**8. Conclusions**

The increasing evidences on the role of miRNAs in pathophysiology are radically changing the established paradigms of disease onset and development. However, we can assert that our undestanding of miRNA functions is still preliminary and further work is awaited to better define how these molecules integrate with known intracellular pathways. Indeed, we know that miRNAs exert a very finely tuned regulation of intracellular pathways. This effect is attained through a modulation of miR levels, that is very complex to study in simplified models both in vitro and in vivo. Indeed, the best method to study miRNAs is to over express or completely inhibit its expression, but it is unlikely that this method can perfectly mirror the real intracellular conditions. Immune responses represent an attracting system to explore miR functions, since they have to be tightly regulated. The data have shown that miRNA modulation is an efficient way to rapidly turn on and off immune responses, both preceding and integrating with the classical gene mastered pathways. Therefore, we believe that the study of miRNAs within

immune system may represent an excellent model to understand miRNA pathophysiology, providing critical insights to be extended to the other branches of biopathology.

Emerging Role of MicroRNAs in the Pathophysiology of Immune System 215

[11] Li, Q. J., Chau, J, Ebert, P. J. R., Sylvester, G, Min, H, Liu, G, Braich, R, Manoharan, M Soutschek, J, Skare, P, Klein, L. O., Davis, M. M., and Chen, C. Z. miR-181a is an

[12] Ventura, A, Young, A. G, Winslow, M. M, Lintault, L, Meissner, A, Erkeland, S. J, Newman, J, Bronson, R. T., Crowley, D, Stone, J. R., Jaenisch, R, Sharp, P. A., Jacks, T. Targeted deletion reveals essential and overlapping functions of the miR-17 through 92

[13] Xiao, C, Rajewsky, K. MicroRNA control in the immune system: basic principles. *Cell*,

[14] Lin, Y. C., Kuo, M. W., Yu, J, Kuo, H. H., Lin, R. J., Lo, W. L., Yu, A. L. c-Myb is an evolutionary conserved miR-150 target and miR-150/c-Myb interaction is important for

[15] Thomas, M. D., Kremer, C. S., Ravichandran, K. S., rajewsky, K, Bender, T. P. c-Myb is critical for B cell development and maintenance of follicular B cells. *Immunity,* 2005, *23*,

[16] Xiao, C., Calado, D. P., Galler, G, Thai, T.H., Patterson, H. C., Wang, J, Rajewsky, N, Bender, T. P., Rajewsky, K. MiR-150 controls B cell differentiation by targeting the

[17] Ghisi, M, Corradin, A, Basso, K, Frasson, C, Serafin, V, Mukherjee, S, Mussolin, L, Ruggero, K, Bonanno, L, Guffanti, A, De Bellis, G, Gerosa, G, Stellin, G, D'agostino, D. M., Basso, G, Bronte, V, Indraccolo, S, Amadori, A, Zanovello, P. Modulation of microRNA expression in human T-cell development: targeting of NOTCH3 by miR-150.

[18] Johnnidis, J. B., Harris, M. H., Wheeler, R. T., Stehling-Sun, S, Lam M. H., Kirak, O, Brummelkamp, T. R., Fleming, M. D., Camargo, F. D. Regulation of progenitor cell proliferation and granulocyte function by microRNA-223. *Nature*, 2008, *451*, 1125-

[19] Velu, C. S., Baktula, A. M., Grimes, H. L. Gfi1 regulates miR-21 and miR-196b to control

[20] Taganov, K. D., Boldin, M. P., Chang, K. J., Baltimore, D. NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate

[21] Hou, J, Wang, P, Liu, L, Liu, X, Ma, F, An, H, Wang, Z, Cao, X. MicroRNA-146a feedback inhibits RIG-1-dependent type I IFN production in macrophage by targeting

[22] Rom, S, Rom, I, Passiatore, G, Pacifici M, Radhakrishnan, S, Del Valle, L, Pina-Oveido, S, Khalili, K, Eletto D, Peruzzi F. CCL8/MCP-2 is a target for miR-146a in HIV1-infected

[23] Androulidaki, A, Iliopoulos, D, Arranz, A, Doxaki, C, Schworer, S, Zacharioudaki, V, Margioris, A. N., Tsichlis, P. N., Tsatsanis, C. The kinase Akt1 controls

immune responses. *Proc Natl Acad Sci USA*, 2006, *103*, 12481–12486

TRAF6, IRAK1 and IRAK2. *J Immunol*, 2009, *183*, 2150–2158

human microglial cells. *FASEB J*, 2010, *24*, 2292–2300

intrinsic modulatorof T Cell sensitivity and selection *Cell*, 2007, *129*, 147–161.

family of miRNA clusters. *Cell*, 2008, *132*, 875–886

transcription factor c-Myb. Cell, 2007, *131*, 146–159

embryonic development. *Mol. Biol. Evol.* 2008, *25,* 2189–2198

2009, *136*, 26-36

275–286

1129

*Blood*, 2011, *117*, 7053-7062

myelopoiesis. *Blood*, 2009, *113*, 4720–4728
