Biology subjects

Schmelz, M.

Publications and source records attributed to Schmelz, M..

3 recordsLinked to original sources

bioRxiv2026

Direct sensitizing and activating effects of interleukin 31 are restricted to a single, functionally and transcriptionally classified porcine DRG neuron subtype.

Interleukin-31 (IL-31) drives chronic pruritus in patients with dermatological and even certain systemic diseases. However, fast-onset anti-pruritic effects of blocking IL-31 receptors, for instance with nemolizumab in atopic dermatitis patients, are incompletely understood, in part due to ethical restrictions in humans and species differences to mice. Therefore, we used sensory neuron cultures from pig to investigate direct neuronal IL-31 effects. We first mapped functional characteristics of afferents encoding histamine itch in humans onto a recently established transcriptome-based DRG neuron taxonomy to identify pig pruriceptors. IL-31 acutely sensitized responses to repeated pruritogen and electrical stimulation only in these histamine- and capsaicin-responsive pruriceptors and also activated these afferents with silent nociceptor phenotype in vivo as validated by dermal axon-reflex erythema measurements. Thus, our data functionally and transcriptionally identifies the likely sensory neuron class underlying IL-31-driven chronic pruritus and opens a perspective for translational research on distinct neuronal classes differentially driving skin inflammation and clinical chronic pruritus via specific neuro-immune signaling patterns.

neuroscience↗

bioRxiv2026

Hyperglycemia transcriptionally regulates the paranodal protein (Caspr1) in retinal neurons and modulates neurite extension

Hyperglycemia is a hallmark of diabetes, affecting neuronal structure and function by altering molecular signalling pathways. Here, we explore the role of hyperglycemia in regulating Caspr1 expression and its downstream effects on neurite outgrowth. Caspr1, a critical protein implicated in neurodegenerative diseases, was found to be significantly downregulated in N2a and 661W cell lines cultured under hyperglycemic conditions (25mM glucose) and, as a result, promoted neurite outgrowth. Knockout of Caspr1 using CRISPR-Cas9 further confirmed its inhibitory role on neurite outgrowth, as Caspr1-deficient cells exhibited enhanced neurite elongation. Caspr1 downregulation was mediated by decreased expression of C/EBP, a key transcription factor with a binding site on the Caspr1 promoter. Overexpression of C/EBP restored Caspr1 promoter activity and mRNA levels, establishing C/EBP as a critical regulator. Additionally, hyperglycemia was observed to inhibit Akt phosphorylation, which further contributed to Caspr1 downregulation. Adding insulin to the culture medium under hyperglycemic conditions shows inhibition of Akt phosphorylation and downregulation of Caspr1, resulting in a shorter length of neurites in retinal neurons. In vivo, studies in diabetic mouse models and diabetic patient samples demonstrated reduced expression of Caspr1 in retinal tissues. These results suggest that hyperglycemia regulates Caspr1 expression through Akt and C/EBP pathways, promoting neurite outgrowth in retinal neurons. In contrast, adding insulin to the medium under hyperglycemia downregulates the Caspr1 expression and reduces neurite length in retinal neurons. Targeting this pathway may offer new therapeutic approaches to mitigate neurodegeneration in diabetic retinopathy.

cell biology↗

bioRxiv2024

Molecular architecture of human dermal sleeping nociceptors

Human dermal sleeping nociceptors display ongoing activity in neuropathic pain, affecting 10% of the population. Despite advances in rodents, a molecular marker for these mechano-insensitive C-fibers (CMis) in human skin remains elusive, preventing targeted therapy. In this translational Patch-seq study, we combine single-cell transcriptomics following electrophysiological characterization with single-nucleus and spatial transcriptomics from pigs and humans. We functionally identified CMis in pig sensory neurons with patch-clamp using adapted protocols from human microneurography. We identified oncostatin-M-receptor (OSMR) and somatostatin (SST) as marker genes for CMis. Following dermal injection in healthy human volunteers, oncostatin-M, the ligand of OSMR, exclusively modulates CMis. We identified the entire molecular architecture of human dermal sleeping nociceptors, providing new therapeutic targets and the basis for a mechanistic understanding of neuropathic pain. One Sentence SummaryWe identify the molecular architecture and specifically OSMR and SST as molecular markers for human dermal sleeping nociceptors, key players in the generation of neuropathic pain. Short versionIn this Patch-seq study, we identify OSMR and SST as molecular markers for human dermal sleeping nociceptors, key players in the generation of neuropathic pain.

neuroscience↗