title: Lymphotoxin β receptor activation on macrophages induces cross-tolerance to TLR4 and TLR9 ligands.
abstract: 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 (LTβR(flox/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 (LTβR(flox/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 α(1)β(2) controls proinflammatory responses by activation of a TRIM30α-controlled, counterregulatory signaling pathway to protect against exacerbating inflammatory reactions.
authors.affiliation: Institute of Immunology, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Nadin
authors.initials: N
authors.lastname: Wimmer
authors.forename: Barbara
authors.initials: B
authors.lastname: Huber
authors.forename: Nicola
authors.initials: N
authors.lastname: Barabas
authors.forename: Johann
authors.initials: J
authors.lastname: Röhrl
authors.forename: Klaus
authors.initials: K
authors.lastname: Pfeffer
authors.forename: Thomas
authors.initials: T
authors.lastname: Hehlgans
mesh_terms: D000818:Animals; D002460:Cell Line / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D007249:Inflammation / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008024:Ligands; D053259:Lymphotoxin beta Receptor / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000276:immunology*
chemical_list: D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; C505699:Ltbr protein, mouse; D053259:Lymphotoxin beta Receptor; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; C528084:TRIM30 alpha protein, mouse; C493487:Tlr4 protein, mouse; C495370:Tlr9 protein, mouse; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9