Open AccessDysregulated expression of miR‐146a contributes to age‐related dysfunction of macrophages
Author(s) -
Jiang Minghong,
Xiang Yang,
Wang Dongsheng,
Gao Jing,
Liu Dan,
Liu Yanxin,
Liu Shilian,
Zheng Dexian
Publication year - 2012
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/j.1474-9726.2011.00757.x
Subject(s) - trichostatin a , biology , histone deacetylase , proinflammatory cytokine , histone deacetylase inhibitor , histone , dna methylation , inflammation , immune system , hdac3 , dna damage , lipopolysaccharide , acetylation , immunology , regulation of gene expression , cancer research , gene expression , dna , genetics , gene
Summary Age‐associated immune dysfunction, characterized by increased systemic levels of cytokines, manifests as an increased susceptibility to infections. Thus, understanding these negative regulators of the immune response has paved the way to delineating signaling pathways that impact immune senescence. In the present study, we found that miR‐146a, which negatively regulated the expression of IL‐1β and IL‐6, was highly expressed in aged mice. However, there was a lack of response to the stimulation of lipopolysaccharide (LPS) and proinflammatory cytokines in macrophages of aged mice. As a result, the negative feedback regulation loop with miR‐146a involving down‐regulation of inflammation factors was interrupted in aged mice. Aberrant NF‐κB binding to the miR‐146a promoter was demonstrated to be associated with the abnormal expression of miR‐146a in aged mice. The DNA methyltransferase inhibitor (5‐aza‐2‐deoxycytidine) and the histone deacetylase inhibitor [trichostatin A (TSA)] both significantly up‐regulated miR‐146a transcriptional activation by altering the DNA‐binding activity of NF‐κB in macrophages isolated from aged mice, which suggests that DNA methylation and histone acetylation are involved in the suppression of age‐dependent miR‐146a expression. Additionally, high levels of histone deacetylase (HDACs) expressions contributed to the inhibition of miR‐146a expression in LPS‐stimulated macrophages from aged mice in vitro. While the suppression of HDACs activities by TSA could improve LPS‐induced inflammatory responses owing to up‐regulation of miR‐146a expression in macrophages from aged mice. These data indicate that the dysregulated expression of miR‐146a results in the age‐associated dysfunction of macrophages, and miR‐146a may be a good target for the treatment of age‐related inflammatory diseases.