Volume 10 Issue 3
Mar.  2019
Turn off MathJax
Article Contents
Yali Jiang, Yuanyuan Wang, Pengfei Ma, Dongjie An, Junlong Zhao, Shiqian Liang, Yuchen Ye, Yingying Lu, Peng Zhang, Xiaowei Liu, Hua Han, Hongyan Qin. Myeloid-specific targeting of Notch ameliorates murine renal fibrosis via reduced infiltration and activation of bone marrowderived macrophage[J]. Protein&Cell, 2019, 10(3): 196-210. doi: 10.1007/s13238-018-0527-6
Citation: Yali Jiang, Yuanyuan Wang, Pengfei Ma, Dongjie An, Junlong Zhao, Shiqian Liang, Yuchen Ye, Yingying Lu, Peng Zhang, Xiaowei Liu, Hua Han, Hongyan Qin. Myeloid-specific targeting of Notch ameliorates murine renal fibrosis via reduced infiltration and activation of bone marrowderived macrophage[J]. Protein&Cell, 2019, 10(3): 196-210. doi: 10.1007/s13238-018-0527-6

Myeloid-specific targeting of Notch ameliorates murine renal fibrosis via reduced infiltration and activation of bone marrowderived macrophage

doi: 10.1007/s13238-018-0527-6
  • Received Date: 2017-11-28
  • Macrophages play critical roles in renal fibrosis. However, macrophages exhibit ontogenic and functional heterogeneities, and which population of macrophages contributes to renal fibrosis and the underlying mechanisms remain unclear. In this study, we genetically targeted Notch signaling by disrupting the transcription factor recombination signal binding protein-Jκ (RBP-J), to reveal its role in regulation of macrophages during the unilateral ureteral obstruction (UUO)-induced murine renal fibrosis. Myeloid-specific disruption of RBP-J attenuated renal fibrosis with reduced extracellular matrix deposition and myofibroblast activation, as well as attenuated epithelial-mesenchymal transition, likely owing to the reduced expression of TGF-β. Meanwhile, RBP-J deletion significantly hampered macrophage infiltration and activation in fibrotic kidney, although their proliferation appeared unaltered. By using macrophage clearance experiment, we found that kidney resident macrophages made negligible contribution, but bone marrow (BM)-derived macrophages played a major role in renal fibrogenesis. Further mechanistic analyses showed that Notch blockade reduced monocyte emigration from BM by down-regulating CCR2 expression. Finally, we found that myeloid-specific Notch activation aggravated renal fibrosis, which was mediated by CCR2+ macrophages infiltration. In summary, our data have unveiled that myeloid-specific targeting of Notch could ameliorate renal fibrosis by regulating BM-derived macrophages recruitment and activation, providing a novel strategy for intervention of this disease.
