Lymphotoxin ß receptor activation on macrophages induces cross-tolerance to TLR4 and TLR9 ligands.

ABSTRACT

Our previous studies indicated that lymphotoxin ß receptor (LTßR) activation controls and downregulates inflammatory reactions. In this study, we report that LTßR activation on primary mouse macrophages results in induction of tripartite motif containing (TRIM) 30α, which negatively regulates NF-κB activation induced by TLR signaling. LTßR activation results in a downregulation of proinflammatory cytokine and mediator expression upon TLR restimulation, demonstrating that LTßR signaling is involved in the induction of TLR cross-tolerance. Specific knockdown experiments using TRIM30α-specific small interfering RNA abolished the LTßR-dependent induction of TRIM30α and LTßR-mediated TLR cross-tolerance. Concordantly, LTßR activation on bone marrow-derived macrophages induced cross-tolerance to TLR4 and TLR9 ligands in vitro. Furthermore, we have generated cell type-specific LTßR-deficient mice with ablation of LTßR expression on macrophages/neutrophils (LTßR(flox/flox) × LysM-Cre). In bone marrow-derived macrophages derived from these mice LTßR-induced cross-tolerance to TLR4 and TLR9 ligands was impaired. Additionally, mice with a conditional ablation of LTßR expression on macrophages (LTßR(flox/flox) × LysM-Cre) are resistant to LTßR-induced TLR4 tolerance in vivo. Collectively, our data indicate that LTßR activation on macrophages by T cell-derived lymphotoxin α(1)ß(2) controls proinflammatory responses by activation of a TRIM30α-controlled, counterregulatory signaling pathway to protect against exacerbating inflammatory reactions.