Toll like receptor signaling in “inflammaging”: microRNA as new players

Immunity & Ageing

Antonio Domenico Procopio²  Rina Recchioni²  Laura Graciotti¹  Lucia Babini¹  Francesco Prattichizzo¹  Maria Rita Rippo¹  Fabiola Olivieri² 

[1] Department of Clinical and Molecular Sciences, Università Politecnica delle Marche, Ancona Via Tronto 10/A, Ancona, 60020, Italy;Center of Clinical Pathology and Innovative Therapy, I.N.R.C.A. National Institute, Ancona, Italy

关键词: Innate immunity cells;    Endothelial cells;    SASP;    Inflammaging;    Cellular senescence;    Aging;    TLR;    MicroRNA;   

Others  :  815092
DOI  :  10.1186/1742-4933-10-11

 received in 2012-12-21, accepted in 2013-03-10,  发布年份 2013

【 摘 要 】

The age-related changes of immune system functions are complex phenomena incompletely understood. The acquired immune system shows a functional decline in ability to respond to new pathogens during aging, whereas serum levels of inflammatory cytokines are increased with age. The source of this age-related systemic chronic inflammation, named inflammaging, was mainly attributed to the progressive activation of immune cells over time. However, recent studies have shown that the process of cellular senescence can be an important additional contributor to chronic inflammation, since senescent cells acquire a phenotype named “senescence-associated secretory phenotype” (SASP), characterized by the enhanced secretion of many inflammation modulators. Pathogen-associated molecular pattern receptors, in particular Toll-like receptors (TLRs), are key molecules in the response of innate immunity cells to pathological stimuli. An intriguing and innovative hypothesis is that the dysfunction of TLRs signaling and the acquisition of SASP can be two interconnected phenomena. The TLR family, including receptors and co-effector molecules, do not show a consistent age-dependent change across model systems. However, there is evidence for impaired downstream signaling events, including inhibition of positive and activation of negative modulators of TLR signaling. MicroRNAs (miRNAs) are a newly discovered class of gene regulators acting as post-transcriptional repressors of a number of genes. The miRNA property to finely-tune gene expression makes them right for immune system regulation, which requires precise control for proper activity. We reviewed evidences suggesting that miRNAs can modulate TLR signaling mainly by three different mechanisms: 1) miRNAs can directly target components of the TLR signaling system, 2) miRNA expression can be directly regulated by TLRs pathway activation and 3) miRNAs can directly activate the RNA-sensing TLRs, like TLR-8, in humans. We also reviewed how TLR signaling is modulated by miRNAs during aging, and how an impaired miRNAs/TLR signaling interaction in immune system cells and related cells, i.e. endothelial cells and adipocytes, can contribute to inflammaging observed in normal aging. Interestingly, this impairment appears accelerated in presence of the majors age-related diseases, such as cardiovascular diseases, diabetes, neurodegenerative diseases and cancers.

【 授权许可】

   
2013 Olivieri et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

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