Lymphotoxin β Receptor Activation on Macrophages Induces Cross-Tolerance to TLR4 and TLR9 Ligands

Our previous studies indicated that lymphotoxin beta receptor (LT beta R) activation controls and downregulates inflammatory reactions. In this study, we report that LT beta R activation on primary mouse macrophages results in induction of tripartite motif containing (TRIM) 30 alpha, which negatively regulates NF-kappa B activation induced by TLR signaling. LT beta R activation results in a downregulation of proinflammatory cytokine and mediator expression upon TLR restimulation, demonstrating that LT beta R signaling is involved in the induction of TLR cross-tolerance. Specific knockdown experiments using TRIM30 alpha-specific small interfering RNA abolished the LT beta R-dependent induction of TRIM30 alpha and LT beta R-mediated TLR cross-tolerance. Concordantly, LT beta R activation on bone marrow-derived macrophages induced cross-tolerance to TLR4 and TLR9 ligands in vitro. Furthermore, we have generated cell type-specific LT beta R-deficient mice with ablation of LT beta R expression on macrophages/neutrophils (LT beta R-flox/flox x LysM-Cre). In bone marrow-derived macrophages derived from these mice LT beta R-induced cross-tolerance to TLR4 and TLR9 ligands was impaired. Additionally, mice with a conditional ablation of LT beta R expression on macrophages (LT beta R flox/flox 3 LysM-Cre) are resistant to LT beta R-induced TLR4 tolerance in vivo. Collectively, our data indicate that LT beta R activation on macrophages by T cell-derived lymphotoxin alpha(1)beta(2) controls proinflammatory responses by activation of a TRIM30 alpha-controlled, counterregulatory signaling pathway to protect against exacerbating inflammatory reactions. The Journal of Immunology, 2012, 188: 3426-3433.