ROLE OF MICRORNA IN MACROPHAGE POLARIZED ACTIVATION

Macrophages are cells from the innate branch of immune system with central roles both under physiologic and pathologic conditions. Such complex behaviour relies on extreme functional plasticity of these cells. Cellular activation and plasticity in macrophages are complex phenomena that require tight regulation. In recent years, microRNAs and lncRNAs emerged as important regulators of many cellular processes and have been proposed as key mediators of the plasticity observed in macrophages. In this study we investigate the possible roles of different microRNAs on macrophage activation and functionality, taking advantage of animal models selectively depleted of candidate miRNA in macrophages. We found that selective depletion of miR-125a in macrophages did not affect clinical outcome in different in vivo models of inflammation. Nonetheless it altered macrophage activation and functions, as evidenced by reduced secretion of TNF\u3b1 after endotoxin challenges. Consistently, macrophages deficient in miR-125a displayed reduced killing of extracellular bacteria although they showed increased phagocytic rate as compared to miR-125a competent cells. With a similar approach, we confirmed that miR-9 is induced in macrophages upon inflammatory stimuli. Increased expression of miR-9 mature form in mice was sustained by the synchronous activation of transcription in both pri-miR-9.1 and pri-miR-9.3 loci, in contrast to human. Finally we identified a lncRNA interfering with the processing of a pro-inflammatory miRNA in differentially activated human macrophages, highlighting a new layer of regulation of macrophage activation. The finding of the present project give new insights into the complex mechanism regulating macrophage activation and underscores the need for future studies to thoroughly identify the molecular mechanisms and the involvement of different miRNA in macrophage activation. Moreover, such studies could set the basis for the transition from basic research to new therapeutic options enabling precise regulation of macrophages activation in different immune pathologies

ESSAYS ON MEDIA ECONOMICS

In the present work, I focus on micro-industrial organization's and political economy's theories used in the study of media economics, referring to two particular streams of the recent literature: media as two-sided market (I.O. field) and the effects of the presence of media bias (political economy field). I provide three different essays on the issue of media markets. In the first part, I deal with the I.O. analysis of media as two-sided markets: the first chapter provides a general framework of vertical differentiated media, analysing the effects of real and potential competition; the second work extented the setting of the first, by comparing different markets structures from a welfare point of view. Finally, in the second part, I move to the political economy approach of media markets, by presenting a theoretical essay on the issue of the interaction between media and politicians during elections

Multi-Step Regulation of the TLR4 Pathway by the miR-125a~99b~let-7e Cluster

An appropriate immune response requires a tight balance between pro- and anti-inflammatory mechanisms. IL-10 is induced at late time-points during acute inflammatory conditions triggered by TLR-dependent recognition of infectious agents and is involved in setting this balance, operating as a negative regulator of the TLR-dependent signaling pathway. We identified miR-125a~99b~let-7e as an evolutionary conserved microRNA cluster late-induced in human monocytes exposed to the TLR4 agonist LPS as an effect of this IL-10-dependent regulatory loop. We demonstrated that microRNAs generated by this cluster perform a pervasive regulation of the TLR signaling pathway by direct targeting receptors (TLR4, CD14), signaling molecules (IRAK1), and effector cytokines (TNFα, IL-6, CCL3, CCL7, CXCL8). Modulation of miR-125a~99b~let-7e cluster influenced the production of proinflammatory cytokines in response to LPS and the IL-10-mediated tolerance to LPS, thus identifying this gene as a previously unrecognized major regulatory element of the inflammatory response and endotoxin tolerance

Multi-Step Regulation of the TLR4 Pathway by the miR-125a~99b~let-7e Cluster

An appropriate immune response requires a tight balance between pro- and anti-inflammatory mechanisms. IL-10 is induced at late time-points during acute inflammatory conditions triggered by TLR-dependent recognition of infectious agents and is involved in setting this balance, operating as a negative regulator of the TLR-dependent signaling pathway. We identified miR-125a~99b~let-7e as an evolutionary conserved microRNA cluster late-induced in human monocytes exposed to the TLR4 agonist LPS as an effect of this IL-10-dependent regulatory loop. We demonstrated that microRNAs generated by this cluster perform a pervasive regulation of the TLR signaling pathway by direct targeting receptors (TLR4, CD14), signaling molecules (IRAK1), and effector cytokines (TNFα, IL-6, CCL3, CCL7, CXCL8). Modulation of miR-125a~99b~let-7e cluster influenced the production of proinflammatory cytokines in response to LPS and the IL-10-mediated tolerance to LPS, thus identifying this gene as a previously unrecognized major regulatory element of the inflammatory response and endotoxin tolerance

Problemi Inversi

none1G. DrufucaDrufuca, Giusepp