Inflammatory gene silencing in activated monocytes by a cholesterol tagged-miRNA/siRNA: a novel approach to ameliorate diabetes induced inflammation

Cell Tissue Res. 2022 May 23. doi: 10.1007/s00441-022-03637-6. Online ahead of print.ABSTRACTThere is a major unmet need for the development of effective therapies for diabetes induced inflammation. Increased adenosine-uridine rich elements (AREs) containing mRNAs of inflammatory molecules are reported in inflamed monocytes. Destabilizing these inflammatory mRNAs by the miR-16 could reduce inflammation. DNA microarrays and in vitro cell studies showed that exogenous miR16 and its mimic treatment, in LPS/PMA induced monocytes, significantly downregulated several ARE containing inflammatory cytokine mRNAs similar to those seen in the normal monocytes. Ingenuity pathway analyses showed exogenous miR-16 or its synthetic mimic treatment alleviates inflammatory responses. To selectively target uptake, especially to inflamed cells, one of the CD36 substrate cholesterol was tagged to miR16/siRNA. Cholesterol tagged miR-16/ARE-siRNA showed enhanced uptake in CD36 expressing inflamed cells. In LPS or PMA, treated monocytes, candidate genes expressions levels such as IL-6, IL-8, IL-12β, IP-10, and TNF-α mRNA were increased, as measured by RT-qPCR as seen in primary monocytes of diabetes patients. Exogenous miR16 or ARE-siRNA transfection reduced mRNAs of pro-inflammatory cytokines levels in monocyte, and its adhesion. Increased uptake of cholesterol tagged miR-16 through the CD36 receptor was observed. This destabilizes numerous inflammatory ARE containing mRNAs and alleviates inflamm...
Source: Cell Research - Category: Cytology Authors: Source Type: research