Lymphotoxin β receptor activation on macrophages induces cross-tolerance to TLR4 and TLR9 ligands
| Autor: | Johann Röhrl, Thomas Hehlgans, Klaus Pfeffer, Nadin Wimmer, Barbara Huber, Nicola Barabas |
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| Rok vydání: | 2012 |
| Předmět: |
Small interfering RNA
Recombinant Fusion Proteins Immunology Ligands Proinflammatory cytokine Cell Line Mice Downregulation and upregulation Lymphotoxin beta Receptor Immune Tolerance Immunology and Allergy Animals RNA Small Interfering Inflammation Mice Knockout Gene knockdown Chemistry Macrophages Intracellular Signaling Peptides and Proteins TLR9 Cell biology Mice Inbred C57BL Toll-Like Receptor 4 Lymphotoxin Gene Expression Regulation Toll-Like Receptor 9 TLR4 Cytokines Female RNA Interference Signal transduction |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 188(7) |
| ISSN: | 1550-6606 |
| Popis: | Our previous studies indicated that lymphotoxin β receptor (LTβR) activation controls and downregulates inflammatory reactions. In this study, we report that LTβR activation on primary mouse macrophages results in induction of tripartite motif containing (TRIM) 30α, which negatively regulates NF-κB activation induced by TLR signaling. LTβR activation results in a downregulation of proinflammatory cytokine and mediator expression upon TLR restimulation, demonstrating that LTβR signaling is involved in the induction of TLR cross-tolerance. Specific knockdown experiments using TRIM30α-specific small interfering RNA abolished the LTβR-dependent induction of TRIM30α and LTβR-mediated TLR cross-tolerance. Concordantly, LTβR activation on bone marrow-derived macrophages induced cross-tolerance to TLR4 and TLR9 ligands in vitro. Furthermore, we have generated cell type-specific LTβR-deficient mice with ablation of LTβR expression on macrophages/neutrophils (LTβRflox/flox × LysM-Cre). In bone marrow-derived macrophages derived from these mice LTβR-induced cross-tolerance to TLR4 and TLR9 ligands was impaired. Additionally, mice with a conditional ablation of LTβR expression on macrophages (LTβRflox/flox × LysM-Cre) are resistant to LTβR-induced TLR4 tolerance in vivo. Collectively, our data indicate that LTβR activation on macrophages by T cell-derived lymphotoxin α1β2 controls proinflammatory responses by activation of a TRIM30α-controlled, counterregulatory signaling pathway to protect against exacerbating inflammatory reactions. |
| Databáze: | OpenAIRE |
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