Study of IL-17A Treatment Underscores Potential of circRNA as Biomarker in Psoriasis

Circular RNA may have potential as a biomarker in psoriasis, suggest new study findings.

The study, which assessed changes in circRNA and miRNA after beginning interleukin-17A (IL-17) treatment, revealed a prompt change in circRNA abundance upon initiation of treatment and a strong correlation between circRNA and the psoriasis area and severity index (PASI).

“Psoriasis is a multifaceted, chronic inflammatory skin disorder characterized by a complex pathogenesis, in which ncRNA classes, such as long ncRNAs and especially miRNAs, have been established to be deregulated and to play essential roles. In addition, we have previously shown that global circRNA abundance is decreased in lesional relative to non-lesional skin of psoriatic patients," the authors wrote. "However, no knowledge exists about miRNAs and circRNA expression dynamics upon anti-IL-17A treatment.”

Over 84 days of treatment, secukinumab resulted in progressive normalization of circDNAs that were originally deregulated at baseline. Notably, within 4 days of treatment—predating clinical and histological improvements—most circRNAs were significantly upregulated, with lesional and nonlesional samples showing similar expression profiles. Prior to treatment, the samples of nonlesional and lesional skin samples were significantly different.

These changes in circRNA throughout treatment were shown to be either negatively or positively correlated with the PASI, which was dependent on whether the circRNAs were down or upregulated in lesional relative to nonlesional samples prior to treatment. Various circRNAs, including ciRS-7 and circPTPRA—2 of the most deregulated circRNAs in psoriatic skin—were strongly correlated with the PASI. While less pronounced, there was also a positive correastion between significantly upregulated circRNAs before treatment and changes in PASI.

In contrast to circRNA, the researchers observed that the normalization of miRNAs from baseline through treatment was delayed and occurred in a small subset of miRNAs.

“A potential explanation for these discrepancies could be that a circRNA-specific regulation through biogenesis and/or decay occurs, or that an active regulation of miRNA and mRNA transcripts arises,” wrote the researchers.“On one hand, previous publications demonstrated that global circRNA levels can be influenced by viral infection triggering RNAse L-mediated degradation or upon modulation of circRNA biogenesis through RBP interaction. Although we observed no changes in the transcript levels of five mRNAs coding for circRNA biogenesis regulators, additional endonucleases or RBPs could have an impact on global expression levels.”

The researchers also analyzed circRNA changes in peripheral blood mononuclear cells (PBMCs), finding no significant changes after treatment with secukinumab, which suggests IL-17A treatment does not affect circRNA expression in these cells. RNA was extracted from the same patient cohort, showing no clear clustering of samples based on duration of treatment nor any differentially expressed circRNAs at any check point relative to pretreatment. Neither ciRS-7 nor circPTPRA had no significant differences in absolute counts from the start of treatment through follow up.

Reference

Seeler S, Moldovan L, Bertelsen T, et al. Global circRNA expression changes predate clinical and histological improvements of psoriasis patients upon secukinumab treatment. PLoS One. 2022;17(9):e0275219