The dysfunctional innate immune response triggered by Toll-like receptor activation is restored by TLR7/TLR8 and TLR9 ligands in cutaneous lichen planus

Domingues, Rosana; Carvalho, Gabriel Costa de; Oliveira, Luanda Mara da Silva; Taniguchi, E. Futata; Zimbres, J.M.; Aoki, Valéria; Duarte, Alberto José da Silva; Sato, Maria Notomi

doi:10.1111/bjd.13214

Cited by 24 publications

(30 citation statements)

References 36 publications

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“…TLR8 agonist may overcome the inhibitory function of adenosine/cAMP avoiding fully dendritic cells activation [28]. Thus, the adjuvant effect of CL097 must be further evaluated, although our previous reports also demonstrated improvement in cytokine production induced by CL097 in cutaneous diseases, such as lichen planus [29], and during HIV infection [30]. …”

Section: Discussionmentioning

confidence: 99%

Toll-like receptor agonists partially restore the production of pro-inflammatory cytokines and type I interferon in Sézary syndrome

et al. 2016

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Sézary syndrome (SS) carries a poor prognosis, and infections represent the most frequent cause of death in SS patients. Toll-like receptors (TLRs) are a family of innate immune receptors that induce protective immune responses against infections. We sought to evaluate the ability of TLR agonists to induce inflammatory cytokine, Th2 cytokine, and type I interferon (IFN-I) production by peripheral blood mononuclear cells (PBMC) of untreated SS patients. We detected impaired IL-6, IL-10 and IL-13 secretion by PBMC induced by the agonists for TLR5, TLR3, TLR7 and TLR9 in SS patients, while it was partially recovered by TLR2/TLR4 and TLR7/8 agonists TNF secretion was restored following stimulation with TLR2/TLR4 agonists. IFN-γ was scarcely produced upon TLR activation in SS cells, albeit TLR 7/8 (CL097) enhanced their secretion at lower levels than the control group. TLR9 agonist efficiently induced IFN-I in SS patients, although this positive regulation was not observed for other cytokines, in direct contrast to the broad activity of CL097. Among the TLR agonists, TLR4 was able to induce pro-inflammatory, IL-10 and Th2 secretion, while TLR7-8 agonist induced the inflammatory cytokines, IFN-I and IFN-γ. These findings reveal a dysfunctional cytokine response upon both extracellular and intracellular TLR activation in SS patients, which was partially restored by TLRs agonists.

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Section: Discussionmentioning

confidence: 99%

Toll-like receptor agonists partially restore the production of pro-inflammatory cytokines and type I interferon in Sézary syndrome

et al. 2016

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“…Because TLR agonists mimic PAMPs as viral components, the use of synthetic TLR agonists is an interesting approach because of the possible viral aetiology of LP. We previously demonstrated that a dual TLR7/TLR8 agonist is a potent adjuvant for inducing cytokines, including proinflammatory and regulatory cytokines, and for restoring type I IFN in other diseases . TLR7 and TLR8 interact with MyD88: TLR8 leads to nuclear factor‐κB activation, whereas TLR7 interacts with IL‐1 receptor‐associated kinase (IRAK)1/4, tumour necrosis factor receptor‐associated factor (TRAF)3 and TRAF6 to activate IFN regulatory factor (IRF) family members .…”

Section: Discussionmentioning

confidence: 99%

“…LP has been associated with certain viral infections, and factors such as DAMPs and PAMPs may also contribute to the inflammatory response of the disease. The involvement of PAMPs/DAMPs has been described in LP, including differential expression of Toll‐like receptor (TLR)2 and TLR4 in oral epithelial cells from oral (O)LP; defects in the TLR signalling pathways in peripheral blood mononuclear cells (PBMCs) in cutaneous LP, such as impaired interferon (IFN)‐α secretion that can be ameliorated by agonists of TLR7/TLR8 or TLR9; DAMP High mobility group box 1 protein (HMGB1)‐mediated proinflammatory conditions via the Receptor for advanced glycation end products (RAGE) and TLR4 signalling axes in OLP; and upregulation of HMGB1 and TLR4 in skin lesions of LP . Moreover, skin lesions of LP exhibit increased NLRP3 mRNA expression, upregulation of interferon‐inducible genes, and low levels of human endogenous retrovirus .…”

