Reprogramming immune responses via microRNA modulation
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It is becoming increasingly clear that there are unique sets of miRNAs that have distinct governing roles in several aspects of both innate and adaptive immune responses. In addition, new tools allow selective modulation of the expression of individual miRNAs, both in vitro and in vivo. Here, we summarize recent advances in our understanding of how miRNAs drive the activity of immune cells, and how their modulation in vivo opens new avenues for diagnostic and therapeutic interventions in multiple diseases, from immunodeficiency to cancer. Recent contributions from our laboratory and other groups to novel formulations for miRNA mimetics are further discussed
1 - 1 - 2014
15 - 1 - 2013
15 - 3 - 2013
26 - 4 - 2013
- Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA / The Ragon Institute of MGH, MIT and Harvard. 149 13th Street, Charlestown, MA 02129, USA
- Tumor Microenvironment and Metastasis Program, The Wistar Institute, 3601 Spruce St, Philadelphia, PA 19104, USA
- Division of Endocrine and Oncologic Surgery, Department of Surgery, and the Rena Rowan Breast Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia 19104, USA
- Tumor Microenvironment and Metastasis Program, The Wistar Institute, 3601 Spruce St, Philadelphia, PA 19104, USA, jrconejo@Wistar.org
-  Kaya E, Doudna JA. Biochemistry. Guided tour to the heart of RISC. Science. 2012;336:985-6.
-  Schirle NT, MacRae IJ. The crystal structure of human Argonaute2. Science. 2012;336:1037-40.
-  Sempere LF, and Conejo-Garcia JR. Modulation of cancer progression by tumor microenvironmental leukocyteexpressed microRNAs. In Tumor Microenvironment and Myelomonocytic Cells. 2012, Subhra K. Biswas, ed. (Rijeka, Croatia: InTech Open Access Publisher): 221-54.
-  Lodish HF, Zhou B, Liu G, Chen CZ. Micromanagement of the immune system by microRNAs. Nat Rev Immunol. 2008;8:120-30.[Crossref]
-  Li QJ, Chau J, Ebert PJ, et al. miR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell. 2007;129:147-61.
-  Rodriguez A, Vigorito E, Clare S, et al. Requirement of bic/microRNA-155 for normal immune function. Science. 2007;316:608-11.
-  Shen N, Liang D, Tang Y, de Vries N, Tak PP. MicroRNAs-novel regulators of systemic lupus erythematosus pathogenesis. Nat Rev Rheumatol. 2012.[Crossref]
-  Josefowicz SZ, Lu LF, Rudensky AY. Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol. 2012;30:531-64.[Crossref]
-  Contreras J, Rao DS. MicroRNAs in inflammation and immune responses. Leukemia. 2012;26:404-13.[Crossref]
-  Asirvatham AJ, Gregorie CJ, Hu Z, Magner WJ, Tomasi TB. MicroRNA targets in immune genes and the Dicer/ Argonaute and ARE machinery components. Mol Immunol. 2008;45:1995-2006.[Crossref]
-  Chen CZ, Li L, Lodish HF, Bartel DP. MicroRNAs modulate hematopoietic lineage differentiation. Science. 2004;303:83-6.
-  Alemdehy MF, van Boxtel NG, de Looper HW, et al. Dicer1 deletion in myeloid-committed progenitors causes neutrophil dysplasia and blocks macrophage/dendritic cell development in mice. Blood. 2012;119:4723-30.
-  Xu S, Guo K, Zeng Q, Huo J, Lam KP. The RNase III enzyme Dicer is essential for germinal center B-cell formation. Blood. 2012;119:767-76.
-  Koralov SB, Muljo SA, Galler GR, et al. Dicer ablation affects antibody diversity and cell survival in the B lymphocyte lineage. Cell. 2008;132:860-74.
-  Cichocki F, Felices M, McCullar V, et al. Cutting edge: microRNA-181 promotes human NK cell development by regulating Notch signaling. J Immunol. 2011;187:6171-5.
-  Spierings DC, McGoldrick D, Hamilton-Easton AM, et al. Ordered progression of stage-specific miRNA profiles in the mouse B2 B-cell lineage. Blood. 2011;117:5340-9.
