MiR-146a potentially promotes IVIg-mediated inhibition of TLR4 signaling in LPS-activated human monocytes

IVIg is used as an immunomodulatory agent in inflammatory disorders such as sepsis. IVIg also affects monocyte differentiation and functions, two processes in which microRNAs play a crucial role. Monocytes detect microorganisms through pathogen recognition receptors (PRRs) such as TLR4. MiR-146a has been shown to supress NF-kappa B and IRF3 activity, two key components of TLR4 signaling. To evaluate whether miR-146a is involved in the anti-inflammatory effects of IVIg, monocytes were treated with LPS or IVIg alone or, alternately, first activated with LPS followed by washing and addition of IVIg. MiR-146a, IRF3, TNF-alpha, IL-1 beta IL-6, IL-10, IFN-beta, TGF-beta 1 and IL-1Ra expression was analyzed by qPCR, while IRAK1, TRAF6 and IKBa expression was measured by Western blotting. We found that addition of IVIg to LPS-activated monocytes significantly upregulated the expression of miR-146a, which was associated with a significant reduction in the expression of its targets IRF3 and its regulated gene IFN-beta. Furthermore, expression of IRAK1,TRAF6, and consequently NF-kappa B activation, was also reduced in LPS-activated monocytes following addition of IVIg, whereas TGF-beta 1, IL-10 and IL-1Ra were increased. Our results thus suggest that miR146a is a mediator of Mg effects in inflammatory disorders, point to an important role for miR-146a in the control of inflammation during sepsis and highlight a new mechanism by which IVIg exerts its anti-inflammatory effects in sepsis. (C) 2017 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.