Paired Transcriptomic and Proteomic Analysis Implicates IL-1β in the Pathogenesis of Papulopustular Rosacea Explants

Abstract

Papulopustular rosacea (PPR) is a chronic inflammatory skin disease with limited treatment options. Although multiple pathways have been described to be upregulated in PPR, a mechanistic understanding of the key drivers and interaction between pathways in PPR pathology is lacking. In this study, we utilized PPR skin biopsy explants to integrate both differentially expressed genes and differentially expressed proteins in paired nonlesional and lesional PPR tissue (n ¼ 5 patients). The results of this study identified 92 differentially expressed genes and 20 differentially expressed proteins between paired PPR lesional and nonlesional explants. MAPK and TNF signaling pathways were the most significantly upregulated pathways in PPR lesional tissue and aligned with differently expressed proteins identified in this study. Both MAPK and TNF signaling pathways highlighted IL-1b as a potential central mediator for PPR pathogenesis. In support of this, stimulation of nonlesional explants with IL-1b resulted in transcriptomic and proteomic profiles similar to those of lesional PPR. In this integrative transcriptomic and quantitative protein analysis, we identified several inflammatory genes, proteins, and pathways, which may be contributing to PPR, as well as highlighted a potential role of IL-1b in driving inflammation in PPR.

SnapshotDx Quiz: January 2021

“…Together, these findings suggest an important role for IL-1b in the pathogenesis of PPR. To test this hypothesis, Harden et al (2020) performed an ex vivo experiment in which they exposed nonlesional skin from individuals with PPR to exogenous IL-1b and then quantified gene and protein expression. Compared with baseline, Harden et al (2020) found that exposure to IL-1b induced similar transcriptomic and proteomic changes to what they observed in PPR tissues.…”

“…Papulopustular rosacea (PPR) is a chronic inflammatory syndrome characterized by a combination of erythema, telangiectasias, papules, and pustules; increased skin sensitivity; and thickening or phymatous changes of the skin (Gallo et al, 2018;Harden et al, 2020;Marson and Baldwin, 2020). These symptoms primarily present in a centrofacial distribution, which includes the cheeks, chin, nose, and middle forehead (Gallo et al, 2018).…”

“…Whereas rosacea has been most frequently reported in individuals with lighter skin types, it does not appear to be more common in any particular genetic ancestry group (Gallo et al, 2018;Marson and Baldwin, 2020). In addition to a genetic risk component (Chang et al, 2015), environmental triggers include UV light, intense emotions and stress, and heat or spice exposure (Harden et al, 2020;Marson and Baldwin, 2020). The immune and nervous systems and vascular and microbiome dysregulation are all thought to contribute to the pathophysiology (Harden et al, 2020;Marson and Baldwin, 2020).…”

“…In addition to a genetic risk component (Chang et al, 2015), environmental triggers include UV light, intense emotions and stress, and heat or spice exposure (Harden et al, 2020;Marson and Baldwin, 2020). The immune and nervous systems and vascular and microbiome dysregulation are all thought to contribute to the pathophysiology (Harden et al, 2020;Marson and Baldwin, 2020). In their Journal of Investigative Dermatology article, Harden et al (2020) propose a mechanism of PPR pathogenesis where IL-b stimulates MAPK and TNF pathway signaling to drive inflammation.…”

“…The immune and nervous systems and vascular and microbiome dysregulation are all thought to contribute to the pathophysiology (Harden et al, 2020;Marson and Baldwin, 2020). In their Journal of Investigative Dermatology article, Harden et al (2020) propose a mechanism of PPR pathogenesis where IL-b stimulates MAPK and TNF pathway signaling to drive inflammation. Treatment of PPR includes avoidance of environmental triggers such as UV light or spicy foods; gentle skin hygiene and photoprotection; brimonidine and oxymetazoline for persistent erythema; topical ivermectin or azelaic acid; and metronidazole or oral tetracycline antibiotics for papules and pustules (Ebbelaar et al, 2018;Elewski et al, 2003;Marson and Baldwin, 2020;Stein et al, 2014).…”