-  Garzon R, Croce CM. MicroRNAs in normal and malignant hematopoiesis. Curr Opin Hematol. 2008;15:352-8.[Crossref]
-  Sandhu SK, Volinia S, Costinean S, et al. miR-155 targets histone deacetylase 4 (HDAC4) and impairs transcriptional activity of B-cell lymphoma 6 (BCL6) in the Emu-miR-155 transgenic mouse model. Proc Natl Acad Sci U S A. 2012.
-  Jiang X, Huang H, Li Z, et al. Blockade of miR-150 Maturation by MLL-Fusion/MYC/LIN-28 Is Required for MLL-Associated Leukemia. Cancer Cell. 2012;22:524-35.
-  Schwind S, Maharry K, Radmacher MD, et al. Prognostic significance of expression of a single microRNA, miR-181a, in cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol. 2010;28:5257-64.
-  Wu H, Neilson JR, Kumar P, et al. miRNA profiling of naive, effector and memory CD8 T cells. PLoS ONE. 2007;2:e1020.[Crossref]
-  Wang XS, Gong JN, Yu J, et al. MicroRNA-29a and microRNA-142-3p are regulators of myeloid differentiation and acute myeloid leukemia. Blood. 2012;119:4992-5004.
-  Lv M, Zhang X, Jia H, et al. An oncogenic role of miR-142-3p in human T-cell acute lymphoblastic leukemia (T-ALL) by targeting glucocorticoid receptor-alpha and cAMP/PKA pathways. Leukemia. 2012;26:769-77.
-  Robbiani DF, Bunting S, Feldhahn N, et al. AID produces DNA double-strand breaks in non-Ig genes and mature B cell lymphomas with reciprocal chromosome translocations. Mol Cell. 2009;36:631-41.[Crossref]
-  Sun Y, Varambally S, Maher CA, et al. Targeting of microRNA-142-3p in dendritic cells regulates endotoxin-induced mortality. Blood. 2011;117:6172-83.
-  Huang B, Zhao J, Lei Z, et al. miR-142-3p restricts cAMP production in CD4+CD25- T cells and CD4+CD25+ TREG cells by targeting AC9 mRNA. EMBO Rep. 2009;10:180-5.
-  Ding S, Liang Y, Zhao M, et al. Decreased microRNA-142-3p/5p expression causes CD4+ T cell activation and B cell hyperstimulation in systemic lupus erythematosus. Arthritis Rheum. 2012;64:2953-63.
-  Anglicheau D, Sharma VK, Ding R, et al. MicroRNA expression profiles predictive of human renal allograft status. Proc Natl Acad Sci U S A. 2009;106:5330-5.[Crossref]
-  O’Connell RM, Rao DS, Baltimore D. microRNA regulation of inflammatory responses. Annu Rev Immunol. 2012;30:295-312.[Crossref]
-  Fazi F, Racanicchi S, Zardo G, et al. Epigenetic silencing of the myelopoiesis regulator microRNA-223 by the AML1/ETO oncoprotein. Cancer Cell. 2007;12:457-66.
-  Johnnidis JB, Harris MH, Wheeler RT, et al. Regulation of progenitor cell proliferation and granulocyte function by microRNA-223. Nature. 2008;451:1125-9.
-  Fazi F, Rosa A, Fatica A, et al. A minicircuitry comprised of microRNA-223 and transcription factors NFI-A and C/EBPalpha regulates human granulopoiesis. Cell. 2005;123:819-31.
-  Lindsay MA. microRNAs and the immune response. Trends Immunol. 2008;29:343-51.[Crossref]
-  Stehling-Sun S, Dade J, Nutt SL, DeKoter RP, Camargo FD. Regulation of lymphoid versus myeloid fate ‘choice’ by the transcription factor Mef2c. Nat Immunol. 2009;10:289-96.[Crossref]
-  Xu Y, Sengupta T, Kukreja L, Minella AC. MicroRNA-223 regulates cyclin E activity by modulating expression of F-box and WD-40 domain protein 7. J Biol Chem. 2010;285:34439-46.
-  Fehniger TA, Wylie T, Germino E, et al. Next-generation sequencing identifies the natural killer cell microRNA transcriptome. Genome Res. 2010;20:1590-604.[Crossref]
-  Allantaz F, Cheng DT, Bergauer T, et al. Expression profiling of human immune cell subsets identifies miRNA-mRNA regulatory relationships correlated with cell type specific expression. PLoS ONE. 2012;7:e29979.[Crossref]
-  Tili E, Michaille JJ, Cimino A, et al. Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating the response to endotoxin shock. J Immunol. 2007;179:5082-9.
