IL-4 Augments IL-31/IL-31 Receptor Alpha Interaction Leading to Enhanced Ccl 17 and Ccl 22 Production in Dendritic Cells: Implications for Atopic Dermatitis

Abstract

Severe pruritus is a characteristic feature of atopic dermatitis (AD) and is closely related to its activity. Recent studies have shown that IL-31 is a key determinant of pruritus in AD. Anti-IL-31 receptor alpha (IL-31RA) antibody treatment has also been reported to improve pruritus clinically, subsequently contributing to the attenuation of AD disease activity. Therefore, IL-31 has been thought to be an important cytokine for regulating pruritus and AD disease activity; however, how IL-31 is involved in the immune response in AD has remained largely unknown. Epidermal Langerhans cells (LCs) and dermal dendritic cells (DCs) derived from bone marrow cells have been reported to play a critical role in AD pathogenesis. LCs and DCs produce Ccl 17 and Ccl 22, which chemoattract Th2 cells, leading to AD development. Therefore, we aimed to clarify how IL-31/IL-31RA interaction affects Ccl 17 and Ccl 22 production. To test this, we analyzed murine bone marrow-derived DCs (BMDCs) stimulated with IL-4, an important cytokine in AD development. We found that IL-31RA expression was upregulated by IL-4 stimulation in a dose-dependent manner in BMDCs. Furthermore, IL-31 upregulates Ccl 17 and Ccl 22 production in the presence of IL-4, whereas IL-31 stimulation alone did not produce Ccl 17 and Ccl 22. These findings suggest that IL-4 mediates IL-31RA expression and IL-31/IL-31RA interaction augments Ccl 17 and Ccl 22 production in BMDCs, which promotes Th2-deviated immune response in AD. Since we previously reported that soybean tar Glyteer, an aryl hydrocarbon receptor (AHR) ligand, impairs IL-4/Stat 6 signaling in BMDCs, we examined whether Glyteer affects IL-31RA expression induced by IL-4 stimulation. Glyteer inhibited upregulation of IL-31RA expression induced by IL-4 stimulation in a dose-dependent manner. Glyteer also inhibited Ccl 17 and Ccl 22 production induced by IL-4 and IL-31 stimulation. Taken together, these findings suggest that Glyteer treatment may improve AD disease activity by impairing IL-31/IL-31RA interaction in DCs.

<p>IL-33/13 Axis and IL-4/31 Axis Play Distinct Roles in Inflammatory Process and Itch in Psoriasis and Atopic Dermatitis</p>

“…19 The association between IL-31 and IL-4 is further confirmed by a recent study which shows that IL-31 receptor alpha (IL-31-RA) expression and its association with IL-31 in dendritic cells were enhanced in the presence of IL-4. 20 Nattkemper and co-authors investigated the transcriptome of pruritic skin from AD and Ps patients in addition to controls. Their results identified IL-31 transcript, among others, as being overexpressed in both itchy atopic and psoriatic skin.…”

Regulation of Filaggrin, Loricrin, and Involucrin by IL-4, IL-13, IL-17A, IL-22, AHR, and NRF2: Pathogenic Implications in Atopic Dermatitis

“…IL-4 also stimulates dendritic cells via STAT6 activation to produce CCL17 and CCL22, which are potent chemokines for recruiting Th2 cells [166]. In addition, IL-4 stimulates dendritic cells to upregulate the expression of receptors for IL-31, which is the major pruritogenic cytokine in AD [167]. In addition, antioxidative glyteer inhibits the IL-4/STAT6-mediated expression of CCL17 and CCL22 expression as well as upregulation of the IL-31 receptor [166,167].…”

Aryl Hydrocarbon Receptor in Atopic Dermatitis and Psoriasis

“…Soybean tar Glyteer inhibits the IL-4/IL-13-mediated STAT6 activation and subsequent production of CCL17 and CCL22 in dendritic cells [68]. In addition, pruritogenic Th2 cytokine IL-31 synergistically upregulates the IL-4/IL-13-mediated CCL17 and CCL22 production in dendritic cells because IL-4/IL-13 increase IL-31 receptor A (IL31RA) expression [105]. Glyteer again attenuates the IL-4/IL-13-mediated IL31RA upregulation and subsequent CCL17 and CCL22 production by inhibiting STAT6 activation [105].…”