TLR2 and its co-receptors determine responses of macrophages and dendritic cells to lipoproteins of Mycobacterium tuberculosis

Drage, Michael G.; Pecora, Nicole; Hise, Amy G.; Febbraio, Maria; Silverstein, Roy L.; Golenbock, Douglas T.; Boom, W. Henry; Harding, Clifford V.

doi:10.1016/j.cellimm.2009.03.008

Cited by 144 publications

(124 citation statements)

References 46 publications

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“…38 We have previously shown that under hyperglycemia, TLR2/ TLR6 association results in cytokine secretion in human monocytes 26 consistent with the present data. Also, we did not observe changes in TLR1 mRNA expression and it is not known if TLR6 by itself is inflammatory.…”

Section: Discussionsupporting

confidence: 82%

TLR2 expression and signaling-dependent inflammation impair wound healing in diabetic mice

Dasu

Thangappan

Bourgette

et al. 2010

Laboratory Investigation

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Toll-like receptor-2 (TLR2) is a pivotal pathogen recognition receptor that has a key role in inflammation, diabetes, and injury. Hyperglycemia, inflammation, and oxidative stress induce TLR2-myeloid differentiation factor-88 (MyD88) expression and signaling, and are major pathophysiological mechanisms in the impaired diabetic wound-healing process. The aim of the study was to examine the contribution of TLR2-MyD88 expression and signaling to the prolonged inflammation observed in diabetic wounds. Diabetes was induced in male C57BL/6J and TLR2 À/À mice using streptozotocin (STZ) with matching nondiabetic mice as control. In addition, nonobese diabetic (NOD) mice were used to represent the spontaneous type 1 diabetes condition. After 2 weeks of persistent hyperglycemia in the mice, fullthickness excision wounds were made on the backs aseptically. Total RNA and protein were subjected to real-time PCR and western blot analyses. Wound sizes were measured using digital planimetry. TLR2 mRNA and protein expression increased significantly in wounds of C57BL/6J þ STZ and NOD mice (Po0.05) compared with nondiabetic C57BL/6J mice. MyD88 expression, interleukin receptor-associated kinase-1 phosphorylation, and nuclear factor-k B (NF-kB) activation were increased in diabetic wounds compared with nondiabetic wounds. Wounds of TLR2 À/À þ STZ mice showed less oxidative stress, decreased MyD88 signaling, NF-kB activation, and cytokine secretion. The wound closure was significant in TLR2 À/À þ STZ mice compared with C57BL/6J þ STZ mice. Collectively, our findings show that increased TLR2 mRNA and protein expression, signaling, and activation contribute to the prolonged inflammation in the diabetic wounds and that absence of TLR2 may result in decreased inflammation and improved wound healing.

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Section: Discussionsupporting

confidence: 82%

TLR2 expression and signaling-dependent inflammation impair wound healing in diabetic mice

Dasu

Thangappan

Bourgette

et al. 2010

Laboratory Investigation

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“…These effects were abrogated in the presence of PAFR antagonists or anti-CD36 blocking antibody [17]. Comparing to macrophages, DCs express less CD36 [32,33] and TLR4 in the membrane [34], thus these mechanisms above mentioned for macrophages are less significant in DCs. Additionally, it was demonstrated that PAFR activation induced CD36 expression in macrophages by mechanisms dependent on PPARγ [17].…”

Section: Discussionmentioning

confidence: 80%

Platelet-Activation Factor Receptor Induces Interleukin 10 Production through STAT3 Activation in Dendritic Cells

Koga¹,

Filgueiras²,

Jancar³

2017

J immuno Biol

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The activation of the platelet-activating factor receptor (PAFR) is associated to a suppressor phenotype in macrophages and dendritic cells (DCs). In the present study, we investigated mechanisms underlying the production of the interleukin 10 (IL-10) through PAFR activation in murine DCs. For this purpose, BALB/c mice bone marrowderived DCs were differentiated by GM-CSF treatment and stimulated with LPS in the presence of the PAFR antagonist WEB2086. Signalling pathways downstream to TLR4 activation were investigated. We found that LPS stimulus induced PAFR ligands generation by DCs, but it did not affect the PAFR expression. The LPS-induced IL-10 production was found to be partially dependent of PAFR, since it was reduced in the presence of WEB2086. The IL-10 production through PAFR activation was independent on CREB and PPARγ, as the treatment with selective inhibitors of these pathways did not affect the IL-10 production. TLR4 adaptor molecules (MyD88 and TRIF) expression, MAPK, or NF-κB (p105/50 and p65 subunits) activation pathways were also excluded, since they were not affected by the treatment with WEB2086. The blockage of PAFR by WEB2086 downregulated the STAT3 (Tyr705) phosphorylation induced by LPS. Additionally, DCs treated with STAT3 inhibitor (S3I-201) showed reduced IL-10 production to the same levels observed in DCs treated with WEB2086. The requirement of STAT3 was confirmed in PAFR-KO DCs, since the STAT3 inhibition did not affect IL-10 production by these cells. Our data show an additional molecular mechanism whereby PAFR contributes to IL-10 production in DCs and support the importance of the PAFR activation in DCs phenotype and function.

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“…However, Mtbinduced macrophage activation was not augmented by overexpression of ectopic MD-2, and cells expressing a lipopolysaccharide-unresponsive MD-2 mutant responded normally to Mtb (Means et al, 2001). Therefore, TLR4 signaling, and the accessory protein MD-2, may not play a significant role in immunity to Mtb compared with other TLR signaling pathways, such as TLR2 signaling (Jo et al, 2007;Drage et al, 2009;Velez et al, 2010). This is supported by the findings of our study, in which genetic variation in the MD-2 gene promoter region was found to be unrelated to susceptibility to TB.…”

Section: Discussionmentioning

confidence: 91%

Lack of association between MD-2 promoter gene variants and tuberculosis

Xue¹,

Zq²,

Hong³

et al. 2010

Genet. Mol. Res.

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DOI 10.4238/vol9-3gmr771 ABSTRACT. Myeloid differentiation-2 (MD-2) is an essential component of the CD14-TLR4/MD-2 receptor complex involved in microbial cell wall component recognition during infection. Genetic variations in the MD-2 gene may influence human susceptibility to infectious diseases. To date, a predisposition of MD-2 gene variants to contract tuberculosis has not been reported. We investigated whether MD-2 gene polymorphisms were associated with the development of tuberculosis in a Chinese population. The six common polymorphisms (rs11465996, rs1809442, rs1809441, rs1809440, rs16938754, and rs7842342) within the MD-2 gene promoter region were all detected in 259 patients with tuberculosis and 276 healthy control subjects by DNA sequencing. None of the allelic frequencies, haplotype patterns or genotype distributions of the assayed polymorphisms was found to be significantly different between patients and controls (P> 0.05). We conclude that these gene variants in the MD-2 gene promoter region are not associated with tuberculosis, and apparently do not play a role in susceptibility to tuberculosis in the Chinese population

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TLR2 and its co-receptors determine responses of macrophages and dendritic cells to lipoproteins of Mycobacterium tuberculosis

Cited by 144 publications

References 46 publications

TLR2 expression and signaling-dependent inflammation impair wound healing in diabetic mice

TLR2 expression and signaling-dependent inflammation impair wound healing in diabetic mice

Platelet-Activation Factor Receptor Induces Interleukin 10 Production through STAT3 Activation in Dendritic Cells

Lack of association between MD-2 promoter gene variants and tuberculosis

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