Molecular pathways of JAK in the pathogenesis of inflammation in acne

• Alexander G. Rumyantsev
• Olga M. Demina

Abstract

Introduction. Acne is a multifactorial disease, in the pathogenesis of which the leading role belongs to the inflammatory reaction, which develops at all stages of the disease, sometimes even subclinically. It has been established that Cutibacterium acne (C. acne) activates the innate immune system component TLR2 both in the early and late stages of the course of acne. TLR induction causes the expression of immune response genes that encode cytokines and chemokines that induce chemotaxis of cells of the immune system. It has been shown that among the non-receptor tyrosine kinases, Janus kinases (JAKs) have been described, which provide phosphorylation of transcription factors - STAT (signal transducer and activator of transcription) of the JAK-STAT signaling pathway. It has been established that the chains of type I and II cytokine receptors are interconnected with the signaling pathway JAK-STAT, which regulates the action of more than 50 cytokines, interferons (IFN), and growth factors.

The aim of this study was to determine and analyze the difference in the frequencies of SNP polymorphisms of the JAK genes family (JAK1, JAK2, JAK3, and TYK2) in Russian patients with severe acne.

Material and methods. We observed 70 patients (42 men and 28 women) aged 15 to 46 years (median - 22.1 years). The main group included 50 patients (29 men and 21 women) with severe acne. The group of comparison consisted of 20 conditionally healthy individuals (13 men and 7 women). Molecular genetic diagnostics was carried out in all study participants by the high-throughput DNA sequencing - next-generation sequencing (NGS).

Results. Analysis of the genetic defects identified in our study showed that severe acne is associated with 16 polymorphic loci of the JAK1 gene (5 SNPs in exons, 11 SNPs in introns), 22 SNPs in the JAK2 gene (3 SNPs in exons, 16 SNPs in introns, 1 SNP in 3'UTR and 2 SNPs in 5'UTR), 19 SNPs of the JAK3 gene (4 SNPs in exons, 12 SNPs in introns, 2 SNPs in the 3'UTR and 1 SNP in the 5'UTR), and 26 SNPs in the TYK2 gene (7 SNPs in exons, 17 SNPs in introns, 1 SNP in the 5'UTR region, and 1 SNP in upstream).

Conclusion. The obtained results indicate the probable activation of the JAK genes family (JAK1, JAK2, JAK3, and TYK2), which causes excessive activity of cytotoxic cells, stimulates apoptosis and increased secretion of interferons, which inhibit the differentiation and activity of all immune effectors. This, apparently, leads to a slowdown in the activity of the immune response and to a prolonged course of acne.

Keywords:acne; JAK; JAK-STAT signaling pathways; genes; inflammation

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