TRPV1-positive sensory nerves and neuropeptides are involved in epidermal barrier repair after tape stripping in mice.

BACKGROUND: The integumentary system of the skin serves as an exceptional protective barrier, with the stratum corneum situated at the forefront. This outermost layer is composed of keratinocytes that biosynthesize filaggrin (encoded by the gene Flg), a pivotal constituent in maintaining skin health. Nevertheless, the precise role of sensory nerves in restoration of the skin barrier after tape stripping-induced epidermal disruption, in contrast to the wound-healing process, remains a tantalizing enigma. OBJECTIVE: This study aimed to elucidate the cryptic role of sensory nerves in repair of the epidermal barrier following tape stripping-induced disruption. METHODS: Through the implementation of resiniferatoxin (RTX)-treated denervation mouse model, we investigated the kinetics of barrier repair after tape stripping and performed immunophenotyping and gene expression analysis in the skin or dorsal root ganglia (DRG) to identify potential neuropeptides. Furthermore, we assessed the functional impact of candidates on the recovery of murine keratinocytes and RTX-treated mice. RESULTS: Ablation of TRPV1-positive sensory nerve attenuated skin barrier recovery and sustained subcutaneous inflammation, coupled with elevated IL-6 level in ear homogenates after tape stripping. Expression of the keratinocyte differentiation marker Flg in the ear skin of RTX-treated mice was decreased compared with that in control mice. Through neuropeptide screening, we found that the downregulation of Flg by IL-6 was counteracted by somatostatin or octreotide (a chemically stable somatostatin analog). Furthermore, RTX-treated mice given octreotide exhibited a partial improvement in barrier recovery after tape stripping. CONCLUSION: Sensory neurons expressing TRPV1 play an indispensable role in restoring barrier function following epidermal injury. Our findings suggest the potential involvement of somatostatin in restoring epidermal repair after skin injury.

Sphingosine-1-phosphate induces Ca2+ signaling and CXCL1 release via TRPC6 channel in astrocytes.

A biologically active lipid, sphingosine-1-phosphate (S1P) is highly abundant in blood, and plays an important role in regulating the growth, survival, and migration of many cells. Binding of the endogenous ligand S1P results in activation of various signaling pathways via G protein-coupled receptors, some of which generates Ca2+ mobilization. In astrocytes, S1P is reported to evoke Ca2+ signaling, proliferation, and migration; however, the precise mechanisms underlying such responses in astrocytes remain to be elucidated. Transient receptor potential canonical (TRPC) channels are Ca2+ -permeable cation channels expressed in astrocytes and involved in Ca2+ influx after receptor stimulation. In this study, we investigated the involvement of TRPC channels in S1P-induced cellular responses. In Ca2+ imaging experiments, S1P at 1 µM elicited a transient increase in intracellular Ca2+ in astrocytes, followed by sustained elevation. The sustained Ca2+ response was markedly suppressed by S1P2 receptor antagonist JTE013, S1P3 receptor antagonist CAY10444, or non-selective TRPC channel inhibitor Pyr2. Additionally, S1P increased chemokine CXCL1 mRNA expression and release, which were suppressed by TRPC inhibitor, inhibition of Ca2+ mobilization, MAPK pathway inhibitors, or knockdown of the TRPC channel isoform TRPC6. Taken together, these results demonstrate that S1P induces Ca2+ signaling in astrocytes via Gq -coupled receptors S1P2 and S1P3 , followed by Ca2+ influx through TRPC6 that could activate MAPK signaling, which leads to increased secretion of the proinflammatory or neuroprotective chemokine CXCL1.