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. 2018 May 8;9:504. doi: 10.3389/fphys.2018.00504

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Copyright © 2018 Alonso-Pérez, Franco-Trepat, Guillán-Fresco, Jorge-Mora, López, Pino, Gualillo and Gómez.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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TLR4 signaling pathway. TLR4 activates two different pathways. Both of them share the co-factor (TIR)-domain-containing adapter protein (TIRAP, also known as MAL). In myeloid factor 88 (Myd88)-dependent signaling pathway, Myd88 polymerizes with IL1-receptor-associated kinases (IRAK) 1 and 2, inducing the activation of TNF-receptor-associated factor 6 (TRAF6). This activation boosts the signaling of different kinases like phosphatidylinositol-4,5-biphosphate 3 kinases (PI3K) and mitogen-activated- protein kinases (MAPKs), as well as the activation and transnucleation of Nuclear Factor kappa B (NF-κB). This leads to the production of pro-inflammatory cytokines and inflammatory mediators. Myd88-independent signaling pathway rather than recruit Myd88 it recruits TIR-domain-containing adapter protein inducing interferon-beta (TRIF) and TRIF-related adapter molecule (TRAM). The recruitment activates proteins like TNF-receptor-associated factor 6 (TRAF6), receptor-interacting serine/threonine-protein kinase 1 (RIPK1), and secondarily, TANK binding kinase 1 (TBK1). This elicits the transnucleation of interferon-regulatory factor (IRF) 3 and 7 transcription factors that leads to the production of different inflammatory factors like type I interferons.