Toll-like receptors in the pathogenesis of autoimmune diseases: recent and emerging translational developments

Duffy, Laura; O’Reilly, Steven

doi:10.2147/itt.s89795

Cited by 87 publications

(43 citation statements)

References 82 publications

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“…5b , Supplementary Fig. 15 ), which is in agreement with previous reports of TLR8 involvement in these autoimmune diseases 39 . The negative control compound 6 did not show significant inhibition up to 80 μM ( Supplementary Fig.…”

Section: Resultssupporting

confidence: 92%

“…While previous evidence suggests that TLR8 plays an important role in autoimmune disorders 39 , the feasibility of targeting these diseases by suppressing TLR8 has not been firmly established. After identifying highly potent and selective TLR8 inhibitors, we aimed to validate their therapeutic potential using a more pathologically relevant system.…”

Section: Resultsmentioning

confidence: 99%

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Small-molecule inhibition of TLR8 through stabilization of its resting state

et al. 2017

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Endosomal Toll-like receptors (TLR3/7/8/9) are highly analogous sensors for various viral or bacterial RNA/DNA molecular patterns. Nonetheless, few small-molecules can selectively modulate these TLRs. In this manuscript, we identified the first human TLR8-specific small-molecule antagonists via a novel inhibition mechanism. Crystal structures of two distinct TLR8-ligand complexes validated a unique binding site on the protein-protein interface of the TLR8 homodimer. Upon binding to this new site, the small-molecule ligands stabilize the preformed TLR8 dimer in its resting state, preventing activation. As a proof of concept of their therapeutic potential, we have demonstrated that these drug-like inhibitors are able to suppress TLR8-mediated proinflammatory signaling in various cell lines, human primary cells, and patient specimens. These results not only suggest a novel strategy for TLR inhibitor design, but also shed critical mechanistic insight into these clinically important immune receptors.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Small-molecule inhibition of TLR8 through stabilization of its resting state

et al. 2017

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“…The stability of tolerogenic DCs and preservation of anti-inflammatory phenotype in inflammatory surrounding is the most important issue when creating cell-based therapies for autoimmune diseases ( 61 ). TLRs were shown to be critically involved in the recognition of damage-associated molecular patterns (DAMPs), driving the unwanted inflammatory response in autoimmune diseases ( 66 ). In addition to TLR3, which was shown to be involved in the recognition of self-RNAs released from necrotic synovial fluid cells in rheumatoid arthritis patients ( 67 ), TLR4 has been implicated in the recognition of various DAMPs in different autoimmune processes ( 68 ).…”

Section: Discussionmentioning

confidence: 99%

Trichinella spiralis Excretory–Secretory Products Induce Tolerogenic Properties in Human Dendritic Cells via Toll-Like Receptors 2 and 4

et al. 2018

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Trichinella spiralis, as well as its muscle larvae excretory–secretory products (ES L1), given either alone or via dendritic cells (DCs), induce a tolerogenic immune microenvironment in inbred rodents and successfully ameliorate experimental autoimmune encephalomyelitis. ES L1 directs the immunological balance away from T helper (Th)1, toward Th2 and regulatory responses by modulating DCs phenotype. The ultimate goal of our work is to find out if it is possible to translate knowledge obtained in animal model to humans and to generate human tolerogenic DCs suitable for therapy of autoimmune diseases through stimulation with ES L1. Here, the impact of ES L1 on the activation of human monocyte-derived DCs is explored for the first time. Under the influence of ES L1, DCs acquired tolerogenic (semi-matured) phenotype, characterized by low expression of HLA-DR, CD83, and CD86 as well as moderate expression of CD40, along with the unchanged production of interleukin (IL)-12 and elevated production of IL-10 and transforming growth factor (TGF)-β, compared to controls. The interaction with DCs involved toll-like receptors (TLR) 2 and 4, and this interaction was mainly responsible for the phenotypic and functional properties of ES L1-treated DCs. Importantly, ES L1 potentiated Th2 polarizing capacity of DCs, and impaired their allo-stimulatory and Th1/Th17 polarizing properties. Moreover, ES L1-treated DCs promoted the expansion of IL-10- and TGF-β- producing CD4+CD25hiFoxp3hi T cells in indolamine 2, 3 dioxygenase (IDO)-1-dependent manner and increased the suppressive potential of the primed T cell population. ES L1-treated DCs retained the tolerogenic properties, even after the challenge with different pro-inflammatory stimuli, including those acting via TLR3 and, especially TLR4. These results suggest that the induction of tolerogenic properties of DCs through stimulation with ES L1 could represent an innovative approach for the preparation of tolerogenic DC for treatment of inflammatory and autoimmune disorders.

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“…TLRs are evolutionary conserved receptors that, upon binding to their ligands, trigger the inflammatory response and induce several cellular changes ( 44 ). In addition to microbial antigens, TLRs can recognize endogenous molecules, contributing to the pathogenesis of many autoimmune diseases, including SSc ( 45 , 46 ). The damage-associated molecular patterns (DAMPs), released from endogenous cells upon necrosis or tissue injury, generated by stressed cells, or resulting from mechanical or biochemical fragmentation of extracellular molecules, serve as an alarm “signal” for cells via TLRs ( 47 ).…”

Section: Immune Cells and Vascular Leaking In Sscmentioning

confidence: 99%

Vascular Leaking, a Pivotal and Early Pathogenetic Event in Systemic Sclerosis: Should the Door Be Closed?

et al. 2018

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The early phase of systemic sclerosis (SSc) presents edema as one of the main features: this is clinically evident in the digital swelling (puffy fingers) as well as in the edematous skin infiltration of the early active diffuse subset. Other organs could be affected by this same disease process, such as the lung (with the appearance of ground glass opacities) and the heart (with edematous changes on cardiac magnetic resonance imaging). The genesis of tissue edema is tightly linked to pathological changes in the endothelium: various reports demonstrated the effect of transforming growth factor β, vascular endothelial growth factor and hypoxia-reperfusion damage with reactive oxygen species generation in altering vascular permeability and extravasation, in particular in SSc. This condition has an alteration in the glycocalyx thickness, reducing the protection of the vessel wall and causing non-fibrotic interstitial edema, a marker of vascular leak. Moreover, changes in the junctional adhesion molecule family and other adhesion molecules, such as ICAM and VCAM, are associated with an increased myeloid cells' extravasation in the skin and increased myofibroblasts transformation with further vascular leak and cellular migration. This mini-review examines current knowledge on determinants of vascular leak in SSc, shedding light on the role of vascular protection. This could enhance further studies in the light of drug development for early treatment, suggesting that the control of vascular leakage should be considered in the same way that vasodilation and inflammation reduction, as potential therapeutic targets.

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Toll-like receptors in the pathogenesis of autoimmune diseases: recent and emerging translational developments

Cited by 87 publications

References 82 publications

Small-molecule inhibition of TLR8 through stabilization of its resting state

Small-molecule inhibition of TLR8 through stabilization of its resting state

Trichinella spiralis Excretory–Secretory Products Induce Tolerogenic Properties in Human Dendritic Cells via Toll-Like Receptors 2 and 4

Vascular Leaking, a Pivotal and Early Pathogenetic Event in Systemic Sclerosis: Should the Door Be Closed?

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