-  Cubillos-Ruiz JR, Baird JR, Tesone AJ, et al. Reprogramming tumor-associated dendritic cells in vivo using microRNA mimetics triggers protective immunity against ovarian cancer. Cancer Res. 2012;72:1683-93.[Crossref]
-  Scarlett UK, Cubillos-Ruiz JR, Nesbeth YC, et al. In situ stimulation of CD40 and Toll-like receptor 3 transforms ovarian cancer-infiltrating dendritic cells from immunosuppressive to immunostimulatory cells. Cancer Res. 2009;69:7329-37.[Crossref]
-  O’Connell RM, Taganov KD, Boldin MP, Cheng G, Baltimore D. MicroRNA-155 is induced during the macrophage inflammatory response. Proc Natl Acad Sci U S A. 2007;104:1604-9.
-  Thai TH, Calado DP, Casola S, et al. Regulation of the germinal center response by microRNA-155. Science. 2007;316:604-8.
-  Vigorito E, Perks KL, Abreu-Goodger C, et al. microRNA-155 regulates the generation of immunoglobulin class-switched plasma cells. Immunity. 2007;27:847-59.
-  Androulidaki A, Iliopoulos D, Arranz A, et al. The kinase Akt1 controls macrophage response to lipopolysaccharide by regulating microRNAs. Immunity. 2009;31:220-31.
-  Marigo I, Bosio E, Solito S, et al. Tumor-induced tolerance and immune suppression depend on the C/EBPbeta transcription factor. Immunity. 2010;32:790-802.[Crossref]
-  Rai D, Kim SW, McKeller MR, Dahia PL, Aguiar RC. Targeting of SMAD5 links microRNA-155 to the TGF-beta pathway and lymphomagenesis. Proc Natl Acad Sci U S A. 2010;107:3111-6.
-  Curiel TJ, Coukos G, Zou L, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004;10:942-9.[Crossref]
-  Unlu S, Tang S, Wang E, et al. Damage associated molecular pattern molecule-induced microRNAs (DAMPmiRs) in human peripheral blood mononuclear cells. PLoS ONE. 2012;7:e38899.[Crossref]
-  Sonkoly E, Stahle M, Pivarcsi A. MicroRNAs and immunity: Novel players in the regulation of normal immune function and inflammation. Semin Cancer Biol. 2008. [Crossref]
-  Taganov KD, Boldin MP, Chang KJ, Baltimore D. NF-kappaBdependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci U S A. 2006;103:12481-6.
-  Tang Y, Luo X, Cui H, et al. MicroRNA-146A contributes to abnormal activation of the type I interferon pathway in human lupus by targeting the key signaling proteins. Arthritis Rheum. 2009;60:1065-75.
-  Boldin MP, Taganov KD, Rao DS, et al. miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice. J Exp Med. 2011;208:1189-201.
-  Li G, Yu M, Lee WW, et al. Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity. Nat Med. 2012;18:1518-24.
-  Ebert PJ, Jiang S, Xie J, Li QJ, Davis MM. An endogenous positively selecting peptide enhances mature T cell responses and becomes an autoantigen in the absence of microRNA miR-181a. Nat Immunol. 2009;10:1162-9.
-  Zhang N, Bevan MJ. Dicer controls CD8+ T-cell activation, migration, and survival. Proc Natl Acad Sci U S A. 2010;107:21629-34.[Crossref]
-  Lu TX, Hartner J, Lim EJ, et al. MicroRNA-21 limits in vivo immune response-mediated activation of the IL-12/ IFN-gamma pathway, Th1 polarization, and the severity of delayed-type hypersensitivity. J Immunol. 2011;187:3362-73.
-  Ma F, Xu S, Liu X, et al. The microRNA miR-29 controls innate and adaptive immune responses to intracellular bacterial infection by targeting interferon-gamma. Nat Immunol. 2011;12:861-9.[Crossref]
-  Steiner DF, Thomas MF, Hu JK, et al. MicroRNA-29 regulates T-box transcription factors and interferon-gamma production in helper T cells. Immunity. 2011;35:169-81.[Crossref]
-  Oertli M, Engler DB, Kohler E, Koch M, Meyer TF, Muller A. MicroRNA-155 is essential for the T cell-mediated control of Helicobacter pylori infection and for the induction of chronic Gastritis and Colitis. J Immunol. 2011;187:3578-86.
