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The dysfunctional innate immune response triggered by Toll‐like receptor activation is restored by TLR 7/ TLR 8 and TLR 9 ligands in cutaneous lichen planus
Author(s) -
Domingues R.,
Carvalho G. Costa,
Silva Oliveira L.M.,
Futata Taniguchi E.,
Zimbres J.M.,
Aoki V.,
Silva Duarte A.J.,
Sato M.N.
Publication year - 2015
Publication title -
british journal of dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.304
H-Index - 179
eISSN - 1365-2133
pISSN - 0007-0963
DOI - 10.1111/bjd.13214
Subject(s) - tlr2 , tlr7 , proinflammatory cytokine , tlr9 , tlr5 , immunology , toll like receptor , innate immune system , tlr4 , tlr3 , chemokine , cytokine , biology , immune system , inflammation , biochemistry , gene expression , dna methylation , gene
Summary Background Lichen planus ( LP ) is a chronic inflammatory mucocutaneous disease. Toll‐like receptors ( TLR s) bind numerous exogenous and endogenous antigens by recognizing conserved pathogen‐associated molecular patterns ( PAMP s) and have the ability to induce the production of proinflammatory cytokines. Therefore, alterations in innate immunity could explain the inflammation and T‐cell autoreactivity leading to the development of LP disease. Objectives To evaluate how the host innate immune response to PAMP s is affected by cutaneous LP , primarily by using TLR agonists to induce proinflammatory cytokine secretion from peripheral blood mononuclear cells ( PBMC s). Methods PBMC s from patients with LP and healthy control ( HC ) individuals were stimulated with agonists of TLR 2/ TLR 1 (pam3csk4), TLR 3 [poly(I:C)‐ RIG ], TLR 4 (lipopolysaccharide), TLR 5 (flagellin), TLR 7 (imiquimod), TLR 7/ TLR 8 ( CL 097) and TLR 9 (CpG). Cytokines from culture supernatants ( n = 10–12) and serum chemokines and cytokines ( n = 22–24) were measured using flow cytometry. Results Activation through the TLR 2, TLR 4 and TLR 5 pathways induced increased tumour necrosis factor ( TNF )‐α secretion by PBMC s from individuals with LP compared with the HC group. In contrast, activation through TLR 3 and TLR 7 was impaired in the LP group, leading to decreased TNF ‐α secretion. Moreover, intracellular TLR activation resulted in reduced interleukin ( IL )‐1β and IL ‐6 secretion. Notably, individuals with LP became responders on stimulation with TLR 7/ TLR 8 and TLR 9 agonists; responses were measured as increases in interferon ( IFN )‐α production. Detectable TNF ‐α and high CXCL 9 and CXCL 10 serum levels were observed in patients with LP , suggesting their potential use as markers of the inflammatory status in LP . Conclusions These findings point to a defect in the TLR signalling pathways in cutaneous LP . Agonists of TLR 7/ TLR 8 or TLR 9 overcame impaired IFN ‐α secretion in LP , strategically acting as adjuvants to improve the type I response.