Transcriptional Analysis-Based Alterations Affecting Neuritogenesis of the Peripheral Nervous System in Psoriasis

An increasing amount of evidence indicates the critical role of the cutaneous nervous system in the initiation and maintenance of psoriatic skin lesions by neurogenic inflammation. However, molecular mechanisms affecting cutaneous neurons are largely uncharacterized. Therefore, we reanalyzed a psoriatic RNA sequencing dataset from published transcriptome experiments of nearly 300 individuals. Using the Ingenuity Pathway Analysis software, we associated several hundreds of differentially expressed transcripts (DETs) to nervous system development and functions. Since neuronal projections were previously reported to be affected in psoriasis, we performed an in-depth analysis of neurite formation-related process. Our in silico analysis suggests that SEMA-PLXN and ROBO-DCC-UNC5 regulating axonal growth and repulsion are differentially affected in non-lesional and lesional skin samples. We identified opposing expressional alterations in secreted ligands for axonal guidance signaling (RTN4/NOGOA, NTNs, SEMAs, SLITs) and non-conventional axon guidance regulating ligands, including WNT5A and their receptors, modulating axon formation. These differences in neuritogenesis may explain the abnormal cutaneous nerve filament formation described in psoriatic skin. The processes also influence T-cell activation and infiltration, thus highlighting an additional angle of the crosstalk between the cutaneous nervous system and the immune responses in psoriasis pathogenesis, in addition to the known neurogenic pro-inflammatory mediators.

Automated summary

An increasing amount of evidence suggests the critical role of the cutaneous nervous system in the initiation and maintenance of psoriatic skin lesions through neurogenic inflammation. This study reanalyzed a psoriatic RNA sequencing dataset to identify molecular mechanisms affecting cutaneous neurons. The analysis revealed differential expression of transcripts related to nervous system development and functions, particularly those involved in neurite formation. These findings suggest that SEMA-PLXN and ROBO-DCC-UNC5, which regulate axonal growth and repulsion, are differentially affected in non-lesional and lesional skin samples. The study also identified expressional alterations in axonal guidance signaling ligands, including WNT5A, which may explain the abnormal cutaneous nerve filament formation observed in psoriatic skin. Furthermore, these processes also influence T-cell activation and infiltration, adding to the understanding of the crosstalk between the cutaneous nervous system and immune responses in psoriasis pathogenesis, alongside known neurogenic pro-inflammatory mediators.