Glucocorticoid insensitivity by staphylococcal enterotoxin B in keratinocytes of allergic dermatitis is associated with impaired nuclear translocation of the Glucocorticoid Receptor α

Abstract

Background: staphylococcal enterotoxin plays an important role in patients with glucocorticoid (GC)resistant atopic dermatitis (AD), but the exact mechanism is not fully understood. Objective: The aim of this study was to investigate the mechanisms underlying the ability of staphylococcal enterotoxin B (SEB) to induce steroid insensitivity through impaired nuclear translocation of GRα in keratinocytes. Methods: The steroid-resistant AD induced by SEB was assessed by analyzing dermatitis score, dermal thickness, scratching behavior, infiltrating cells/HPF, levels of SEB-specific IgE and IgG2a antibody. In addition, dexamethasone (DEX)-induced GRα nuclear translocation and keratinocyte-derived cytokines and chemokines were analyzed in the lesional keratinocytes of AD and in HaCaT cells. Furthermore, the expressions of immunophilins FKBP51, FKBP52 and HSP90 responsive to GC in HaCaT cells were determined in the presence of SEB. Results: SEB dose-dependently diminished the inhibitory effect of DEX on dermatitis score, dermal thickness, scratching behavior, infiltrating cells/HPF, keratinocyte-derived cytokines and chemokines such as RANTES, MCP-1, TSLP and GM-CSF. In vivo and in vitro data showed that in the presence of DEX, SEB dose-dependently caused a marked decrease of GRα nuclear translocation in lesional keratinocytes of AD and in HaCaT cells. Importantly, in the presence of DEX, SEB increased the expression of FKBP51 and the product of keratinocyte-derived cytokines and chemokines in HaCaT cells. Conclusion: These results demonstrate that GC insensitivity by SEB in keratinocytes of AD is associated with impaired nuclear translocation of the GRα. Increased DEX-induced FKBP51 by SEB may contribute to accumulation of the GRα in cytoplasm of keratinocytes.

Regulation of Skin Barrier Function via Competition between AHR Axis versus IL-13/IL-4‒JAK‒STAT6/STAT3 Axis: Pathogenic and Therapeutic Implications in Atopic Dermatitis

“…Colonization of Staphylococcus aureus up-regulates the expression of antimicrobial peptides such as human β-defensin 2 and -3 and RNAse7; however, IL-31 inhibits their expression and may accelerate the Staphylococcal infection [73]. Staphylococcal superantigen may also induce glucocorticoid insensitivity by inhibiting the nuclear translocation of glucocorticoid receptor α [74].…”

Molecular mechanisms of glucocorticoid resistance

“…72 A recent study in glucocorticoid-resistant patients with atopic dermatitis found that exotoxin A (SEA) from Staphylococcus aureus increased FKBP51 expression in human epidermal keratin-forming cells (HaCaT), disrupted GRα nuclear translocation and inhibited GR signal-transduction. 73 Impaired nuclear translocation in keratinocytes resulted in a lower ratio of GRα in nucleus to GRα in cytoplasm, which had also been observed in psoriasis 74 and atopic dermatitis. 75 It has been proved that high level of GRβ expression is associated with GC insensitivity.…”

“…High FKBP51 levels may contribute to retention of GRα in the cytoplasm, which lead to GC resistance in keratinocytes. 73 Some investigators reported that melatonin (MEL) can hinder the nuclear translocation of GR by inhibiting the dissociation of Hsp90 from GR. They found that in mouse thymocytes, MEL did not affect the ability of GR to bind steroids, but rather inhibited the steroid effect by inhibiting the separation of Hsp90 from GR, allowing inactivated GR to remain in the cytoplasm.…”

Exploring the Role of Staphylococcus Aureus Toxins in Atopic Dermatitis

“…Though glucocorticoids (GC) are a common therapeutic strategy in AD management, utilizing the glucocorticoid receptor (GR) to dampen the inflammatory reaction, some patients become unresponsive to treatment. Huang et al (2018) showed that SEB can block GC action by impeding the nuclear translocation of GR in keratinocytes, favoring the persistence of inflammation [58]. Also, staphylococcal enterotoxins can modulate the induction of myeloid-derived suppressor cells (MDSCs).…”