Contribution of aberrant miRNA expression in SLE PBMCs. (A) miR-146a is down-regulated in systemic lupus erythematosus (SLE) peripheral blood mononuclear cells (PBMCs) and this may amplify the activation of NF-kB through its direct regulation of NF-kB upstream regulators IRAK1 (IL-1 receptor-associated kinase 1) and TRAF6 (TNF receptor-associated factor 6). Activation of NF-kB leads to increased type I IFN production and thus increased expression of 'IFN signature genes', including LY6E, OAS1, and MX1 . (B) miR-125a is down-regulated in PBMCs from SLE patients, which leads to elevated expression of its target transcriptional factor KLF13. KLF13 can trigger the expression of the pro-inflammatory chemokine RANTES (Regulated upon activation, normal T-cell expressed, and secreted), which is known to enhance inflammatory processes such as arthritis and nephritis . (C) Up-regulation of miR-21, miR-148, and miR-126 can either directly or indirectly inhibit DNA methyltransferase 1 (DNMT1) levels. This inhibition in turn reduces the CpG methylation level and causes over-expression of autoimmune-associated genes in SLE, such as those encoding CD70, LFA-1 (CD11a) and EGFL7 (epidermal growth factor-like domain 7) [50,51]. An, poly-A tail; CH3, methyl groups; RASGRP1, RAS guanyl-releasing protein 1.
Ceribelli et al. Arthritis Research & Therapy 2011 13:229 doi:10.1186/ar3377