Activation of p38 and Erk Mitogen-Activated Protein Kinases Signaling in Ocular Rosacea

Wladis, Edward J.; Swamy, Supraja; Herrmann, Alyssa; Yang, Jing; Carlson, John A.; Adam, Alejandro P.

doi:10.1167/iovs.16-20275

Cited by 14 publications

(6 citation statements)

References 46 publications

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“…The upregulation of these pathways could be attributed to the enhanced expression of multiple inflammatory proteins identified in this study, including IL-1b, OSM, LIF, and IL-6. Interestingly, both MAPK and TNF signaling pathways have also been associated with ocular rosacea (Wladis et al, 2019(Wladis et al, , 2017, suggesting a shared mechanism between PPR and ocular rosacea. Furthermore, the TNF signaling pathway can also be triggered by the activation of toll-like receptor 2 with Demodex mites, a known external stimulus of rosacea (Lacey et al, 2018), and toll-like receptor upregulation has been previously described for rosacea (Buhl et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

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

Harden

Shih

et al. 2021

Journal of Investigative Dermatology

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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.

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Section: Discussionmentioning

confidence: 99%

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

Harden

Shih

et al. 2021

Journal of Investigative Dermatology

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“…Wladis et al previously implicated p38 and ERK in the pathogenesis of rosacea, 9 suggesting a role for suppression of the MAPK pathway to arrest rosacea. MAPK inhibition has emerged as a meaningful treatment strategy for several diseases, including melanoma, non‐small cell lung cancer, and neurofibromatosis 33–35 .…”

Section: Discussionmentioning

confidence: 99%

“…Recent work provided new insights into the biology of the disease by identifying discrete activation of mitogen‐associated protein kinase (mitogen activated kinase pathway [MAPK]) signalling governing its cutaneous inflammation, thus raising hopes for highly targeted therapeutic interventions. Previously, Wladis et al identified increased activation of p38 and ERK in cutaneous specimens of rosacea 9 . Similarly, Harden et al demonstrated upregulation of MAPK signalling in explants of papulopustular skin specimens 10 .…”

Section: Introductionmentioning

confidence: 94%

Safety and tolerability of topical trametinib in rosacea: Results from a phase I clinical trial

Wladis,

Busingye,

Saavedra

et al. 2024

Skin Health and Disease

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PurposeOveractivation of the mitogen activated kinase pathway has been associated with rosacea. We hypothesised that inhibitors of this pathway can be repurposed to alleviate rosacea symptoms.MethodsIn order to test this hypothesis, we designed a double‐blind, randomised, placebo‐controlled phase I clinical trial to assess the safety and tolerability of a first‐in‐kind topical formulation of a MEK kinase inhibitor, trametinib. Subjects applied daily trametinib‐containing cream (0.05 mg in 0.5 mL) to one cheek and cream without inhibitor to the other for consecutive 21 days. Skin irritation scores and blood samples were obtained during visits on days 8, 15 and 22.ResultsOn analysis of high‐performance liquid chromatography, no systemic trametinib absorption was detected during this treatment period. Subjects demonstrated a slight but significant improvement in both cheeks, regardless of drug contents. No adverse effects were reported during this time.ConclusionsTopical trametinib was well tolerated at a dose of 0.05 mg per day without meaningful systemic absorption or local adverse events. A dose escalation trial is warranted to determine optimal dosing to treat rosacea while avoiding the adverse effects of systemic treatment.

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“…Pulsed dye laser, intense pulsed light and potassium titanyl phosphate have been used to treat erythema and telangiectasias, and phymatous change can be treated using carbon dioxide or erbium-doped yttrium aluminium garnet lasers. [31][32][33] Papulopustular lesions in rosacea are mainly treated with oral or topical medications such as doxycycline, minocycline, isotretinoin, azelaic acid, metronidazole, calcineurin inhibitors or ivermectin. [34,35] However, erythema tends to persist after these treatments, and often requires laser or pulsed light treatment.…”

Section: Discussionmentioning

confidence: 99%

Radiofrequency irradiation attenuates angiogenesis and inflammation in UVB‐induced rosacea in mouse skin

Son

Park²,

et al. 2020

Experimental Dermatology

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Rosacea is a skin inflammatory condition accompanied by cutaneous signs such as oedema, flushing, erythema, telangiectasia and pustules. Generally, rosacea is triggered by ultraviolet B (UVB) exposure. When exposed to UVB, skin epidermis thickens and produces elevated levels of pro‐inflammatory cytokines, especially keratinocyte‐related VEGF, a potent angiogenic factor. The upregulations of VEGF expression and its secretion promote the formation of new blood vessels and exacerbates rosacea. In this study, radiofrequency (RF) irradiation reduced keratinocyte proliferation in the epidermal layer, the expressions of pro‐inflammatory cytokines, angiogenesis‐related inflammatory factors and VEGF in our UVB‐induced model of rosacea in vitro and in vivo. RF irradiation attenuated VEGF‐induced angiogenesis‐associated processes such as tube formation, cell migration and endothelial cell proliferation. Notably, blood vessel densities in the skins of UVB‐treated mice and rosacea patients were significantly decreased by RF irradiation. These results provide experimental and molecular evidence regarding the effectiveness of RF irradiation for the treatment of rosacea.

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Activation of p38 and Erk Mitogen-Activated Protein Kinases Signaling in Ocular Rosacea

Cited by 14 publications

References 46 publications

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

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

Safety and tolerability of topical trametinib in rosacea: Results from a phase I clinical trial

Radiofrequency irradiation attenuates angiogenesis and inflammation in UVB‐induced rosacea in mouse skin

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