  • loading
  • [1]
    Artavanis-Tsakonas S, Rand MD, Lake RJ (1999) Notch signaling:cell fate control and signal integration in development. Science 284:770–776
    Beattie L, Sawtell A, Mann J, Frame TC, Teal B, de Labastida Rivera F, Brown N, Walwyn-Brown K, Moore JW, MacDonald S, Lim EK, Dalton JE, Engwerda CR, Macdonald KP, Kaye PM (2016) Bone marrow-derived and resident liver macrophages display unique transcriptomic signatures but similar biological functions. J Hepatol 65(64):758–768
    Border WA, Noble NA (1994) Transforming growth factor beta in tissue fibrosis. N Engl J Med 331:1286–1292
    Böttinger EP (2007) TGF-beta in renal injury and disease. Semin Nephrol 27:309–320
    Chen L, Al-Awqati Q (2005) Segmental expression of Notch and Hairy genes in nephrogenesis. Am J Physiol Renal Physiol 288:F939–F952
    Chevalier RL, Forbes MS, Thornhill BA (2009) Ureteral obstruction as a model of renal interstitial fibrosis and obstructive nephropathy. Kidney Int 75:1145–1152
    Clausen BE, Burkhardt C, Reith W, Renkawitz R, Förster I (1999)
    Conditional gene targeting in macrophages and granulocytes using LysMcre mice. Transgenic Res 8:265–277
    Cochrane AL, Kett MM, Samuel CS, Campanale NV, Anderson WP, Hume DA, Little MH, Bertram JF, Ricardo SD (2005) Renal structural and functional repair in a mouse model of reversal of ureteral obstruction. J Am Soc Nephrol 16:3623–3630
    Duffield JS (2014) Cellular and molecular mechanisms in kidney fibrosis. J Clin Invest 124:2299–2306
    Falke LL, Gholizadeh S, Goldschmeding R, Kok RJ, Nguyen TQ (2015) Diverse origins of the myofibroblast-implications for kidney fibrosis. Nat Rev Nephrol 11:233–244
    Franklin RA, Liao W, Sarkar A, Kim MV, Bivona MR, Liu K, Pamer EG, Li MO (2014) The cellular and molecular origin of tumorassociated macrophages. Science 344:921–925
    Ginhoux F, Guilliams M (2016) Tissue-resident macrophage ontogeny and homeostasis. Immunity 44:439–449
    Han H, Tanigaki K, Yamamoto N, Kuroda K, Yoshimoto M, Nakahata T, Ikuta K, Honjo T (2002) Inducible gene knockout of transcription factor recombination signal binding protein-J reveals its essential role in T versus B lineage decision. Int Immunol 14:637–645
    Han Y, Masaki T, Hurst LA, Ikezumi Y, Trzaskos JM, Atkins RC, Nikolic-Paterson DJ (2008) Extracellular signal-regulated kinase dependent interstitial macrophage proliferation in the obstructed mouse kidney. Nephrology (Carlton) 13:411–418
    Hashimoto D, Chow A, Noizat C, Teo P, Beasley MB, Leboeuf M, Becker CD, See P, Price J, Lucas D et al (2013) Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38:792–804
    He F, Guo FC, Li Z, Yu HC, Ma PF, Zhao JL, Feng L, Li WN, Liu XW, Qin HY et al (2015) Myeloid-specific disruption of recombination signal binding protein Jκ ameliorates hepatic fibrosis by attenuating inflammation through cylindromatosis in mice. Hepatology 61:303–314
    Henderson NC, Mackinnon AC, Farnworth SL, Kipari T, Haslett C, Iredale JP, Liu FT, Hughes J, Sethi T (2008) Galectin-3 expression and secretion links macrophages to the promotion of renal fibrosis. Am J Pathol 172:288–298
    Hu B, Phan SH (2016) Notch in fibrosis and as a target of anti-fibrotic therapy. Pharmacol Res 108:157–164
    Hu M, Ou-Yang HF, Wu CG, Qu SY, Xu XT, Wang P (2014) Notch signaling regulates col1α1 and col1α2 expression in airway fibroblasts. Exp Biol Med (Maywood). 239:1589–1596
    Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119:1420–1428
