Cathelicidin Antimicrobial Peptide LL-37 in Psoriasis Enables Keratinocyte Reactivity against TLR9 Ligands

Morizane, Shin; Yamasaki, Kenshi; Mühleisen, Beda; Kotol, Paul; Murakami, Masamoto; Aoyama, Yumi; Iwatsuki, Keiji; Hata, Tissa; Gallo, Richard L.

doi:10.1038/jid.2011.259

Cited by 175 publications

(171 citation statements)

References 22 publications

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“…The results support the involvement of innate immune response elements in the pathophysiology of psoriasis, in line with previous studies (12,17,(22)(23)(24)26,27,(32)(33)(34)(35)(36), although some previous studies have reported conflicting results regarding TLR-9 expression in psoriasis (22,34). The activation of IL-33, TLR-2 and TLR-9 in psoriatic plaques may be important since such activation has been previously associated with the activation of NF-κB (12,23,37).…”

Section: Discussionsupporting

confidence: 80%

“…TLR-2 is a type of TLR that is highly expressed in keratinocytes, and Langerhans and mast cells of psoriatic plaques (14)(15)(16) and is activated by various microorganism antigens (17)(18)(19)(20) or endogenous heat-shock proteins present at sites of tissue injury and inflammation (21). TLR-9 is another type of TLR that has been observed to be elevated in the keratinocytes of psoriatic skin lesions (22) and is activated by unmethylated DNA sequences (CpG dinucleotides) that are present in bacterial DNA and viruses (17).…”

Section: Introductionmentioning

confidence: 99%

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Effect of TNF-α inhibitors on transcriptional levels of pro-inflammatory interleukin-33 and Toll-like receptors-2 and -9 in psoriatic plaques

Vageli

Exarchou

Zafiriou

et al. 2015

Experimental and Therapeutic Medicine

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Abstract. Tumor necrosis factor (TNF)-α inhibitors are considered to be effective in the treatment of psoriatic plaques, although the precise therapeutic pathway is not clear. Pro-inflammatory molecules, such as Toll-like receptor (TLR)-2 and -9 and interleukin (IL)-33, a member of the IL-1 receptor/TLR superfamily, have been found to be expressed in psoriatic plaques. The aim of the present study was to investigate whether TNF-α inhibitor treatment has an effect on the expression of IL-33 and TLR-2 and -9 in psoriatic plaques. Seventeen patients with psoriatic plaques were treated with a TNF-α inhibitor (etanercept or infliximab) for 12 weeks in an open-label study, and the transcriptional levels of IL-33 and TLR-2 and -9 were determined by reverse transcription-quantitative polymerase chain reaction in paired biopsies of psoriatic plaques obtained at baseline (B) and following the 12 weeks of treatment (P). The psoriasis area severity index (PASI) score was also determined. At B, elevated IL-33 and TLR-2 mRNA levels were observed in all cases, while TLR-9 showed elevated mRNA levels in 76% of cases. At P, reductions in the mRNA levels of IL-33, TLR-2 and TLR-9 were observed, with TLR-2 and -9 levels exhibiting significant reductions (P<0.0001, Wilcoxon signed-rank test). PASI scores were significantly reduced by the treatment (P<0.0001, Wilcoxon signed-rank test) and the changes in PASI scores exhibited a significant positive Pearson's correlation with the P/B mRNA expression ratios of TLR-2 or -9 in males (P<0.05), particularly in the etanercept group (P<0.0001). The findings support the efficacy of anti-TNF-α treatment on the innate immune response in psoriatic skin, with a focus on TLR-2 and -9 inhibition, suggesting their role in the pathogenic mechanism of plaque psoriasis, which may be associated with gender.

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Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Effect of TNF-α inhibitors on transcriptional levels of pro-inflammatory interleukin-33 and Toll-like receptors-2 and -9 in psoriatic plaques

Vageli

Exarchou

Zafiriou

et al. 2015

Experimental and Therapeutic Medicine

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“…For example, LL37 is an endogenous antimicrobial peptide that can be overproduced and released into inflammatory sites in psoriatic skin. This antimicrobial peptide has been shown to form complexes with self-nucleic acids, thus rendering these nonstimulatory self-nucleic acids into potent immune stimuli (24)(25)(26). This finding suggests a role for selfnucleic acids in inducing psoriatic inflammation via TLR7-9 activation.…”

mentioning

confidence: 59%

“…This peptide forms complexes with self-DNA and self-RNA molecules released from dying cells and enables these self-nucleic acids to activate TLR7-9 in DCs at inflammatory sites (24)(25)(26). Therefore, we further investigated the effects of thiostrepton on the inhibition of LL37/ DNA and LL37/RNA complex-induced activation in DCs.…”

Section: Thiostrepton Inhibits Tlr7-9 Activation In Dcsmentioning

confidence: 99%

Identification of Thiostrepton as a Novel Inhibitor for Psoriasis-like Inflammation Induced by TLR7–9

