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WIREs Syst Biol Med
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Decoding the functions of post‐transcriptional regulators in the determination of inflammatory states: focus on macrophage activation

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Abstract Inflammation involves a continuum of intercellular interactions and cellular responses targeting infectious or tissue damage while maintaining homeostasis. At its core, this continuum encompasses the alternating phenotypes of innate immune cells; each phenotype is typified by the expression of molecules which either support host defence or aid tissue restoration and the resolution of inflammation. The aberrant persistence of any such phenotype can drive chronic inflammatory pathology. For macrophages, these phenotypes arise as changes in cellular plasticity because of adaptation. As such their underlying gene expression programs may not be determined by robust transcriptomic and epigenetic programs but by more flexible means like post‐transcriptional mechanisms affecting mRNA use. These mechanisms require the assemblies of RNA‐binding proteins (RBPs) and non‐coding RNAs onto specific elements on their RNA targets in Ribonucleoprotein particles (RNPs) which control mRNA maturation, turnover and translation. The collection of RNPs within a cell defines the ribonome, that is, a high order system of coordinative post‐transcriptional determination. mRNAs involved in the definition of different macrophage activation phenotypes share elements of RBP recognition rendering them amenable to ribonomic regulation. The molecular features of their cognitive RBPs and the pathologies developing in the corresponding mouse mutants support their involvement in inflammatory reactions. We view this information in the context of macrophage activation states to propose that these states can be determined via differential—synergistic or antagonistic—RNP associations. In doing so, we substantiate the need for the use of systems platforms to model RNP hierarchies controlling the continuum of inflammation. WIREs Syst Biol Med 2012. doi: 10.1002/wsbm.1179 This article is categorized under: Biological Mechanisms > Cell Signaling Models of Systems Properties and Processes > Organ, Tissue, and Physiological Models Biological Mechanisms > Regulatory Biology

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Proposed models for ribonomic associations modulating macrophage activation states during inflammatory progression: the ‘antagonistic’ model. The ‘antagonistic’ model of an inflammatory post‐transcriptional regulon in macrophages predicts that RNPs can be assembled by RNA activators (i.e., HuR) and suppresors (RISC complex/miRNAs, TIA‐1, TTP, AUF1) which compete for the onset and resolution of inflammation in a temporal and/or signal dependent‐manner. This RNP regulates a subset of RNAs activated by a transcriptionally primed state that marks an activation phenotype (CAM or AAM1). Circles denote global mRNA targets for each RBP. According to the model, the association of RNAs to an activator‐RBP decreases toward the resolution of inflammation, whereas the reverse occurs for the RNAs associated to negative regulators leading ultimately to the regulatory AAM2 and resting macrophage states. CAM, Classically activated macrophages; AAM, Alternatively activated macrophages.

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Proposed models for ribonomic associations modulating macrophage activation states during inflammatory progression: the ‘synergistic’ model. The ‘synergistic’ model of inflammatory post‐transcriptional regulons in macrophages predicts that HuR acts as an organizer/operon determinant for RNAs involved in the determination of the CAM/AAM responses. Circles denote global mRNA targets for each RBP. In that sense, HuR first clusters the CAM‐related RNAs (orange circle) in response to the priming signals and guides their utilization by synergies to negative regulators sharing RNA association profiles. The outcome of these associations is the temporal prevalence of the CAM response and the competition with progressive AAM responses (blue circles). The latter may also involve HuR's organizing functions via different RNP compositions in regulons (blue circles) thus conforming to the continuum of inflammation. Ultimately, a prevalent AAM2 phenotype leads in inflammatory resolution. CAM, Classically activated macrophages; AAM, Alternatively activated macrophages.

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Models of Systems Properties and Processes > Organ, Tissue, and Physiological Models
Biological Mechanisms > Cell Signaling
Biological Mechanisms > Regulatory Biology

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