    Kitagawa K, Wada T, Furuichi K, Hashimoto H, Ishiwata Y, Asano M, Takeya M, Kuziel WA, Matsushima K, Mukaida N et al (2004)Blockade of CCR2 ameliorates progressive fibrosis in kidney. Am J Pathol 165:237–246
    Kitamoto K, Machida Y, Uchida J, Izumi Y, Shiota M, Nakao T, Iwao H, Yukimura T, Nakatani T, Miura K (2009) Effects of liposome clodronate on renal leukocyte populations and renal fibrosis in murine obstructive nephropathy. J Pharmacol Sci 111:285–292
    Kluth DC, Erwig LP, Rees AJ (2004) Multiple facets of macrophages in renal injury. Kidney Int 66:542–557
    Le Meur Y, Tesch GH, Hill PA, Mu W, Foti R, Nikolic-Paterson DJ, Atkins RC (2002) Macrophage accumulation at a site of renal inflammation is dependent on the M-CSF/c-fms pathway.J Leukoc Biol 72:530–537
    LeBleu VS, Taduri G, O’Connell J, Teng Y, Cooke VG, Woda C, Sugimoto H, Kalluri R (2013) Origin and function of myofibroblasts in kidney fibrosis. Nat Med 19:1047–1053
    Li Y, Ma J, Qian X, Wu Q, Xia J, Miele L, Sarkar FH, Wang Z (2013)Regulation of EMT by Notch signaling pathway in tumor progression. Curr Cancer Drug Targets 13:957–962
    Lin SL, Castano AP, Nowlin BT, Lupher ML, Lupher ML Jr, Duffield JS (2009) Bone marrow Ly6Chigh monocytes are selectively recruited to injured kidney and differentiate into functionally distinct populations. J Immunol 183:6733–6743
    Ma FY, Sachchithananthan M, Flanc RS, Nikolic-Paterson DJ (2009)
    Mitogen activated protein kinases in renal fibrosis. Front Biosci(Schol Ed) 1:171–187
    Meng XM, Wang S, Huang XR, Yang C, Xiao J, Zhang Y, To KF, Nikolic-Paterson DJ, Lan HY (2016) Inflammatory macrophages can transdifferentiate into myofibroblasts during renal fibrosis.Cell Death Dis 7:e2495
    Miyajima A, Chen J, Lawrence C, Ledbetter S, Soslow RA, Stern J, Jha S, Pigato J, Lemer ML, Poppas DP et al (2000)Antibody to transforming growth factor-beta ameliorates tubular apoptosis in unilateral ureteral obstruction. Kidney Int 58(56):2301–2313
    Monsalve E, Ruiz-García A, Baladrón V, Ruiz-Hidalgo MJ, SánchezSolana B, Rivero S, García-Ramírez JJ, Rubio A, Laborda J, Díaz-Guerra MJ (2009) Notch1 upregulates LPS-induced macrophage activation by increasing NF-kappaB activity. Eur J Immunol 39:2556–2570
    Nikolic-Paterson DJ, Wang S, Lan HY (2014) Macrophages promote renal fibrosis through direct and indirect mechanisms. Kidney Int Suppl 4:34–38
    Nishida M, Okumura Y, Fujimoto S, Shiraishi I, Itoi T, Hamaoka K (2005) Adoptive transfer of macrophages ameliorates renal fibrosis in mice. Biochem Biophys Res Commun 332:311–316
    Qi W, Chen X, Polhill TS, Sumual S, Twigg S, Gilbert RE, Pollock CA (2006) TGF-beta1 induces IL-8 and MCP-1 through a connective tissue growth factor-independent pathway. Am J Physiol Renal Physiol 290:F703–F709
    Ramachandran P, Pellicoro A, Vernon MA, Boulter L, Aucott RL, Ali A, Hartland SN, Snowdon VK, Cappon A, Gordon-Walker TT et al(2012) Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis. Proc Natl Acad Sci USA 109:E3186–E3195
    Seki E, de Minicis S, Inokuchi S, Taura K, Miyai K, van Rooijen N, Schwabe RF, Brenner DA (2009) CCR2 promotes hepatic fibrosis in mice. Hepatology 50:185–197
    Stamatiades EG, Tremblay ME, Bohm M, Crozet L, Bisht K, Kao D, Coelho C, Fan X, Yewdell WT, Davidson A et al (2016) Immune monitoring of trans-endothelial transport by kidney-resident macrophages. Cell 166:991–1003
    Tang Y, Urs S, Liaw L (2008) Hairy-related transcription factors inhibit Notch-induced smooth muscle alpha-actin expression by interfering with Notch intracellular domain/CBF-1 complex interaction with the CBF-1-binding site. Circ Res 102:661–668