Lai

Yeh

et al. 2015

The Journal of Immunology

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Activation of TLR7–9 has been linked to the pathogenesis of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and psoriasis. Thus, therapeutic applications of antagonists of these TLRs for such disorders are being investigated. Bortezomib (Velcade) is a proteasome inhibitor known to suppress activation of these TLRs. To identify novel TLR7–9 inhibitors, we searched the Gene Expression Omnibus database for gene expression profiles of bortezomib-treated cells. These profiles were then used to screen the Connectivity Map database for chemical compounds with similar functions as bortezomib. A natural antibiotic, thiostrepton, was identified for study. Similar to bortezomib, thiostrepton effectively inhibits TLR7–9 activation in cell-based assays and in dendritic cells. In contrast to bortezomib, thiostrepton does not inhibit NF-κB activation induced by TNF-α, IL-1, and other TLRs, and it is less cytotoxic to dendritic cells. Thiostrepton inhibits TLR9 localization in endosomes for activation via two mechanisms, which distinguish it from currently used TLR7–9 inhibitors. One mechanism is similar to the proteasome inhibitory function of bortezomib, whereas the other is through inhibition of endosomal acidification. Accordingly, in different animal models, thiostrepton attenuated LL37- and imiquimod-induced psoriasis-like inflammation. These results indicated that thiostrepton is a novel TLR7–9 inhibitor, and compared with bortezomib, its inhibitory effect is more specific to these TLRs, suggesting the potential therapeutic applications of thiostrepton on immunologic disorders elicited by inappropriate activation of TLR7–9.

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“…Dombrowski et al (2011) demonstrated that intracellular LL-37 serves as an anti-inflammatory agent by blocking the DNA-triggered formation of AIM2 inflammasomes in keratinocytes, inhibiting IL-1␤ release. However, several studies have shown that extracellular or endosomal LL-37 enhances TLR9 expression and function in keratinocytes, leading to increased IFN-␣/␤ production (Morizane et al, 2012). Therefore, understanding the mechanisms that suppress the inflammatory response during skin inflammation may help identify therapeutic targets for treatments that are relevant to multiple inflammatory skin diseases.…”

Section: Discussionmentioning

confidence: 99%

LL-37 attenuates inflammatory impairment via mTOR signaling-dependent mitochondrial protection

Sun

Zheng

et al. 2014

The International Journal of Biochemistry & Cell Biology

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a b s t r a c tThe human cationic antimicrobial protein LL-37 is a multifunctional host defense peptide with a wide range of immunomodulatory activities. Previous work has shown that LL-37 exerts both pro-and antiinflammatory effects. The role of mitochondria in the skin inflammatory effects of LL-37 has not been well studied. Therefore, our aim was to investigate the immunomodulatory effect of LL-37 in HaCaT cells and to delineate the underlying mechanisms related to mitochondrial function. Immunohistochemistry results from tissue microarrays showed strong cytoplasmic LL-37 staining in inflammatory cells in chronic dermatic inflammation. Using exogenous LL-37 stimulation and LL-37 knockdown and overexpression, LL-37 was demonstrated to dramatically reduce the mRNA levels and protein secretion of inflammatory cytokines including IL-6, IL-8, IL-1␣ and tumor necrosis factor-␣ (TNF-␣), which are induced by lipopolysaccharides (LPS). The anti-inflammatory effects of LL-37 are dependent upon its ability to increase mitochondrial biogenesis and to maintain mitochondrial homeostasis. Furthermore, we observed that LL-37 enhances the LPS-induced phosphorylation of extracellular signal-regulated kinase (ERK1/2) and mammalian target of rapamycin (mTOR). The mTOR inhibitor rapamycin can neutralize the protective effects of LL-37 on mitochondria. In conclusion, these results suggest that high LL-37 expression levels correlate with chronic skin inflammation; mitochondrial dysfunction occurs in HaCaT cells during inflammation; and LL-37 attenuates inflammatory impairment by stimulating mitochondrial biogenesis and protecting mitochondrial function, which are dependent upon mTOR signaling. These findings provide new insights into targeting mitochondria with LL-37 to prevent skin inflammatory reactions.

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Cathelicidin Antimicrobial Peptide LL-37 in Psoriasis Enables Keratinocyte Reactivity against TLR9 Ligands

Cited by 175 publications

References 22 publications

Effect of TNF-α inhibitors on transcriptional levels of pro-inflammatory interleukin-33 and Toll-like receptors-2 and -9 in psoriatic plaques

Effect of TNF-α inhibitors on transcriptional levels of pro-inflammatory interleukin-33 and Toll-like receptors-2 and -9 in psoriatic plaques

Identification of Thiostrepton as a Novel Inhibitor for Psoriasis-like Inflammation Induced by TLR7–9

LL-37 attenuates inflammatory impairment via mTOR signaling-dependent mitochondrial protection

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