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

Abstract

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.

Optical Coherence Tomography Angiography Characteristics Serve as Retinal Vein Occlusion Therapeutic Biomarkers for Dexamethasone Intravitreal Implant

“…The hallmark gene sets, KEGG gene sets and GO gene sets including GO_BP, GO_CC, and GO_MF subsets were served as references. As shown in Figures 4(d) and 4(e) , GSVA revealed that, in the RVO model, the significantly upregulated pathways were related with inflammatory events, such as TNF- α -NF- κ B signaling, interleukin 6 (IL6) signaling, and mechanistic target of rapamycin kinase complex1 (mTORC1) [ 25 ] signaling, which were consistent with GSEA results.…”

mTORC1-Mediated Angiogenesis is Required for the Development of Rosacea

“…BALB/c mice (purchased from Slack Company), the previous reported TSC2 knockout (TSC2 +/− ) and wild-type (WT) mice namely TSC2 +/+ mice on C57BL/6 background (Deng et al, 2021) were housed and bred in standard specific pathogen-free laboratory conditions. DNA was extracted from mice tails for genotyping.…”

“…GenePattern 2.0 was utilized to process RNA-seq data for gene set enrichment analysis, which was run using the default settings (100 iterations, weighted). Gene enrichment was conducted on RNA-seq datasets of human skin biopsies from healthy individuals (n 10) and rosacea patients (n 10), described in our previous study (Deng et al, 2021). The gene set associated with angiogenesis signalling pathway downloaded from The Molecular Signatures Database (MSigDB) was tested.…”

“…The heterodimer consisting of tuberous sclerosis protein complex 1 (TSC1) and TSC2 is a key negative regulator of mTORC1 (Saxton and Sabatini, 2017). Our recent study has demonstrated that mTORC1 signaling played an important role in the pathogenesis of rosacea through forming a positive feedback loop between mTORC1 and cathelicidin (Deng et al, 2021). In addition, mTORC1 signaling is involved in some other skin diseases, such as atopic dermatitis (Naeem et al, 2017) and psoriasis (Buerger, 2018).…”

Analysis of Potential Hub Genes and Related Transcription Factors in Rosacea Patients using Bioinformatics Analysis

“…The mammalian target of rapamycin (mTOR) plays an irreplaceable role in regulating nutrients and energy status, cellular stressors, and cytokines [11]. It has been reported in the literature that hyperactivated mTORC1 signaling is signi cantly associated with rosacea patients by binding to Toll-like receptor 2 (TLR2) with the regulation of immune responses and in ammatory responses [12,13]. Therefore, we have reason to speculate that there should be many potential genes in the pathological process of rosacea that may play important regulatory roles.…”