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TLR4 and TLR9 Ligands Macrophages Induces Cross Lymphotoxin β Receptor Activation on Macrophages Induces Cross-Tolerance to TLR4 and TLR9 Ligands This information is current as Nadin Wimmer, Barbara Huber, Nicola Barabas, Johann of September 27, 2021. Röhrl, Klaus Pfeffer and Thomas Hehlgans J Immunol 2012; 188:3426-3433; Prepublished online 22 February 2012; doi: 10.4049/jimmunol.1103324 http://www.jimmunol.org/content/188/7/3426 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2012/02/23/jimmunol.110332 Material 4.DC1 http://www.jimmunol.org/ References This article cites 42 articles, 13 of which you can access for free at: http://www.jimmunol.org/content/188/7/3426.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 27, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Lymphotoxin b Receptor Activation on Macrophages Induces Cross-Tolerance to TLR4 and TLR9 Ligands Nadin Wimmer,* Barbara Huber,* Nicola Barabas,* Johann Ro¨hrl,* Klaus Pfeffer,† and Thomas Hehlgans* Our previous studies indicated that lymphotoxin b receptor (LTbR) activation controls and downregulates inflammatory reac- tions. In this study, we report that LTbR activation on primary mouse macrophages results in induction of tripartite motif containing (TRIM) 30a, which negatively regulates NF-kB activation induced by TLR signaling. LTbR activation results in a downregulation of proinflammatory cytokine and mediator expression upon TLR restimulation, demonstrating that LTbR signaling is involved in the induction of TLR cross-tolerance. Specific knockdown experiments using TRIM30a-specific small interfering RNA abolished the LTbR-dependent induction of TRIM30a and LTbR-mediated TLR cross-tolerance. Concordantly, LTbR activation on bone marrow-derived macrophages induced cross-tolerance to TLR4 and TLR9 ligands in vitro. Further- Downloaded from more, we have generated cell type-specific LTbR-deficient mice with ablation of LTbR expression on macrophages/neutrophils (LTbRflox/flox 3 LysM-Cre). In bone marrow-derived macrophages derived from these mice LTbR-induced cross-tolerance to TLR4 and TLR9 ligands was impaired. Additionally, mice with a conditional ablation of LTbR expression on macrophages (LTbRflox/flox 3 LysM-Cre) are resistant to LTbR-induced TLR4 tolerance in vivo. Collectively, our data indicate that LTbR activation on macrophages by T cell-derived lymphotoxin a1b2 controls proinflammatory responses by activation of a TRIM30a- controlled, counterregulatory signaling pathway to protect against exacerbating inflammatory reactions. The Journal of Immu- http://www.jimmunol.org/ nology, 2012, 188: 3426–3433. nflammation is a complex pathophysiological condition ini- and cells of the myeloid lineage (7, 8). So far, most studies have tially mediated primarily by innate immune cells in response focused on the critical role of LTbR signaling in the development I to infection and/or tissue damage (1, 2). Innate immune cells and maintenance of secondary lymphoid organ integrity (9–11) detect and respond to danger signals such as pathogens and/or and the control of dendritic cell-mediated immune homeostasis tissue damage by activating their TLRs on their cell surface. (12, 13). Furthermore, some reports have demonstrated a critical However, chronic and repeated stimulation through TLRs renders role for LTbR signaling for the protection against Citrobacter by guest on September 27, 2021 immune cells hyporesponsive to subsequent stimulation, a phe- rodentium-induced colitis (14, 15) and Mycobacterium tubercu- nomenon known as TLR tolerance (3). The activation of innate losis, Listeria monocytogenes (16), as well as cytomegalovirus immune cells triggers a robust but essential inflammatory re- (17) infections. Recent results have shown that ablation of LTbR sponse that needs to be tightly regulated (4, 5). Uncontrolled in- signaling using either a functional inhibitor of LTbR activation flammatory reactions lead to extensive tissue damage and the (LTbR:Ig) or LTbR-deficient mice or mice deficient for the T cell- manifestation of pathophysioplogical conditions such as chronic derived ligand LTb results in a significant aggravation of inflam- inflammation, sepsis, and autoimmune disease (6). Membrane- mation (18). Activation of the LTbR by its membrane-associated anchored lymphotoxin (LT)a1b2 and LIGHT, both members ligand LTab, but not LIGHT, seems to