Lymphotoxin β Receptor Activation on Macrophages Induces Cross-Tolerance to TLR4 and TLR9 Ligands

Wimmer, Nadin; Huber, Bárbara; Barabas, Nicola; Röhrl, Johann; Pfeffer, Klaus; Hehlgans, Thomas

doi:10.4049/jimmunol.1103324

Cited by 45 publications

(40 citation statements)

References 41 publications

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“…The agonist-mediated activation of LTβR signaling in macrophages has been shown previously to inhibit their capability to upregulate NO and cytokine production upon re-stimulation with lipopolysaccharide in vitro [42]. This suggests that the downregulation of iNOS, TNFα and IFNγ in MAMs in our model may occur through a direct interaction between LTβ on cancer cells and the LTβR on MAMs.…”

Section: Discussionmentioning

confidence: 61%

“…LTβ was the most suitable candidate because (i) it was the most significantly differentially expressed cytokine (~45-fold) between the brain parenchyma- and dura-derived 4T1 cancer cell variants; (ii) its role in the regulation of inflammatory microenvironments in secondary lymphoid organs is well established [39]; (iii) recent data linked LTβ to inflammation-induced carcinogenesis [41] and (iv) the agonist-induced activation of LTβR on macrophages has been previously linked to a reduction in their nitric oxide (NO) and cytokine production in vitro [42]. …”

Section: Resultsmentioning

confidence: 99%

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Metastatic site-specific polarization of macrophages in intracranial breast cancer metastases

et al. 2016

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In contrast to primary tumors, the understanding of macrophages within metastases is very limited. In order to compare macrophage phenotypes between different metastatic sites, we established a pre-clinical mouse model of intracranial breast cancer metastasis in which cancer lesions develop simultaneously within the brain parenchyma and the dura. This mimics a situation that is commonly occurring in the clinic. Flow cytometry analysis revealed significant differences in the activation state of metastasis-associated macrophages (MAMs) at the two locations. Concurrently, gene expression analysis identified significant differences in molecular profiles of cancer cells that have metastasized to the brain parenchyma as compared to the dura. This included differences in inflammation-related pathways, NF-kB1 activity and cytokine profiles. The most significantly upregulated cytokine in brain parenchyma- versus dura-derived cancer cells was Lymphotoxin β and a gain-of-function approach demonstrated a direct involvement of this factor in the M2 polarization of parenchymal MAMs. This established a link between metastatic site-specific properties of cancer cells and the MAM activation state.

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Section: Discussionmentioning

confidence: 61%

Section: Resultsmentioning

confidence: 99%

Metastatic site-specific polarization of macrophages in intracranial breast cancer metastases

et al. 2016

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“…prising, since other intestinal cells, such as mucosal macrophages, are barely responsive to TLR ligands to avoid excessive release of inflammatory mediators in response to leaking bacterial products (55).…”

Section: Discussionmentioning

confidence: 99%

TAK1 is a key modulator of the profibrogenic phenotype of human ileal myofibroblasts in Crohn's disease

Grillo

Scarpa

D’Incà

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…It has been previously reported that TLR responses can be inhibited by extracellular stimuli such as cytokines 39 or integrin ligation 40,41 . Since Cdc42 activation occurs downstream integrin, receptor tyrosine kinase or G-protein-coupled receptors signaling 42 , it could affect actin polymerization and the anchoring of CpG + -TLR9 + endosomes by IRAP.…”

Section: ! Disscussionmentioning

confidence: 99%

IRAP+ endosomes restrict TLR9 activation and signaling

et al. 2017

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Retention of intracellular Toll-Like Receptors (TLRs) in the endoplasmic reticulum prevents their activation under basal conditions. TLR9 is activated by sensing ligands in specific endosomal/lysosomal compartments. Here, we describe the identification of insulin responsive aminopeptidase (IRAP) endosomes as major cellular compartments for the early steps of TLR9 activation in dendritic cells (DCs). Both TLR9 and its ligand CpG were found as cargo in IRAP endosomes. In the absence of IRAP, CpG and TLR9 trafficking to lysosomes and TLR9 signaling were enhanced in DCs and in mice following bacterial infection. IRAP stabilized CpG-containing endosomes by interacting with the actin nucleation factor FHOD4, slowing down TLR9 trafficking towards lysosomes. Thus, endosome retention of TLR9 via IRAP interaction with the actin cytoskeleton is a mechanism that prevents TLR9hyper-activation in DCs. discriminate between different classes of microbial products and initiate specific signaling cascades. While microbial products with no equivalent in mammalian cells, such as the components of the bacterial wall, are recognized by surface TLRs (1, 2, 4, 5 and 6), pathogen derived nucleic acids are sensed by intracellular TLRs (3,7, 8 and 9). Recognition of nucleic acids by intracellular TLRs has the potential to trigger autoimmune diseases through interaction with self nucleic acids 1 . To avoid inappropriate activation of endosomal TLRs, their trafficking is tightly controlled. Thus, in basal conditions the receptors are located in the endoplasmic reticulum (ER) and translocate to endocytic vesicles only after cell stimulation by TLR ligands. Although all intracellular TLRs reside in the ER 2,3 , the trafficking pathways that move the receptors into the endocytic pathway show considerable variation among intracellular TLRs 4-6 . For example, TLR7 traffics from Golgi stacks directly to endosomes using the clathrin adaptor AP4, whereas the TLR9 is directed to the cell surface and reaches the endosomes via AP2-mediated clathrin-dependent endocytosis 6 .In addition to the transfer into the endocytic pathway, a second step that controls the activation of endosomal TLRs is their partial proteolysis by an array of different proteases, specific for each TLR 5,7-12 .Although less often mentioned, the intracellular trafficking of its ligand also controls the activation of TLR9. TLR9 ligands (CpG) are internalized via clathrin-mediated endocytosis in early endosomes and translocate to late LAMP + compartments 2 . TLR9 activation depends on CpG localization, since the abrogation of CpG translocation to LAMP + compartments by specific inhibitors decreased TLR9 signaling 13,14 . Thus, the intracellular trafficking of both, the ligand and the receptor are essential for the control of TLR9 activation. RESULTS IRAP deletion increases TLR9 responseTo address the role of IRAP in TLRs signaling, wild-type and IRAP-deficient bone marrow derived dendritic cells (BMDCs) were stimulated with specific TLR ligands: polyIC for TLR3, Imiquimod fo...

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Lymphotoxin β Receptor Activation on Macrophages Induces Cross-Tolerance to TLR4 and TLR9 Ligands

Cited by 45 publications

References 41 publications

Metastatic site-specific polarization of macrophages in intracranial breast cancer metastases

Metastatic site-specific polarization of macrophages in intracranial breast cancer metastases

TAK1 is a key modulator of the profibrogenic phenotype of human ileal myofibroblasts in Crohn's disease

IRAP+ endosomes restrict TLR9 activation and signaling

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