TLR7 and TLR9 ligands regulate antigen presentation by macrophages

Celhar, Teja; Pereira-Lopes, Selma; Thornhill, Susannah I.; Lee, Hui Yin; Dhillon, Manprit Kaur; Poidinger, Michael; Connolly, John E.; Lim, Lina H.K.; Biswas, Subhra K.; Fairhurst, Anna‐Marie

doi:10.1093/intimm/dxv066

Cited by 47 publications

(38 citation statements)

References 39 publications

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“…In a recent mouse model TLR7 ligation was shown to increase clearance of apoptotic cells after stimulation of Ly6C + monocytes with a TLR7 ligand in C57BL6 mice [35]. In addition, an in vitro study indicated that TLR7 ligands shift macrophages toward an M2-like long-lived macrophage subtype cell [36]. Taken together, these studies support our finding of TLR7 expression in macrophages with clearing properties.…”

Section: Discussionsupporting

confidence: 87%

TLR7 Expression Is Associated with M2 Macrophage Subset in Calcific Aortic Valve Stenosis

Karadimou

Plunde

Pawelzik

et al. 2020

Cells

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Calcific aortic valve stenosis (CAVS) is a common age-related disease characterized by active calcification of the leaflets of the aortic valve. How innate immune cells are involved in disease pathogenesis is not clear. In this study we investigate the role of the pattern recognition receptor Toll-like receptor 7 (TLR7) in CAVS, especially in relation to macrophage subtype. Human aortic valves were used for mRNA expression analysis, immunofluorescence staining, or ex vivo tissue assays. Response to TLR7 agonist in primary macrophages and valvular interstitial cells (VICs) were investigated in vitro. In the aortic valve, TLR7 correlated with M2 macrophage markers on mRNA levels. Expression was higher in the calcified part compared with the intermediate and healthy parts. TLR7+ cells were co-stained with M2-type macrophage receptors CD163 and CD206. Ex vivo stimulation of valve tissue with the TLR7 ligand imiquimod significantly increased secretion of IL-10, TNF-α, and GM-CSF. Primary macrophages responded to imiquimod with increased secretion of IL-10 while isolated VICs did not respond. In summary, in human aortic valves TLR7 expression is associated with M2 macrophages markers. Ex vivo tissue challenge with TLR7 ligand led to secretion of immunomodulatory cytokine IL-10. These results connect TLR7 activation in CAVS to reduced inflammation and improved clearance.

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Section: Discussionsupporting

confidence: 87%

TLR7 Expression Is Associated with M2 Macrophage Subset in Calcific Aortic Valve Stenosis

Karadimou

Plunde

Pawelzik

et al. 2020

Cells

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“…Unstimulated DCs from Sle1TLR-9 À/À mouse kidneys induced more T cell proliferation than those from Sle1 controls, which was enhanced with the TLR-7 ligand R848 ( Figure 5C and Supplementary Figure 5A, available on the Arthritis & Rheumatology web site at http://onlinelibrary.wiley.com/doi/10.1002/art.40535/ abstract). Renal macrophages did not show augmented T cell proliferation with R848, consistent with earlier data from bone-marrow derived and peritoneal macrophages (40). Both renal DCs and macrophages had increased TLR-7 protein expression in the absence of TLR-9, and the levels positively correlated with the percentage of infiltrating renal DCs and macrophages ( Figures 5D and E).…”

Section: Tlr-9 Regulates Tlr-7 Protein Expression In Lupussupporting

confidence: 90%

Toll‐Like Receptor 9 Deficiency Breaks Tolerance to RNA‐Associated Antigens and Up‐Regulates Toll‐Like Receptor 7 Protein in Sle1 Mice

