Integration of Canonical and Noncanonical Pathways in TLR4 Signaling: Complex Regulation of the Wound Repair Program

McKeown‐Longo, Paula J.; Higgins, Paul J.

doi:10.1089/wound.2017.0736

Cited by 28 publications

(19 citation statements)

References 76 publications

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“…Proteoenzymatic digestion of these DAMPs may release them from the ECM in soluble form, thereby making them accessible as ligands for TLRs (50). This TLR activation may then promote inflammatory cytokine secretion by numerous cell types, ultimately leading to further ECM degradation (49,(51)(52)(53). Both TLR2 and TLR4 are activated by numerous DAMPs (48).…”

Section: Discussionmentioning

confidence: 99%

“…While the reasons for this are unclear at present, it is possible that differences in the microenvironment of the SMG and the spleen may govern B cell TLR expression in these tissues. Importantly, although the regulation of TLR2 and TLR4 is complex, it is wellestablished that receptor-ligand interactions initiate downstream signaling pathways that regulate TLR expression in an autocrine manner (51,53,63). These TLRs may be up-or downregulated, depending on the specific ligand encountered (51).…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, although the regulation of TLR2 and TLR4 is complex, it is wellestablished that receptor-ligand interactions initiate downstream signaling pathways that regulate TLR expression in an autocrine manner (51,53,63). These TLRs may be up-or downregulated, depending on the specific ligand encountered (51). This elaborate regulatory network provides an elegant feedback loop that allows for the modulation of inflammation.…”

Section: Discussionmentioning

confidence: 99%

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Activation of Myd88-Dependent TLRs Mediates Local and Systemic Inflammation in a Mouse Model of Primary Sjögren's Syndrome

et al. 2020

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Toll-like receptors (TLRs) are important mediators of chronic inflammation in numerous autoimmune diseases, although the role of these receptors in primary Sjögren's syndrome (pSS) remains incompletely understood. Previous studies in our laboratory established Myd88 as a crucial mediator of pSS, although the disease-relevant ligands and the upstream signaling events that culminate in Myd88 activation have yet to be established. The objective of this study was to identify specific Myd88-dependent TLR-related pathways that are dysregulated both locally and systemically in a mouse model of pSS [NOD.B10Sn-H2 b /J (NOD.B10)]. We performed RNA-sequencing on spleens derived from NOD.B10 mice. We then harvested salivary tissue and spleens from Myd88-sufficient and deficient C57BL/10 (BL/10) and NOD.B10 mice and performed flow cytometry to determine expression of Myd88-dependent TLRs. We cultured splenocytes with TLR2 and TLR4 agonists and measured production of inflammatory mediators by ELISA. Next, we evaluated spontaneous and TLR4-mediated inflammatory cytokine secretion in NOD.B10 salivary tissue. Finally, we assessed spontaneous Myd88-dependent cytokine secretion by NOD.B10 salivary cells. We identified dysregulation of numerous TLR-related networks in pSS splenocytes, particularly those employed by TLR2 and TLR4. We found upregulation of TLRs in both the splenic and salivary tissue from pSS mice. In NOD.B10 splenic tissue, robust expression of B cell TLR1 and TLR2 required Myd88. Splenocytes from NOD.B10 mice were hyper-responsive to TLR2 ligation and the endogenous molecule decorin modulated inflammation via TLR4. Finally, we observed spontaneous secretion of numerous inflammatory cytokines and this was enhanced following TLR4 ligation in female NOD.B10 salivary tissue as compared to males. The spontaneous production of salivary IL-6, MCP-1 and TNFα required Myd88 in pSS salivary tissue. Thus, our data demonstrate that Myd88-dependent TLR pathways contribute to the inflammatory landscape in pSS, and inhibition of such will likely have therapeutic utility.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Activation of Myd88-Dependent TLRs Mediates Local and Systemic Inflammation in a Mouse Model of Primary Sjögren's Syndrome

et al. 2020

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“…However, TLR4 has also been shown to signal through noncanonical intracellular pathways, which may partially explain why the MyD88-deficient mice had a less robust delay in wound closure in comparison with the TLR4 knockout. Indeed, there is growing evidence of "noncanonical" TLR4 signaling effectors (e.g., phosphatase and tensin homolog and integrins and the epidermal growth factor receptor) as important downstream participants (44).…”

Section: Discussionmentioning

confidence: 99%

Histone Methylation Directs Myeloid TLR4 Expression and Regulates Wound Healing following Cutaneous Tissue Injury