be crucial for the down- of the TNF superfamily, are functional ligands for the LTb re- regulation of the inflammatory response (19). However, the cel- ceptor (LTbR). Both ligands are expressed only on activated lym- lular and molecular mechanisms underlying this protective role of phocytes, NK cells, and a subset of follicular B cells, whereas LTbR activation have so far not been elucidated. the LTbR is primarily expressed on epithelial and stromal cells In this study we have identified tripartite motif containing (TRIM) 30a, a negative regulator of TLR-induced NF-kB activa- tion, as a target gene of LTbR signaling in bone marrow-derived *Institute of Immunology, University of Regensburg, 93053 Regensburg, Germany; and †Institute of Medical Microbiology and Hospital Hygiene, University of Du¨ssel- macrophages (BMDM). LTbR-induced TRIM30a expression in- dorf, 40225 Du¨sseldorf, Germany hibits the production of proinflammatory cytokines and media- Received for publication November 18, 2011. Accepted for publication January 20, tors upon TLR4 and TLR9 restimulation, demonstrating, to our 2012. knowledge, for the first time that LTbR activation induces cross- This work was supported by Deutsche Forschungsgemeinschaft Grants HE3116/5 tolerance in TLR-induced cytokine and proinflammatory medi- and HE3116/8 (to T.H.). ator production. Address correspondence and reprint requests to Prof. Thomas Hehlgans, Institute of Furthermore, we have generated cell type-specific LTbR-defi- Immunology, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Re- gensburg, Germany. E-mail address: [email protected] cient mice with ablation of LTbR expression on macrophages/ flox/flox 3 The online version of this article contains supplemental material. neutrophils (LTbR LysM-Cre). BMDM derived from these Abbreviations used in this article: BMDM, bone marrow-derived macrophage; mice are resistant to TLR4 and TLR9 tolerance in vitro. Addi- BMDN, bone marrow-derived neutrophil; ES, embryonic stem; LT, lymphotoxin; tionally, no tolerance could be induced in the model of TLR4- LTbR, lymphotoxin b receptor; RPEC, resident peritoneal exudate cell; siRNA, induced cytokine production in vivo. Collectively, our data suggest small interfering RNA; TRIM, tripartite motif containing. that cell-type specific LTbR signaling is critically involved in the Copyright Ó 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00 regulation of innate inflammatory immune reactions. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1103324 The Journal of Immunology 3427 Materials and Methods and rechallenged with 100 ng/ml LPS or 1 mM CpG (Metabion, Mar- Generation of LTbR floxed mice tinsried, Germany) for 8 h or 200 ng/ml LPS and 20 ng/ml mouse IFN-g (AbD Serotec, Kidlington, U.K.) for 24 h. TNF and IL-6 were measured in A genomic clone derived from a mouse 129Sv/J genomic library encom- the supernatants by ELISA. Nitrite accumulation in the cell culture passing the complete coding sequence for the LTbR locus has been de- supernatants was measured by using the Griess assay. scribed earlier (9). This clone was modified by introducing an FRT-flanked On days 25 and 23 mice were i.p. pretreated with PBS, LPS neomycin resistance cassette followed by a loxP signal at the 39 end into (Escherichia coli, 0127:B8; Sigma-Aldrich) (50 mg/kg or 20 mg/kg), rat the EcoRV restriction site within the 59 untranslated region of the LTbR IgG (100 mg/mouse), or agonistic anti-mLTbR mAb (100 mg/mouse). On gene. Additionally, a second loxP site had been introduced into the second day 0 the mice were challenged with LPS at a dose of 10 mg/mouse. Serum intron of the LTbR gene. was collected 1 h later and TNF was measured by ELISA. For analysis of E14.1 embryonic stem (ES) cells were transfected with linearized LTbR the TRIM30a expression in vivo, mice were killed on day 22, resident targeting vector as described (20). G418-resistant ES cell colonies were peritoneal exudate cells (RPEC) were obtained by lavage of the perito- picked. Homologous recombination was screened by PCR and subse- neum with 10 ml ice-cold RPMI 1640 containing 10% FCS. quently confirmed by genomic Southern blotting after digest of the ES cell DNA with EcoR1 and hybridization of the flanking probe, located 59 of the RNA isolation and quantitative RT-PCR targeting vector in the genomic locus. Location and orientation of both
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