let-7 family members, on the other hand, have been reported to directly target expression of TLR4 and regulate responsiveness to LPS (Chen et al., 2007; Androulidaki et al., 2009) and to form an epigenetic switch together with NFκB and interleukin 6 (IL6) that links inflammation to persistent cell transformation (Iliopoulos et al., 2009). The reported upregulation of let-7 miRNAs in human alcoholics could be understood as necessary to turn off expression of TLRs in glial cells and avoid excessive inflammation due to hyper-responsiveness to LPS insult. This potential regulatory loop could contribute to tolerance and dependency in chronic alcoholics. Furthermore, Blednov and colleagues recently demonstrated that LPS-triggered activation of immune signaling mediated by CD14 [a key component of the LPS-sensing co-clustering complex that also includes Hsp70, Hsp90, CXCR4, GDF5, and TLR4 (Triantafilou and Triantafilou, 2002)] promotes alcohol consumption and alters certain aspects of alcohol reward and aversion in mice (Blednov et al., 2011). Our finding that chemokine receptor CXCR4 is downregulated in brain of human alcoholics and is the most significantly miRNA-over-targeted transcript (Lewohl et al., 2011) supports a role
