Thalidomide ameliorates rosacea-like skin inflammation and suppresses NF-κB activation in keratinocytes

Chen, Mengting; Xie, Hongfu; Chen, Zhaohui; Xu, San; Wang, Ben; Peng, Qinqin; Sha, Ke; Xiao, Wenqin; Liu, Tangxiele; Zhang, Yiya; Li, Ji; Deng, Zhili

doi:10.1016/j.biopha.2019.109011

Cited by 35 publications

(25 citation statements)

References 42 publications

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“…However, the role of NF‐κB signaling in the pathogenesis of rosacea is still unclear. Our previous study showed that NF‐κB signaling was activated in the LL37‐induced rosacea mouse model (Chen et al, 2019), and a recent report demonstrated that NF‐κB signaling was enhanced in eyelid specimens of rosacea patients (Wladis et al, 2019). Consistently, our RNA‐sequencing and immunochemistry data both confirmed that NF‐κB signaling was strongly upregulated in the lesional skin of rosacea patients.…”

Section: Discussionmentioning

confidence: 99%

“…Briefly, 8‐week‐old WT, Raptor cKO, and TSC2 +/− mice were shaved a day before injection and then on the back skin were intradermally injected with LL37 peptide (40 μl, 320 μM) or control vehicle twice a day for 2 days. Skin inflammation of mouse model was evaluated by the severity of erythema and edema as previously described (Chen et al, 2019). Briefly, the redness score was evaluated from 1 to 5, and 5 being the reddest.…”

Section: Methodsmentioning

confidence: 99%

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A positive feedback loop between mTORC1 and cathelicidin promotes skin inflammation in rosacea

et al. 2021

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Rosacea is a chronic inflammatory skin disorder whose pathogenesis is unclear. Here, several lines of evidence were provided to demonstrate that mTORC1 signaling is hyperactivated in the skin, especially in the epidermis, of both rosacea patients and a mouse model of rosacea‐like skin inflammation. Both mTORC1 deletion in epithelium and inhibition by its specific inhibitors can block the development of rosacea‐like skin inflammation in LL37‐induced rosacea‐like mouse model. Conversely, hyperactivation of mTORC1 signaling aggravated rosacea‐like features. Mechanistically, mTORC1 regulates cathelicidin through a positive feedback loop, in which cathelicidin LL37 activates mTORC1 signaling by binding to Toll‐like receptor 2 (TLR2) and thus in turn increases the expression of cathelicidin itself in keratinocytes. Moreover, excess cathelicidin LL37 induces both NF‐κB activation and disease‐characteristic cytokine and chemokine production possibly via mTORC1 signaling. Topical application of rapamycin improved clinical symptoms in rosacea patients, suggesting mTORC1 inhibition can serve as a novel therapeutic avenue for rosacea.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

A positive feedback loop between mTORC1 and cathelicidin promotes skin inflammation in rosacea

et al. 2021

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“…SLITs/ROBOs signaling 37 ), as well as the downregulation of proteins related to inflammatory pathways. Indeed, in addition to interleukin-1, interleukins and cytokine signaling, proteins downregulated in HaCaT cells after LAB treatments were highly associated to NF-kB, Hedgehog, and RUNX pathways whose inactivation in HaCaT keratinocytes have been related to attenuated inflammatory cytokine expression and reduced skin inflammation [38][39][40][41] . Among the downregulated proteins involved in these processes we have identified for example ILF2 and DDX3X: reduced levels of ILF2 are implicated in lower transcription of the IL2 42 and other cytokines 43 ; whilst reduced levels of DDX3X modulate the NF-κB signal pathway and attenuate the production of inflammatory cytokines 44 .…”

Section: Discussionmentioning

confidence: 99%

Exploring the wound healing, anti-inflammatory, anti-pathogenic and proteomic effects of lactic acid bacteria on keratinocytes

