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IL-20 promotes cutaneous inflammation and peripheral itch sensation in atopic dermatitis.

ABSTRACT: Atopic dermatitis (AD) is a chronic skin disease, which is associated with intense itch, skin barrier dysfunction and eczematous lesions. Aberrant IL-20 expression has been implicated in numerous inflammatory diseases, including psoriasis. However, the role of IL-20 in AD remains unknown. Here, RNA-seq, Q-PCR, and immunocytochemistry were utilized to examine disease-driven changes of IL-20 and its cognate receptor subunits in skin from healthy human subjects, AD patients and murine AD-models. Calcium imaging, knockdown and cytokine array were used to investigate IL-20-evoked responses in keratinocytes and sensory neurons. The murine cheek model and behavioral scoring were employed to evaluate IL-20-elicited sensations in vivo. We found that transcripts and protein of IL-20 were upregulated in skin from human AD and murine AD-like models. Topical MC903 treatment in mice ear enhanced IL-20R1 expression in the trigeminal sensory ganglia, suggesting a lesion-associated and epidermal-driven mechanism for sensitization of sensory IL-20 signaling. IL-20 triggered calcium influx in both keratinocytes and sensory neurons, and promoted their AD-related molecule release and transcription of itch-related genes. In sensory neurons, IL-20 application increased TLR2 transcripts, implicating a link between innate immune response and IL-20. In a murine cheek model of acute itch, intradermal injection IL-20 and IL-13 elicited significant itch-like behavior, though only when co-injected. Our findings provide novel insights into IL-20 function in peripheral (skin-derived) itch and clinically relevant intercellular neuron-epidermal communication, highlighting a role of IL-20 signaling in the pathophysiology of AD, thus forming a new basis for the development of a novel antipruritic strategy via interrupting IL-20 epidermal pathways.

SUBMITTER: Lu Z

PROVIDER: S-EPMC9321592 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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IL-20 promotes cutaneous inflammation and peripheral itch sensation in atopic dermatitis.

Lu Zhiping Z Xiao Song S Chen Weiwei W Zhu Renkai R Yang Hua H Steinhoff Martin M Li Yanqing Y Cheng Wenke W Yan Xinrong X Li Lianlian L Xue Shanghai S Larkin Ciara C Zhang Wenhao W Fan Qianqian Q Wang Ruizhen R Wang Jiafu J Meng Jianghui J

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20220601 6

Atopic dermatitis (AD) is a chronic skin disease, which is associated with intense itch, skin barrier dysfunction and eczematous lesions. Aberrant IL-20 expression has been implicated in numerous inflammatory diseases, including psoriasis. However, the role of IL-20 in AD remains unknown. Here, RNA-seq, Q-PCR, and immunocytochemistry were utilized to examine disease-driven changes of IL-20 and its cognate receptor subunits in skin from healthy human subjects, AD patients and murine AD-models. Ca ...[more]

PMID: 35486004

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Project description:BackgroundPatients with atopic dermatitis (AD) exhibit heterogeneous clinical phenotypes, reflecting different combinations of itch and lesional severity. AD with severe itch but clear-moderate lesions, also known as itch-dominant AD, is a common clinical phenotype.ObjectivesTo evaluate abrocitinib efficacy in patients with moderate-to-severe AD who have itch-dominant AD.MethodsThis post hoc analysis includes pooled data from clinical trials of patients with moderate-to-severe AD receiving abrocitinib (100 or 200 mg) as monotherapy (phase 2b; phase 3 JADE MONO-1 and JADE MONO-2) or in combination with topical therapy (phase 3 JADE COMPARE). Data from the ongoing long-term JADE EXTEND trial (data cutoff April 2020) were also evaluated. Itch-dominant AD was defined as baseline Peak Pruritus Numerical Rating Scale (PP-NRS) score of 7-10 and Investigator's Global Assessment of 0-3 or Eczema Area and Severity Index of 0‒21. Assessments included a ≥4-point improvement in PP-NRS (PP-NRS4), PP-NRS score of 0 (no itch) or 1 (little itch) in patients with PP-NRS score ≥2 at baseline, ≥4-point improvement from baseline in Patient-Oriented Eczema Measure (POEM-4), Patient Global Assessment (PtGA) of clear or almost clear, and Dermatology Life Quality Index (DLQI) score of 0 or 1 (no impact or little impact of AD on quality of life [QoL]).ResultsIn the pooled monotherapy trials, 37% of patients had itch-dominant AD at baseline. As early as Week 2, more patients with itch-dominant AD achieved PP-NRS4 with abrocitinib 100 mg (35%) and abrocitinib 200 mg (57%) versus placebo (7%); 6% and 22% versus 0%, respectively, achieved PP-NRS 0/1. More patients achieved a PtGA of clear/almost clear at Week 12 with abrocitinib 100 mg (28%) and abrocitinib 200 mg (45%) than placebo (9%). Additionally, abrocitinib led to clinically meaningful improvements in POEM and DLQI. Most patients with itch-dominant AD experienced itch improvement over time with abrocitinib monotherapy or with concomitant topical therapy; 86%-87% and 62%-67% of patients had no itch-moderate itch and clear-moderate lesions by weeks 24 and 48, respectively.ConclusionsAbrocitinib is highly efficacious in patients with itch-dominant AD, demonstrating rapid, deep, and sustained improvements in itch and clinically meaningful improvements in patients' QoL.Trial registration numbersNCT02780167; NCT03349060; NCT03575871; NCT03720470; NCT03422822.

Dataset Information

IL-20 promotes cutaneous inflammation and peripheral itch sensation in atopic dermatitis.

Publications

IL-20 promotes cutaneous inflammation and peripheral itch sensation in atopic dermatitis.

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