Wimmer, Nadin and Huber, Barbara and Barabas, Nicola and Roehrl, Johann and Pfeffer, Klaus and Hehlgans, Thomas (2012) Lymphotoxin beta Receptor Activation on Macrophages Induces Cross-Tolerance to TLR4 and TLR9 Ligands. JOURNAL OF IMMUNOLOGY, 188 (7). pp. 3426-3433. ISSN 0022-1767, 1550-6606
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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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | INDUCED INTESTINAL INFLAMMATION; NECROSIS-FACTOR-RECEPTOR; LYMPH-NODE GENESIS; MYCOBACTERIUM-TUBERCULOSIS; DENDRITIC CELLS; INNATE IMMUNITY; INDUCED COLITIS; L-MONOCYTOGENES; MICE; LIGHT; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Immunologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 15 May 2020 07:26 |
| Last Modified: | 15 May 2020 07:26 |
| URI: | https://pred.uni-regensburg.de/id/eprint/18984 |
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