    Tattersall IW, Du J, Cong Z, Cho BS, Klein AM, Dieck CL, Chaudhri RA, Cuervo H, Herts JH, Kitajewski J (2016) In vitro modeling of endothelial interaction with macrophages and pericytes demonstrates Notch signaling function in the vascular microenvironment. Angiogenesis 19:201–215
    Van Rooijen N, Sanders A (1994) Liposome mediated depletion of macrophages: mechanism of action, preparation of liposomes and applications. J Immunol Methods 174:183–193
    Vernon MA, Mylonas KJ, Hughes J (2010) Macrophages and renal fibrosis. Semin Nephrol 30:302–317
    Vielhauer V, Anders HJ, Mack M, Cihak J, Strutz F, Stangassinger M, Luckow B, Gröne HJ, Schlöndorff D (2001) Obstructive nephropathy in the mouse: progressive fibrosis correlates with tubulointerstitial chemokine expression and accumulation of CC chemokine receptor 2- and 5-positive leukocytes. J Am Soc Nephrol 12:1173–1187
    Wang YP, Harris DC (2011) Macrophages in kidney disease. J Am Soc Nephrol 22:21–27
    Wang Y, Wang YP, Zheng G, Lee VW, Ouyang L, Chang DH, Mahajan D, Coombs J, Wang YM, Alexander SI et al (2007) Ex vivo programmed macrophages ameliorate experimental chronic inflammatory renal disease. Kidney Int 72:290–299
    Wang YC, He F, Feng F, Liu XW, Dong GY, Qin HY, Hu XB, Zheng MH, Liang L, Feng L et al (2010) Notch signaling determines the M1 versus M2 polarization of macrophages in antitumor immune responses. Cancer Res 70:4840–4849
    Wang S, Meng XM, Ng YY, Ma FY, Zhou S, Zhang Y, Yang C, Huang XR, Xiao J, Wang YY et al (2016) TGF-β/Smad3 signalling regulates the transition of bone marrow-derived macrophages into myofibroblasts during tissue fibrosis. Oncotarget 7:8809–8822
    Williams TM, Little MH, Ricardo SD (2010) Macrophages in renal development, injury, and repair. Semin Nephrol 30:255–267
    Wynn TA, Vannella KM (2016) Macrophages in tissue repair, regeneration, and fibrosis. Immunity 44:450–462
    Xu H, Zhu J, Smith S, Foldi J, Zhao B, Chung AY, Outtz H, Kitajewski J, Shi C, Weber S et al (2012) Notch-RBP-J signaling regulates the transcription factor IRF8 to promote inflammatory macrophage polarization. Nat Immunol 13:642–650
    Yamasaki R, Lu H, Butovsky O (2014) Differential roles of microglia and monocytes in the inflamed central nervous system. J Exp Med 211:1533–1549
    Yona S, Kim KW, Wolf Y, Mildner A, Varol D, Breker M, Strauss-Ayali D, Viukov S, Guilliams M, Misharin A et al (2013) Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38:79–91
    Zavadil J, Böttinger EP (2005) TGF-beta and epithelial-to-mesenchymal transitions. Oncogene 24:5764–5774
    Zhang W, Xu W, Xiong S (2010) Blockade of Notch1 signaling alleviates murine lupus via blunting macrophage activation and M2b polarization. J Immunol 184:6465–6478
    Zhao JL, Huang F, He F, Gao CC, Liang SQ, Ma PF, Dong GY, Han H, Qin HY (2016) Forced activation of Notch in macrophages represses tumor growth by upregulating miR-125a and disabling tumor-associated macrophages. Cancer Res 76:1403–1415
    Zigmond E, Samia-Grinberg S, Pasmanik-Chor M, Brazowski E, Shibolet O, Halpern Z, Varol C (2014) Infiltrating monocytederived macrophages and resident kupffer cells display different ontogeny and functions in acute liver injury. J Immunol 193:344– 353
  • 加载中


    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索


    Article Metrics

    Article views (1071) PDF downloads(748) Cited by()
    Proportional views


    DownLoad:  Full-Size Img  PowerPoint