| First Author | Hunt D | Year | 2018 |
| Journal | PLoS One | Volume | 13 |
| Issue | 7 | Pages | e0200764 |
| PubMed ID | 30024985 | Mgi Jnum | J:264096 |
| Mgi Id | MGI:6192158 | Doi | 10.1371/journal.pone.0200764 |
| Citation | Hunt D, et al. (2018) Murine macrophage TLR2-FcgammaR synergy via FcgammaR licensing of IL-6 cytokine mRNA ribosome binding and translation. PLoS One 13(7):e0200764 |
| abstractText | Macrophages (MOs) are sentinels of the immune system that use pattern recognition receptors such as Toll-like receptors (TLR) to detect invading pathogens and immune receptors such as FcgammaR to sense the host's immune state. Crosstalk between these two signaling pathways allows the MO to tailor the cell's overall response to prevailing conditions. However, the molecular mechanisms underlying TLR-FcgammaR crosstalk are only partially understood. Therefore, we employed an immunologically-relevant MO stimulus, an inactivated gram-negative bacterium that bears TLR2 agonists but no TLR4 agonist (iBTLR2) opsonized with a monoclonal antibody (mAb-iBTLR2), as a tool to study FcgammaR regulation of TLR2-driven production of IL-6, a key inflammatory cytokine. We chose this particular agonist as an investigational tool because MO production of any detectable IL-6 in response to mAb-iBTLR2 requires both TLR2 and FcgammaR signaling, making it an excellent system for the study of receptor synergy. Using genetic, pharmacological and immunological approaches, we demonstrate that the murine MO IL-6 response to mAb-iBTLR2 requires activation of both the TLR/NF-kappaB and FcgammaR/ITAM signaling pathways. mAb-iBTLR2 engagement of TLR2 drives NF-kappaB activation and up-regulation of IL-6 mRNA but fails to result in IL-6 cytokine production/release. Here, Src family kinase-driven FcgammaR ITAM signaling is necessary to enable IL-6 mRNA incorporation into polysomes and translation. These results reveal a novel mechanism by which FcgammaR ITAM signaling synergizes with TLR signaling, by "licensing" cytokine mRNA ribosome binding/translation to drive a strong murine MO cytokine response. |