Brandi

Cheri

Manfredi

et al. 2020

Sci Rep

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The topical application of lactic acid bacteria (LAB) is recognized as a useful approach to improve skin health. This work aims to characterize by a multidisciplinary approach, the wound healing, anti-inflammatory, anti-pathogens and proteomic effects of six LAB lysates, belonging to the genus Lactobacillus. Our results demonstrated that the lysates of tested LAB stimulated the proliferation of keratinocytes, and that L. plantarum SGL 07 and L. salivarius SGL 19 accelerated the re-epithelization by inducing keratinocyte migration. The bacterial lysates also reduced the secretion of specific pro-inflammatory mediators from keratinocytes. Furthermore, viable L. salivarius SGL 19 and L. fermentum SGL 10 had anti-pathogenic effects against S. aureus and S. pyogenes, while L. brevis SGL 12 and L. paracasei SGL 04 inhibited S. aureus and S. pyogenes, respectively. The tested lactobacilli lysates also induced specific proteome modulation of the exposed keratinocytes, involving dysregulation of proteins (such as interleukin enhancer-binding factor 2 and ATP-dependent RNA helicase) and pathways (such as cytokine, NF-kB, Hedgehog, and RUNX signaling) associated with their specific wound healing and anti-inflammatory effects. This study indicates the different potential of selected lactobacilli, suggesting that they may be successfully used in the future together with conventional therapies to bring relief from skin disorders. Abbreviations LAB Lactic acid bacteria TNF-α Tumor necrosis factor-alpha IFN-γ Interferon-gamma PBS Phosphate buffered saline DMEM Dulbecco's modified Eagle's medium MCP-1 Monocyte chemoattractant protein-1 RANTES Regulated on activation, normal T cell expressed and secreted LC-MS/MS Liquid chromatography-tandem mass spectrometry SWATH Sequential window acquisition of all theoretical mass spectra The skin, considered the largest organ of the body, is involved in a variety of functions and acts primarily as a protective barrier preventing the entry of potential pathogens. In particular, skin homeostasis is regulated by microorganisms, the so called skin microbiota, which act on keratinocytes and on their cytokine release, ensuring

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“…Thirdly, rosacea is extremely susceptible to external stimuli and its severity can fluctuate in accordance with emotional stress; this can lead to recurrence of signs and symptoms, thus further aggravating the patient's psychological sequelae. Finally, psychological distress being involved in the pathogenesis of rosacea (20) may cause an aggravation of inflammation and neurovascular response by increasing the release of cytokines, chemokines, and neurotransmitters from cutaneous cells (31)(32)(33).…”

Section: Discussionmentioning

confidence: 99%

Prevalence and Risk Factors of Anxiety and Depression in Rosacea Patients: A Cross-Sectional Study in China

et al. 2021

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Rosacea is a chronic inflammatory skin disease characterized by facial redness and bothersome symptoms. It can exert significant psychological effects and impair the quality of life of patients. To investigate the prevalence and risk predictors of anxiety and depression in rosacea patients, we conducted a cross-sectional study in an outpatient setting. Consecutive patients completed a questionnaire, which included questions on sociodemographic information and severity of signs and symptoms; they also completed the Patient Health Questionnaire and the Generalized Anxiety Disorder scale. Disease burden was assessed using Dermatology Life Quality Index (DLQI), Willing-to-Pay, and Time trade-off. Multivariate analysis was conducted to determine the risk factors for anxiety and depression. A total of 774 patients completed the survey. The prevalence of anxiety was 53.9% (95% CI: 50.4–57.4%) and that of depression was 58.1% (95% CI: 54.7–61.6%). The factors associated with anxiety were age, gender, the need to make appearances at work, severity of self-reported symptoms, the number of rosacea signs and adaptive behaviors, and disease burden. Depression was associated with younger age, more severe self-reported symptoms, more adaptive behaviors, and higher disease burden. After adjusting for demographics, the risk of anxiety or depression increased in young patients who had severe self-reported symptoms, high DLQI scores, and many adaptive behaviors. Taken together, there is a high prevalence of anxiety and depression among Chinese rosacea patients. Younger rosacea patients who have more severe self-reported symptoms and higher disease burden are prone to anxiety and depression.

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Thalidomide ameliorates rosacea-like skin inflammation and suppresses NF-κB activation in keratinocytes

Cited by 35 publications

References 42 publications

A positive feedback loop between mTORC1 and cathelicidin promotes skin inflammation in rosacea

A positive feedback loop between mTORC1 and cathelicidin promotes skin inflammation in rosacea

Exploring the wound healing, anti-inflammatory, anti-pathogenic and proteomic effects of lactic acid bacteria on keratinocytes

Prevalence and Risk Factors of Anxiety and Depression in Rosacea Patients: A Cross-Sectional Study in China

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