TRPV3 facilitates lipolysis and attenuates diet-induced obesity via activation of the NRF2/FSP1 signaling axis.

Transient receptor potential vanilloid (TRPV) ion channels play a crucial role in various cellular functions by regulating intracellular Ca2+ levels and have been extensively studied in the context of several metabolic diseases. However, the regulatory effects of TRPV3 in obesity and lipolysis are not well understood. In this study, utilizing a TRPV3 gain-of-function mouse model (TRPV3G568V/G568V), we assessed the metabolic phenotype of both TRPV3G568V/G568V mice and their control littermates, which were randomly assigned to either a 12-week high-fat diet or a control diet. We investigated the potential mechanisms underlying the role of TRPV3 in restraining obesity and promoting lipolysis both in vivo and in vitro. Our findings indicate that a high-fat diet led to significant obesity, characterized by increased epididymal and inguinal white adipose tissue weight and higher fat mass. However, the gain-of-function mutation in TRPV3 appeared to counteract these adverse effects by enhancing lipolysis in visceral fat through the upregulation of the major lipolytic enzyme, adipocyte triglyceride lipase (ATGL). In vitro experiments using carvacrol, a TRPV3 agonist, demonstrated the promotion of lipolysis and antioxidation in 3T3-L1 adipocytes after TRPV3 activation. Notably, carvacrol failed to stimulate Ca2+ influx, lipolysis, and antioxidation in 3T3-L1 adipocytes treated with BAPTA-AM, a cell-permeable calcium chelator. Our results revealed that TRPV3 activation induced the action of transcriptional factor nuclear factor erythroid 2-related factor 2 (NRF2), resulting in increased expression of ferroptosis suppressor protein 1 (FSP1) and superoxide dismutase2 (SOD2). Moreover, the inhibition of NRF2 impeded carvacrol-induced lipolysis and antioxidation in 3T3-L1 adipocytes, with downregulation of ATGL, FSP1, and SOD2. In summary, our study suggests that TRPV3 promotes visceral fat lipolysis and inhibits diet-induced obesity through the activation of the NRF2/FSP1 signaling axis. We propose that TRPV3 may be a potential therapeutic target in the treatment of obesity.

TRPV3-Activated PARP1/AIFM1/MIF Axis through Oxidative Stress Contributes to Atopic Dermatitis.

TRPV3 is a temperature-sensitive calcium-permeable channel. In previous studies, we noticed prominent TUNEL-positive keratinocytes in patients with Olmsted syndrome and Trpv3+/G568V mice, both of which carry gain-of-function variants in the TRPV3 gene. However, it remains unclear how the keratinocytes die and whether this process contributes to more skin disorders. In this study, we showed that gain-of-function variant or pharmacological activation of TRPV3 resulted in poly(ADP-ribose) polymerase 1 (PARP1)/AIFM1/macrophage migration inhibitory factor axis-mediated parthanatos, which is an underestimated form of cell death in skin diseases. Chelating calcium, scavenging ROS, or inhibiting nitric oxide synthase effectively rescued the parthanatos, indicating that TRPV3 regulates parthanatos through calcium-mediated oxidative stress. Furthermore, inhibiting PARP1 downregulated TSLP and IL33 induced by TRPV3 activation in HaCaT cells, reduced immune cell infiltration, and ameliorated epidermal thickening in Trpv3+/G568V mice. Marked parthanatos was also detected in the skin of MC903-treated mice and patients with atopic dermatitis, whereas inhibiting PARP1 largely alleviated the MC903-induced dermatitis. In addition, stimulating parthanatos in mouse skin with methylnitronitrosoguanidine recapitulated many features of atopic dermatitis. These data demonstrate that the TRPV3-regulated parthanatos-associated PARP1/AIFM1/macrophage migration inhibitory factor axis is a critical contributor to the pathogenesis of Olmsted syndrome and atopic dermatitis, suggesting that modulating the PARP1/AIFM1/macrophage migration inhibitory factor axis is a promising therapy for these conditions.

TRPV3 promotes sebocyte inflammation via transcriptional modulating TLR2 in acne.

Acne is a common chronic inflammatory disease of the pilosebaceous unit. Transient receptor potential vanilloid 3 (TRPV3) is an ion channel that is involved in inflammatory dermatosis development. However, the involvement of TRPV3 in acne-related inflammation remains unclear. Here, we used acne-like mice and human sebocytes to examine the role of TRPV3 in the development of acne. We found that TRPV3 expression increased in the skin lesions of Propionibacterium acnes (P. acnes)-injected acne-like mice and the facial sebaceous glands (SGs) of acne patients. TRPV3 promoted inflammatory cytokines and chemokines secretion in human sebocytes and led to neutrophil infiltration surrounding the SGs in acne lesions, further exacerbating sebaceous inflammation and participating in acne development. Mechanistically, TRPV3 enhanced TLR2 level by promoting transcriptional factor phosphorylated-FOS-like antigen-1 (p-FOSL1) expression and its binding to the TLR2 promoter, leading to TLR2 upregulation and downstream NF-κB signaling activation. Genetic or pharmacological inhibition of TRPV3 both alleviated acne-like skin inflammation in mice via the TLR2-NF-κB axis. Thus, our study revealed the critical role of TRPV3 in sebaceous inflammation and indicated its potential as an acne therapeutic target.

SERPINB7 Deficiency Increases Legumain Activity and Impairs the Epidermal Barrier in Nagashima-Type Palmoplantar Keratoderma.

Nagashima-type palmoplantar keratoderma is an autosomal recessive genodermatosis caused by loss-of-function variants in SERPINB7 and is the most prevalent form of inherited palmoplantar keratodermas among Asians. However, there is currently no effective therapy for Nagashima-type palmoplantar keratoderma because its pathogenesis remains unclear. In this study, Serpinb7-/- mice were generated and spontaneously developed a disrupted skin barrier, which was further exacerbated by acetone-ether-water treatment. The skin of these Serpinb7-/- mice showed weakened cytoskeletal proteins. In addition, SERPINB7 deficiency consistently led to decreased epidermal differentiation in a 3-dimensional human epidermal model. We also demonstrated that SERPINB7 was an inhibitory serpin that mainly inhibited the protease legumain. SERPINB7 bound directly with legumain and inhibited legumain activity both in vitro and in vivo. Furthermore, we found that SERPINB7 inhibited legumain in a protease-substrate manner and identified the cleavage sites of SERPINB7 as Asn71 and Asn343. Overall, we found that SERPINB7 showed the nature of a cysteine protease inhibitor and identified legumain as a key target protease of SERPINB7. Loss of SERPINB7 function led to overactivation of legumain, which might disrupt cytoskeletal proteins, contributing to the impaired skin barrier in Nagashima-type palmoplantar keratoderma. These findings may lead to the development of therapeutic strategies for Nagashima-type palmoplantar keratoderma.