Celhar

Yasuga

Lee

et al. 2018

Arthritis & Rheumatology

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ObjectiveToll‐like receptors (TLRs) 7 and 9 are important innate signaling molecules with opposing roles in the development and progression of systemic lupus erythematosus (SLE). While multiple studies support the notion of a dependency on TLR‐7 for disease development, genetic ablation of TLR‐9 results in severe disease with glomerulonephritis (GN) by a largely unknown mechanism. This study was undertaken to examine the suppressive role of TLR‐9 in the development of severe lupus in a mouse model.MethodsWe crossed Sle1 lupus‐prone mice with TLR‐9–deficient mice to generate Sle1 TLR‐9−/− mice. Mice ages 4.5–6.5 months were evaluated for severe autoimmunity by assessing splenomegaly, GN, immune cell populations, autoantibody and total Ig profiles, kidney dendritic cell (DC) function, and TLR‐7 protein expression. Mice ages 8–10 weeks were used for functional B cell studies, Ig profiling, and determination of TLR‐7 expression.Results Sle1 TLR‐9−/− mice developed severe disease similar to TLR‐9–deficient MRL and Nba2 models. Sle1 TLR‐9−/− mouse B cells produced more class‐switched antibodies, and the autoantibody repertoire was skewed toward RNA‐containing antigens. GN in these mice was associated with DC infiltration, and purified Sle1 TLR‐9−/− mouse renal DCs were more efficient at TLR‐7–dependent antigen presentation and expressed higher levels of TLR‐7 protein. Importantly, this increase in TLR‐7 expression occurred prior to disease development, indicating a role in the initiation stages of tissue destruction.ConclusionThe increase in TLR‐7–reactive immune complexes, and the concomitant enhanced expression of their receptor, promotes inflammation and disease in Sle1 TLR9−/− mice.

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“…All but one of the residues under site specific selection seen in TLR7 and TLR9 were located in the ectodomain, which may suggest possible alterations in ligand recognition driven by selection pressure from Y. pestis or other shared pathogens. Stimulation of TLR7 and TLR9 have also been reported to regulate antigen presentation by MHCII in murine macrophages [62]. These data could therefore indicate a possible connection of the selection in TLR7 and TLR9 with the great gerbil duplication in MHCII .…”

Section: Discussionmentioning

confidence: 89%

The genome of the plague-resistant great gerbil reveals species-specific duplication of an MHCII gene

Nilsson

Schmid

et al. 2018

Preprint

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Background The great gerbil (Rhombomys opimus) is a social rodent living in permanent, complex burrow systems distributed throughout Central Asia, where it serves as the main host of several important vector-borne infectious diseases and is defined as a key reservoir species for plague (Yersinia pestis). Studies from the wild have shown that the great gerbil is largely resistant to plague but the genetic basis for resistance is yet to be determined. Results Here, we present a highly contiguous annotated genome assembly of great gerbil, covering over 96 % of the estimated 2.47 Gb genome. Comparative genomic analyses focusing on the immune gene repertoire, reveal shared gene losses within TLR gene families (i.e. TLR8, TLR10 and all members of TLR11-subfamily) for the Gerbillinae lineage, accompanied with signs of diversifying selection of TLR7 and TLR9. Most notably, we find a great gerbil-specific duplication of the MHCII DRB locus. In silico analyses suggest that the duplicated gene provides high peptide binding affinity for Yersiniae epitopes. Conclusion The great gerbil genome provides new insights into the genomic landscape that confers immunological resistance towards plague. The high affinity for Yersinia epitopes could be key in our understanding of the high resistance in great gerbils, putatively conferring a faster initiation of the adaptive immune response leading to survival of the infection. Our study demonstrates the power of studying zoonosis in natural hosts through the generation of a genome resource for further comparative and experimental work on plague survival and evolution of host-pathogen interactions.

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TLR7 and TLR9 ligands regulate antigen presentation by macrophages

Cited by 47 publications

References 39 publications

TLR7 Expression Is Associated with M2 Macrophage Subset in Calcific Aortic Valve Stenosis

TLR7 Expression Is Associated with M2 Macrophage Subset in Calcific Aortic Valve Stenosis

Toll‐Like Receptor 9 Deficiency Breaks Tolerance to RNA‐Associated Antigens and Up‐Regulates Toll‐Like Receptor 7 Protein in Sle1 Mice

The genome of the plague-resistant great gerbil reveals species-specific duplication of an MHCII gene

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