Davis

Kimball

denDekker

et al. 2019

The Journal of Immunology

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Myeloid cells are critical for orchestrating regulated inflammation during wound healing. TLRs, particularly TLR4, and its downstream-signaling MyD88 pathway play an important role in regulating myeloid-mediated inflammation. Because an initial inflammatory phase is vital for tissue repair, we investigated the role of TLR4-regulated, myeloid-mediated inflammation in wound healing. In a cutaneous tissue injury murine model, we found that TLR4 expression is dynamic in wound myeloid cells during the course of normal wound healing. We identified that changes in myeloid TLR4 during tissue repair correlated with increased expression of the histone methyltransferase, mixed-lineage leukemia 1 (MLL1), which specifically trimethylates the histone 3 lysine 4 (H3K4me3) position of the TLR4 promoter. Furthermore, we used a myeloid-specific Mll1 knockout (Mll1 f/f Lyz2 Cre+) to determine MLL1 drives Tlr4 expression during wound healing. To understand the critical role of myeloid-specific TLR4 signaling, we used mice deficient in Tlr4 (Tlr4 2/2), Myd88 (Myd88 2/2), and myeloid-specific Tlr4 (Tlr4 f/f Lyz2 Cre+) to demonstrate delayed wound healing at early time points postinjury. Furthermore, in vivo wound myeloid cells isolated from Tlr4 2/2 and Myd88 2/2 wounds demonstrated decreased inflammatory cytokine production. Importantly, adoptive transfer of monocyte/macrophages from wildtype mice trafficked to wounds with restoration of normal healing and myeloid cell function in Tlr4-deficient mice. These results define a role for myeloid-specific, MyD88-dependent TLR4 signaling in the inflammatory response following cutaneous tissue injury and suggest that MLL1 regulates TLR4 expression in wound myeloid cells.

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“…Staphylococcus aureus [17]. Beyond this, TLR4 recognizes damage associated molecular Patterns (DAMPs) released during tissue damage abundant in cholesteatoma and plays a central role in the in ammatory phase of wound healing [18].The cause of this hyperproliferation is not fully understood, but it is known that TLR4 agonistic PAMPs [19]as well as DAMPs inside the cholesteatoma tissue will activate the expression of different cytokines and growth factors provoking this proliferation [20]. The expression of the cytokines, e.g.…”

Section: Page 3/32mentioning

confidence: 99%

Chronic inflammation of middle ear cholesteatoma promotes its recurrence via a paracrine mechanism

Schuermann

Oppel

Shao

et al. 2020

Preprint

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BackgroundCholesteatoma disease is an expanding lesion in the middle ear. Hearing loss and facial paralysis alongside with other intracranial complications are found. No pharmaceutical treatment is available today and recurrence after surgical extraction occurs. We investigated possible TLR4-based mechanisms promoting recurrence and explore possible treatments strategies.MethodsWe isolated fibroblasts and epidermal stem cells from cholesteatoma tissue and healthy auditory canal skin. Subsequently, their expression under standard culture conditions and after stimulation with LPS was investigated by RT-qPCR. Cell metabolism and proliferation were analysed upon LPS treatment, with and without TLR4 antagonist. An indirect co-culture of fibroblasts and epidermal stem cells isolated from cholesteatoma tissue was utilized to monitor epidermal differentiation upon LPS treatment by RT-qPCR and immunocytochemistry.ResultsUnder standard culture conditions, we detected a tissue-independent higher expression of IL-1β and IL-8 in stem cells, an upregulation of KGF and IGF-2 in both cell types derived from cholesteatoma and higher expression of TLR4 in stem cells derived from cholesteatoma tissue. Upon LPS challenge, we could detect a significantly higher expression of IL-1α, IL-1β, IL-6 and IL-8 in stem cells and of TNF-a, GM-CSF and CXCL-5 in stem cells and fibroblasts derived from cholesteatoma. The expression of the growth factors KGF, EGF, EREG, IGF-2 and HGF was significantly higher in fibroblasts, particularly when derived from cholesteatoma. Upon treatment with LPS the metabolism was elevated in stem cells and fibroblasts, proliferation was only enhanced in fibroblasts derived from cholesteatoma. This could be reversed by the treatment with a TLR4 antagonist. The cholesteatoma fibroblasts could be triggered by LPS to promote the epidermal differentiation of the stem cells, while no LPS treatment or LPS treatment without the presence of fibroblasts did not result in such a differentiation.ConclusionWe propose that cholesteatoma recurrence is based on TLR4 signalling imprinted in the cholesteatoma cells. It induces excessive inflammation of stem cells and fibroblasts, proliferation of perimatrix fibroblasts and the generation of epidermal cells from stem cells thru paracrine signalling by fibroblasts. Treatment of the operation site with a TLR4 antagonist might reduce the chance of cholesteatoma recurrence.

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Integration of Canonical and Noncanonical Pathways in TLR4 Signaling: Complex Regulation of the Wound Repair Program

Cited by 28 publications

References 76 publications

Activation of Myd88-Dependent TLRs Mediates Local and Systemic Inflammation in a Mouse Model of Primary Sjögren's Syndrome

Activation of Myd88-Dependent TLRs Mediates Local and Systemic Inflammation in a Mouse Model of Primary Sjögren's Syndrome

Histone Methylation Directs Myeloid TLR4 Expression and Regulates Wound Healing following Cutaneous Tissue Injury

Chronic inflammation of middle ear cholesteatoma promotes its recurrence via a paracrine mechanism

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