-  Yao R, Ma YL, Liang W, et al. MicroRNA-155 Modulates Treg and Th17 Cells Differentiation and Th17 Cell Function by Targeting SOCS1. PLoS ONE. 2012;7:e46082.
-  O’Connell RM, Kahn D, Gibson WS, et al. MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development. Immunity. 2010;33:607-19.
-  Murugaiyan G, Beynon V, Mittal A, Joller N, Weiner HL. Silencing microRNA-155 ameliorates experimental autoimmune encephalomyelitis. J Immunol. 2011;187:2213-21.
-  Alencar AJ, Malumbres R, Kozloski GA, et al. MicroRNAs are independent predictors of outcome in diffuse large B-cell lymphoma patients treated with R-CHOP. Clin Cancer Res. 2011;17:4125-35.[Crossref]
-  Ventura A, Young AG, Winslow MM, et al. Targeted deletion reveals essential and overlapping functions of the miR-17 through 92 family of miRNA clusters. Cell. 2008;132:875-86.
-  Xiao C, Srinivasan L, Calado DP, et al. Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes. Nat Immunol. 2008;9:405-14.[Crossref]
-  Santanam U, Zanesi N, Efanov A, et al. Chronic lymphocytic leukemia modeled in mouse by targeted miR-29 expression. Proc Natl Acad Sci U S A. 2010;107:12210-5.[Crossref]
-  Yoshimoto M, Sakamoto G, Ohashi Y. Time dependency of the influence of prognostic factors on relapse in breast cancer. Cancer. 1993;72:2993-3001.[Crossref]
-  Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313:1960-4.
-  Clemente CG, Mihm MC, Jr., Bufalino R, Zurrida S, Collini P, Cascinelli N. Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer. 1996;77:1303-10.[Crossref]
-  Zhang L, Conejo-Garcia JR, Katsaros D, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med. 2003;348:203-13.
-  Kalos M, Levine BL, Porter DL, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. 2011;3:95ra73.[Crossref]
-  Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365:725-33.
-  Dudley ME, Wunderlich JR, Robbins PF, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science. 2002;298:850-4.
-  Pardoll D, Drake C. Immunotherapy earns its spot in the ranks of cancer therapy. J Exp Med. 2012;209:201-9.[Crossref]
-  Topalian SL, Hodi FS, Brahmer JR, et al. Safety, Activity, and Immune Correlates of Anti-PD-1 Antibody in Cancer. N Engl J Med. 2012.
-  Cubillos-Ruiz JR, Engle X, Scarlett UK, et al. Polyethyleniminebased siRNA nanocomplexes reprogram tumor-associated dendritic cells via TLR5 to elicit therapeutic antitumor immunity. J Clin Invest. 2009;119:2231-44.
-  Cubillos-Ruiz JR, Martinez D, Scarlett UK, et al. CD277 is a Negative Co-stimulatory Molecule Universally Expressed by Ovarian Cancer Microenvironmental Cells. Oncotarget. 2010;1:329-8.
-  Huarte E, Cubillos-Ruiz JR, Nesbeth YC, et al. Depletion of dendritic cells delays ovarian cancer progression by boosting antitumor immunity. Cancer Res. 2008;68:7684-91.[Crossref]
-  Nesbeth Y, Scarlett U, Cubillos-Ruiz J, et al. CCL5-mediated endogenous antitumor immunity elicited by adoptively transferred lymphocytes and dendritic cell depletion. Cancer Res. 2009;69:6331-8.
-  Nesbeth YC, Martinez DG, Toraya S, et al. CD4+ T cells elicit host immune responses to MHC class II- ovarian cancer through CCL5 secretion and CD40-mediated licensing of dendritic cells. J Immunol. 2010;184:5654-62.
-  Scarlett UK, Rutkowski MR, Rauwerdink AM, et al. Ovarian cancer progression is controlled by phenotypic changes in dendritic cells. J Exp Med. 2012;209:495-506.
-  Xiao C, Rajewsky K. MicroRNA control in the immune system: basic principles. Cell. 2009;136:26-36.
