| First Author | Wimmer N | Year | 2012 |
| Journal | J Immunol | Volume | 188 |
| Issue | 7 | Pages | 3426-33 |
| PubMed ID | 22357629 | Mgi Jnum | J:183109 |
| Mgi Id | MGI:5317493 | Doi | 10.4049/jimmunol.1103324 |
| Citation | Wimmer N, et al. (2012) Lymphotoxin beta receptor activation on macrophages induces cross-tolerance to TLR4 and TLR9 ligands. J Immunol 188(7):3426-33 |
| abstractText | Our previous studies indicated that lymphotoxin beta receptor (LTbetaR) activation controls and downregulates inflammatory reactions. In this study, we report that LTbetaR activation on primary mouse macrophages results in induction of tripartite motif containing (TRIM) 30alpha, which negatively regulates NF-kappaB activation induced by TLR signaling. LTbetaR activation results in a downregulation of proinflammatory cytokine and mediator expression upon TLR restimulation, demonstrating that LTbetaR signaling is involved in the induction of TLR cross-tolerance. Specific knockdown experiments using TRIM30alpha-specific small interfering RNA abolished the LTbetaR-dependent induction of TRIM30alpha and LTbetaR-mediated TLR cross-tolerance. Concordantly, LTbetaR activation on bone marrow-derived macrophages induced cross-tolerance to TLR4 and TLR9 ligands in vitro. Furthermore, we have generated cell type-specific LTbetaR-deficient mice with ablation of LTbetaR expression on macrophages/neutrophils (LTbetaR(flox/flox) x LysM-Cre). In bone marrow-derived macrophages derived from these mice LTbetaR-induced cross-tolerance to TLR4 and TLR9 ligands was impaired. Additionally, mice with a conditional ablation of LTbetaR expression on macrophages (LTbetaR(flox/flox) x LysM-Cre) are resistant to LTbetaR-induced TLR4 tolerance in vivo. Collectively, our data indicate that LTbetaR activation on macrophages by T cell-derived lymphotoxin alpha(1)beta(2) controls proinflammatory responses by activation of a TRIM30alpha-controlled, counterregulatory signaling pathway to protect against exacerbating inflammatory reactions. |
