Th2 Modulation of Transient Receptor Potential Channels: An Unmet Therapeutic Intervention for Atopic Dermatitis.

Jianghui Meng,Jiafu Wang,Martin Steinhoff,Michael J M Fischer,Yanqing Li,Weiwei Chen

doi:10.3389/fimmu.2021.696784

Abstract

Atopic dermatitis (AD) is a multifaceted, chronic relapsing inflammatory skin disease that affects people of all ages. It is characterized by chronic eczema, constant pruritus, and severe discomfort. AD often progresses from mild annoyance to intractable pruritic inflammatory lesions associated with exacerbated skin sensitivity. The T helper-2 (Th2) response is mainly linked to the acute and subacute phase, whereas Th1 response has been associated in addition with the chronic phase. IL-17, IL-22, TSLP, and IL-31 also play a role in AD. Transient receptor potential (TRP) cation channels play a significant role in neuroinflammation, itch and pain, indicating neuroimmune circuits in AD. However, the Th2-driven cutaneous sensitization of TRP channels is underappreciated. Emerging findings suggest that critical Th2-related cytokines cause potentiation of TRP channels, thereby exaggerating inflammation and itch sensation. Evidence involves the following: (i) IL-13 enhances TRPV1 and TRPA1 transcription levels; (ii) IL-31 sensitizes TRPV1 via transcriptional and channel modulation, and indirectly modulates TRPV3 in keratinocytes; (iii) The Th2-cytokine TSLP increases TRPA1 synthesis in sensory neurons. These changes could be further enhanced by other Th2 cytokines, including IL-4, IL-25, and IL-33, which are inducers for IL-13, IL-31, or TSLP in skin. Taken together, this review highlights that Th2 cytokines potentiate TRP channels through diverse mechanisms under different inflammatory and pruritic conditions, and link this effect to distinct signaling cascades in AD. This review strengthens the notion that interrupting Th2-driven modulation of TRP channels will inhibit transition from acute to chronic AD, thereby aiding the development of effective therapeutics and treatment optimization.

Highlights

Chronic-relapsing skin inflammation and intense itch are hallmarks in patients with atopic dermatitis (AD) [1,2,3]
Our findings have recently identified a neuro-immune modulatory cascade for amplification of TRPV3 synthesis and activity in mouse chronic itch [9]
The blockade of activation of transient receptor potential cation channel (TRPV1) by PAC-14028 is confirmed in murine Atopic dermatitis (AD) models induced by Dermatophagoides farina (Df)- and oxazolone (OXZ), whose AD-like symptoms have been improved, including serum IgE increase, mast cell degranulation, scratching behavior, and clinical severity of dermatitis [136]. Another TRPV1 antagonist, AMD9810, was found to block excitation of sensory neurons and dramatically reduce scratching bouts in a mouse acute itch model induced by subcutaneous injection of immepip into the nape of the neck, but this is not observed for TRPA1 antagonist HC030031, suggesting that TRPV1 is implicated in histamine H4 receptor-mediated itch signaling [167]

Summary

Introduction

Chronic-relapsing skin inflammation and intense itch are hallmarks in patients with atopic dermatitis (AD) [1,2,3]. In the IL-13 transgenic mouse model of AD, intensive chronic itch is associated with enhanced expression of TRPA1 in dermal sensory nerve fibers, DRG neurons, and mast cells [83].

Results

Conclusion