-  O’Connell RM, Rao DS, Chaudhuri AA, et al. Sustained expression of microRNA-155 in hematopoietic stem cells causes a myeloproliferative disorder. J Exp Med. 2008;205:585-94.
-  Costinean S, Zanesi N, Pekarsky Y, et al. Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in E(mu)-miR155 transgenic mice. Proc Natl Acad Sci U S A. 2006;103:7024-9.
-  Sempere LF, Preis M, Yezefski T, et al. Fluorescence-based codetection with protein markers reveals distinct cellular compartments for altered MicroRNA expression in solid tumors. Clin Cancer Res. 2010;16:4246-55.[Crossref]
-  Ranganathan P, Heaphy CE, Costinean S, et al. Regulation of acute graft-versus-host disease by microRNA-155. Blood. 2012;119:4786-97.
-  Sui W, Dai Y, Huang Y, Lan H, Yan Q, Huang H. Microarray analysis of MicroRNA expression in acute rejection after renal transplantation. Transpl Immunol. 2008;19:81-5.[Crossref]
-  Hariharan M, Scaria V, Pillai B, Brahmachari SK. Targets for human encoded microRNAs in HIV genes. Biochem Biophys Res Commun. 2005;337:1214-8.
-  Nathans R, Chu CY, Serquina AK, Lu CC, Cao H, Rana TM. Cellular microRNA and P bodies modulate host-HIV-1 interactions. Mol Cell. 2009;34:696-709.
-  Ahluwalia JK, Khan SZ, Soni K, et al. Human cellular microRNA hsa-miR-29a interferes with viral nef protein expression and HIV-1 replication. Retrovirology. 2008;5:117.
-  Ancuta P, Monteiro P, Sekaly RP. Th17 lineage commitment and HIV-1 pathogenesis. Curr Opin HIV AIDS. 2010;5:158-65.
-  Huang J, Wang F, Argyris E, et al. Cellular microRNAs contribute to HIV-1 latency in resting primary CD4+ T lymphocytes. Nat Med. 2007;13:1241-7.
-  Triboulet R, Mari B, Lin YL, et al. Suppression of microRNAsilencing pathway by HIV-1 during virus replication. Science. 2007;315:1579-82.
-  Swaminathan S, Suzuki K, Seddiki N, et al. Differential regulation of the Let-7 family of microRNAs in CD4+ T cells alters IL-10 expression. J Immunol. 2012;188:6238-46.
-  Kulkarni S, Savan R, Qi Y, et al. Differential microRNA regulation of HLA-C expression and its association with HIV control. Nature. 2011;472:495-8.
-  Cubillos-Ruiz JR, Fiering S, Conejo-Garcia JR. Nanomolecular targeting of dendritic cells for ovarian cancer therapy. Future Oncol. 2009;5:1189-92.[Crossref]
-  Cubillos-Ruiz JR, Rutkowski M, Conejo-Garcia JR.Blocking ovarian cancer progression by targeting tumor microenvironmental leukocytes. Cell Cycle. 2010;9:260-8.[Crossref]
-  Huang L, Lemos HP, Li L, et al. Engineering DNA nanoparticles as immunomodulatory reagents that activate regulatory T cells. J Immunol. 2012;188:4913-20.
-  Kim SS, Peer D, Kumar P, et al. RNAi-mediated CCR5 silencing by LFA-1-targeted nanoparticles prevents HIV infection in BLT mice. Mol Ther. 2010;18:370-6.
-  Kim DH, Behlke MA, Rose SD, Chang MS, Choi S, Rossi JJ. Synthetic dsRNA Dicer substrates enhance RNAi potency and efficacy. Nat Biotechnol. 2005;23:222-6.[Crossref]
-  Gu S, Jin L, Zhang Y, et al. The Loop Position of shRNAs and Pre-miRNAs Is Critical for the Accuracy of Dicer Processing In Vivo. Cell. 2012;151:900-11.
-  Park JE, Heo I, Tian Y, et al. Dicer recognizes the 5’ end of RNA for efficient and accurate processing. Nature. 2011;475:201-5.
-  Krutzfeldt J, Rajewsky N, Braich R, et al. Silencing of microRNAs in vivo with ‘antagomirs’. Nature. 2005;438:685-9.
-  Ebert MS, Neilson JR, Sharp PA. MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells. Nat Methods. 2007;4:721-6. [Crossref]
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