MicroRNA-148/152 Impair Innate Response and Antigen Presentation of TLR-Triggered Dendritic Cells by Targeting CaMKIIα

Abstract

MicroRNAs (miRNAs) are involved in the regulation of immunity, including the lymphocyte development and differentiation, and inflammatory cytokine production. Dendritic cells (DCs) play important roles in linking innate and adaptive immune responses. However, few miRNAs have been found to regulate the innate response and APC function of DCs to date. Calcium/calmodulin-dependent protein kinase II (CaMKII), a major downstream effector of calcium (Ca2+), has been shown to be an important regulator of the maturation and function of DCs. Our previous study showed that CaMKIIα could promote TLR-triggered production of proinflammatory cytokines and type I IFN. Inspired by the observations that dicer mutant Drosophila display defect in endogenous miRNA generation and higher CaMKII expression, we wondered whether miRNAs can regulate the innate response and APC function of DCs by targeting CaMKIIα. By predicting with software and confirming with functional experiments, we demonstrate that three members of the miRNA (miR)-148 family, miR-148a, miR-148b, and miR-152, are negative regulators of the innate response and Ag-presenting capacity of DCs. miR-148/152 expression was upregulated, whereas CaMKIIα expression was downregulated in DCs on maturation and activation induced by TLR3, TLR4, and TLR9 agonists. We showed that miR-148/152 in turn inhibited the production of cytokines including IL-12, IL-6, TNF-α, and IFN-β upregulation of MHC class II expression and DC-initiated Ag-specific T cell proliferation by targeting CaMKIIα. Therefore, miRNA-148/152 can act as fine-tuner in regulating the innate response and Ag-presenting capacity of DCs, which may contribute to the immune homeostasis and immune regulation.

MicroRNAs in the regulation of TLR and RIG-I pathways

“…For example, miR-148 and miR-152 impair TLR signaling by targeting calcium/calmodulin-dependent protein kinase II. 12,93 MicroRNA-132 was shown to target acetylcholinesterase, which attenuates TLR-induced responses in macrophages by blocking NF-kB nuclear translocation. 94 Inhibition of miR-181 can also inhibit TNF-induced cytokine production in epithelial cells by targeting p300/cyclic AMP response element binding protein-associated factor, a coactivator and an acetyltransferase that promotes histone acetylation and gene transcription.…”

miRNAs as new molecular insights into inflammatory bowel disease: Crucial regulators in autoimmunity and inflammation

“…Accumulating evidence highlights the importance of specific miRNAs in DC development, antigen presentation capacity, and cytokine release [39] . miR 146a [40] , miR155 [41] , and let7i [42] are involved in the maturation and functional state of DCs, while miR148/152 [43] and miR223 [44] are involved in their antigenpresentation capacity. miR150 is required for the crosspresentation capacity of Langerhans cells (skinresident DCs) [45] .…”

Identification of Resting and Type I IFN-Activated Human NK Cell miRNomes Reveals MicroRNA-378 and MicroRNA-30e as Negative Regulators of NK Cell Cytotoxicity

“…After 24 h, normalized luciferase activities were obtained as previously discribed (22). Alternatively, HeLa cells, which express certain level of endogenous miR-378 and miR-30e, were cotransfected with 80 ng indicated luciferase reporter plasmid, 40 ng pRL-TK-Renilla-luciferase plasmid (Promega), and 80 ng indicated sponge plasmid using JetPEI transfection reagents (PolyPlus Transfection).…”