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

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.

Presence of TRPA1 Modifies CD4+/CD8+ T Lymphocyte Ratio and Activation

“…Our results also indicated the presence of a truncated transcript of TRPA1 in immune cells, similarly to that reported in Supplemental Data Figure S1 by Bautista et al for TRG tissue of the same strain of TRPA1 functional deficient KO mice [58]. Expression of TRPA1 mRNA and protein in immune cells was reported based on comprehensive expression profile analysis of TRP channel gene families including TRPA1 in immune organs [89], end-point RT-PCR analysis, immunostaining by Western blot and other techniques or by functionality analysis in mouse immune cells, e.g., CD4+ splenocytes [7], in Th2 type T cells [44]. However, the levels of mRNA and protein expression have not been completely clarified by comparison to that of primary sensory neurons.…”

“…Its expression and functions has been described in various non-neuronal cells [1,43] such as keratinocytes [44], vascular smooth muscle cells [45], dendritic cells [46] in the gut [7,47], skin [48,49] and lungs [50], in peripheral blood leukocytes [14], in monocytes and macrophage-derived cell lines [51,52] and in lymphocytes, including CD4+ T cells [7,53]. However, both the level of expression and the role of TRPA1 in immune cells is still not unambiguously clear, primarily because of the controversial specificity of the applied antibodies [54], and the existence and regulatory effects of mouse and human TRPA1 splice variants [55,56].…”

Host-Microbe Interaction on the Skin and Its Role in the Pathogenesis and Treatment of Atopic Dermatitis

“…Activation of these receptors leads to the activation of the immune response as well as the accumulation of pro-inflammatory cytokines, chemokines and antibacterial proteins. In the acute phase of AD, it is observed that stimulated dendritic cells activate naive T cells in the regional lymph nodes, with the consequent proliferation of Th2 lymphocytes which return to the skin to produce pro-inflammatory cytokines; interleukins (IL4, IL5, IL13), this process causes the development of inflammation [57,59].…”

Nobel somatosensations and pain

“…TRPV3, activated by warm temperatures (> 32° C), was abundantly expressed in skin keratinocytes, not in rodent but in human sensory (DRG) neurons, and accordingly, from knockout mice no alterations in thermal preference and noxious heat withdrawal were reported [79]. TRPV3 found great attention in dermatology, a human gain-of-function mutation is in part responsible for the hyperkeratotic and mutilating Olmsted syndrome; TRPV3 plays roles in the control of hair growth and lipid secretion, in atopic dermatitis and pruritus [91,107]. However, by optogenetic inhibition of keratinocytes in mice, it was recently shown that stimulated ATP release from these cells contributes to behavioural heat, cold, and mechanosensitivity through neuronal P2X4 purinoceptor channels [109,147], and TRPV3 expression is essential for the heat-induced ATP release that is able to activate nearby DRG neurons in co-culture with keratinocytes [103].…”