About 30% of the 35 miRNAs upregulated in the PFC of human alcoholics (miR-15, miR-34, miR-92, miR-140, miR-146, miR-152, miR-194, miR-196, miR-203, miR-369, let-7) are modulators of immunity and several of them appear to be involved in regulating TLR signaling. Particularly interesting is the miR-146 family, which is upregulated by bacterial endotoxin lipopolysaccharides (LPS) and controls TLR/NFκB signaling through negative feedback loops involving downregulation of IL1 receptor-associated kinase 1 (IRAK1) and TNF receptor-associated factor 6 (TRAF6) protein levels (Taganov et al., 2006; Zhao et al., 2011). TRAF2 has also being implicated as a miR-146 target (Hou et al., 2009). It was suggested that miR-146 regulatory circuit likely fine-tunes TLR and cytokine signaling, rather than totally abrogating the signal, and that expression of miR-146 may be critical in preventing excess inflammation (Sonkoly et al., 2008). Collectively, IRAK1, IRAK2, and TRAF6 represent important components of the myeloid differentiation primary-response protein 88 (MYD88)-dependent pathway for NFκB activation downstream of TLRs (O’Neill et al., 2011). Correspondingly, several reports have implicated IRAK and TRAF6 transducers in alcohol actions in the brain (Vallés et al., 2004; Guasch et al., 2007; Oliva et al., 2011).