Section: Introductionmentioning

confidence: 99%

Lichen planus: altered AIM 2 and NLRP 1 expression in skin lesions and defective activation in peripheral blood mononuclear cells

et al. 2018

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Summary Background Lichen planus (LP) is an inflammatory skin disease with unknown aetiology. Activation by pathogen‐associated molecular patterns or environmental stimuli may activate some components of inflammasomes that contribute to the inflammatory process in LP lesions. Aim To characterize the inflammasomes in skin lesions and peripheral blood mononuclear cells (PBMCs) of patients with LP under Toll‐like receptor (TLR) activation. Methods In total, 15 patients with LP and 14 healthy controls (HCs) were enrolled in the study. Inflammasome expression in skin was evaluated by real‐time PCR and immunohistochemistry, while ELISA was used to assess the production of interleukin (IL)‐1β by PBMCs under stimulation with TLR4 and TLR7/TLR8 agonists and adenosine triphosphate (ATP). Results Compared with the levels in HC samples, increased expression of the inflammasome AIM2 was verified in both epidermal and dermal sections of LP skin lesions, whereas NLRP1 and IL‐β expression levels were enhanced in the dermis. LP skin lesion samples exhibited higher AIM2 transcript levels, similar NLRP1 levels and lower pro‐IL‐1β mRNA levels compared with HC samples. We verified that, compared with PBMCs from HC subjects, PBMCs from patients with LP produced similar amounts of IL‐1β after induction by TLR4 agonists but lower IL‐1β levels after induction by TLR7/TLR8 agonists, regardless of the addition of ATP. Conclusion Alterations in innate immunity, such as inflammasome component expression in skin lesions and PBMCs, were observed in patients with LP. Further investigations of dysfunctional inflammasome activation and the chronic inflammatory status of LP are required.

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“…One study in cutaneous LP patients evaluated the effects of different TLR agonists on peripheral blood mononuclear cells and reported an increase in TNF-a through TLRs 2, 4, 5 and decrease in TNF-a through TLRs 3 and 7. Stimulation of cells with TLRs 7/8 and 9 agonists as adjuvants increased IFN-a production [59].…”

Section: Lichen Planusmentioning

confidence: 97%

Therapeutic targeting of Toll-like receptors in cutaneous disorders

Matin

Tabatabaie

Mohammadinejad

et al. 2015

Expert Opinion on Therapeutic Targets

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Although non-specific therapeutic strategies seem to reduce the symptoms in majority of patients, a considerable proportion remain untreated or have to deal with inevitable adverse effects of such therapies. Since TLRs regulate many patholophysiological processes, they could be good candidates for more specific therapeutic approaches. TLR targeting as the first recipient of invading pathogens is a growing concept in this field.

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The dysfunctional innate immune response triggered by Toll-like receptor activation is restored by TLR7/TLR8 and TLR9 ligands in cutaneous lichen planus

Abstract: These findings point to a defect in the TLR signalling pathways in cutaneous LP. Agonists of TLR7/TLR8 or TLR9 overcame impaired IFN-α secretion in LP, strategically acting as adjuvants to improve the type I response.

Cited by 24 publications

References 36 publications

Toll-like receptor agonists partially restore the production of pro-inflammatory cytokines and type I interferon in Sézary syndrome

Toll-like receptor agonists partially restore the production of pro-inflammatory cytokines and type I interferon in Sézary syndrome

Lichen planus: altered AIM 2 and NLRP 1 expression in skin lesions and defective activation in peripheral blood mononuclear cells

Therapeutic targeting of Toll-like receptors in cutaneous disorders

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