue growth factor gene expression via calcineurin-dependent pathways. Am J Pathol 163: 355–366.
[24]
Puddu P, Fantuzzi L, Borghi P, Varano B, Rainaldi G, et al. (1997) IL-12 induces IFN-gamma expression and secretion in mouse peritoneal macrophages. J Immunol 159: 3490–3497.
[25]
Munder M, Mallo M, Eichmann K, Modolell M (1998) Murine macrophages secrete interferon gamma upon combined stimulation with interleukin (IL)-12 and IL-18: A novel pathway of autocrine macrophage activation. J Exp Med 187: 2103–2108.
[26]
Hochrein H, Shortman K, Vremec D, Scott B, Hertzog P, et al. (2001) Differential production of IL-12, IFN-alpha, and IFN-gamma by mouse dendritic cell subsets. J Immunol 166: 5448–5455.
[27]
Fairweather D, Yusung S, Frisancho S, Barrett M, Gatewood S, et al. (2003) IL-12 receptor beta 1 and Toll-like receptor 4 increase IL-1 beta- and IL-18-associated myocarditis and coxsackievirus replication. J Immunol 170: 4731–4737.
[28]
Fairweather D, Frisancho-Kiss S, Yusung SA, Barrett MA, Davis SE, et al. (2004) Interferon-gamma protects against chronic viral myocarditis by reducing mast cell degranulation, fibrosis, and the profibrotic cytokines transforming growth factor-beta 1, interleukin-1 beta, and interleukin-4 in the heart. Am J Pathol 165: 1883–1894.
[29]
Rogers L, Burchat S, Gage J, Hasu M, Thabet M, et al. (2008) Deficiency of invariant V alpha 14 natural killer T cells decreases atherosclerosis in LDL receptor null mice. Cardiovasc Res 78: 167–174.
[30]
Afanasyeva M, Georgakopoulos D, Belardi DF, Bedja D, Fairweather D, et al. (2005) Impaired up-regulation of CD25 on CD4+ T cells in IFN-gamma knockout mice is associated with progression of myocarditis to heart failure. Proc Natl Acad Sci U S A 102: 180–185.
[31]
Lin AA, Tripathi PK, Sholl A, Jordan MB, Hildeman DA (2009) Gamma interferon signaling in macrophage lineage cells regulates central nervous system inflammation and chemokine production. J Virol 83: 8604–8615.
[32]
Shao J, Nangaku M, Miyata T, Inagi R, Yamada K, et al. (2003) Imbalance of T-cell subsets in angiotensin II-infused hypertensive rats with kidney injury. Hypertension 42: 31–38.
[33]
Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, et al. (2009) CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med 15: 914–920.
[34]
Frangogiannis NG, Dewald O, Xia Y, Ren G, Haudek S, et al. (2007) Critical role of monocyte chemoattractant protein-1/CC chemokine ligand 2 in the pathogenesis of ischemic cardiomyopathy. Circulation 115: 584–592.
[35]
Hilgers KF, Hartner A, Porst M, Mai M, Wittmann M, et al. (2000) Monocyte chemoattractant protein-1 and macrophage infiltration in hypertensive kidney injury. Kidney Int 58: 2408–2419.
[36]
Takahashi M, Suzuki E, Takeda R, Oba S, Nishimatsu H, et al. (2008) Angiotensin II and tumor necrosis factor-alpha synergistically promote monocyte chemoattractant protein-1 expression: roles of NF-kappaB, p38, and reactive oxygen species. Am J Physiol Heart Circ Physiol 294: H2879–2888.
[37]
Pore D, Mahata N, Chakrabarti MK (2012) Outer membrane protein A (OmpA) of Shigella flexneri 2a links innate and adaptive immunity in a TLR2 dependent manner and with the involvement of IL-12 and nitric oxide (NO). J Biol Chem. In press.
[38]
Valentincic NV, de Groot-Mijnes JD, Kraut A, Korosec P, Hawlina M, et al. (2011) Intraocular and serum cytokine profiles in patients with intermediate uveitis. Mol Vis 17: 2003–2010.
[39]
Ponomarev ED, Novikova M, Yassai M, Szczepanik M, Gorski J, et al. (2004) Gamma delta T cell regulation of IFN-gamma production by central nervous system-infiltrating encephalitogenic T cells: correlation with recovery from experimental autoimmune encephalomyelitis. J Immunol 173: 1587–1595.
[40]
Cheng J, Du J (2007) Mechanical stretch simulates proliferation of venous smooth muscle cells through activation of the insulin-like growth factor-1 receptor. Arterioscler Thromb Vasc Biol 27: 1744–1751.
[41]
Kawaguchi M, Takahashi M, Hata T, Kashima Y, Usui F, et al. (2011) Inflammasome activation of cardiac fibroblasts is essential for myocardial ischemia/reperfusion injury. Circulation 123: 594–604.
[42]
Pfister O, Mouquet F, Jain M, Summer R, Helmes M, et al. (2005) CD31- but Not CD31+ cardiac side population cells exhibit functional cardiomyogenic differentiation. Circ Res 97: 52–61.
[43]
Fleetwood AJ, Lawrence T, Hamilton JA, Cook AD (2007) Granulocyte-macrophage colony-stimulating factor (CSF) and macrophage CSF-dependent macrophage phenotypes display differences in cytokine profiles and transcription factor activities: implications for CSF blockade in inflammation. J Immunol 178: 5245–5252.
