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SMOC1 and IL-4 and IL-13 Cytokines Interfere with Ca²⁺ Mobilization in Primary Human Keratinocytes.

ABSTRACT: Immunoregulatory effects of IL-4 and IL-13 and alterations of keratinocyte (KC) differentiation are important factors in the pathogenesis of atopic dermatitis. This study investigated the role of IL-4 and IL-13 in KC responses to changes in extracellular calcium (Ca²⁺) and analyzed differentiation signals elicited via a Ca²⁺ sensor, SMOC1. Real-time dynamics of transmembrane Ca²⁺ influx were assessed in live KCs by flow cytometry and microscopy. Exposure of KCs to a high Ca²⁺ environment (1.3 mM) triggered a rapid intracellular Ca²⁺ influx, whereas IL-4- and IL-13-treated cells exhibited a significant decrease in the peak amplitude of Ca²⁺ influx (P < 0.01). IL-17A and IL-22 did not elicit such responses. Evaluation of intracellular Ca²⁺ dynamics by microscopy confirmed these observations and revealed heterogeneity of individual KC responses. IL-4 and IL-13 significantly inhibited the expression of Ca²⁺-binding protein SMOC1 (P < 0.001). Inhibition of epidermal differentiation markers were also observed in SMOC1 small interfering RNA-transfected KCs. Concurrently, the deletion of SMOC1 increased the amplitude of Ca²⁺ peak response (P < 0.05). In conclusion, our results provide innovative data that IL-4 and IL-13 regulate KC sensitivity to microenvironmental Ca²⁺ changes and inhibit Ca²⁺-induced KC differentiation signals. SMOC1 inhibition by IL-4 and IL-13 alters Ca²⁺ transport in KCs and inhibits differentiation, suggesting a new target for treatment of atopic dermatitis.

SUBMITTER: Lyubchenko T

PROVIDER: S-EPMC9141376 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The clinical features of psoriasis, characterized by sharply demarcated scaly erythematous plaques, are typically so distinctive that a diagnosis can easily be made on these grounds alone. However, there is great variability in treatment response between individual patients, and this may reflect heterogeneity of inflammatory networks driving the disease. In this study, whole-genome transcriptional profiling was used to characterize inflammatory and cytokine networks in 62 lesional skin samples obtained from patients with stable chronic plaque psoriasis. We were able to stratify lesions according to their inflammatory gene expression signatures, identifying those associated with strong (37% of patients), moderate (39%) and weak inflammatory infiltrates (24%). Additionally, we identified differences in cytokine signatures with heightened cytokine-response patterns in one sub-group of lesions (IL-13-strong; 50%) and attenuation of these patterns in a second sub-group (IL-13-weak; 50%). These sub-groups correlated with the composition of the inflammatory infiltrate, but were only weakly associated with increased risk allele frequency at some psoriasis susceptibility loci (e.g., REL, TRAF3IP2 and NOS2). Our findings highlight variable points in the inflammatory and cytokine networks known to drive chronic plaque psoriasis. Such heterogeneous aspects may shape clinical course and treatment responses, and can provide avenues for development of personalized treatments. We used Affymetrix microarrays to evaluate genome-wide expression in primary human keratinocytes exposed to cytokines. Cytokine activity signatures were used to interpret the shifts in gene expression that occur in psoriasis plaques relative to normal uninvolved skin. Primary keratinocytes from three donors (subjects 1, 2, and 3) were obtained and were either untreated (control) or exposed to cytokines (IL-4, IL-13, IFN-alpha, IFN-gamma and TNF). For the IL17A samples, primary keratinocytes were obtained from six donors, with cells derived from three donors treated with IL-17A and cells derived from the other three donors left untreated (i.e., unpaired control samples).

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SMOC1 and IL-4 and IL-13 Cytokines Interfere with Ca²⁺ Mobilization in Primary Human Keratinocytes.

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OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

SMOC1 and IL-4 and IL-13 Cytokines Interfere with Ca2+ Mobilization in Primary Human Keratinocytes.

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OmicsDI is part of the ELIXIR infrastructure

Tweets

SMOC1 and IL-4 and IL-13 Cytokines Interfere with Ca²⁺ Mobilization in Primary Human Keratinocytes.