C-Jun protein linked to psoriasis

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The protein “c-Jun” in dendritic cells has an important role in the inflammation of the skin of psoriasis, according to a study recently published in EMBO Molecular Medicine.1

C-Jun and JunB play prominent roles in the skin and are part of the family of activator protein 1 (AP-1) DNA binding factors.

“Here we investigated the role of a c-Jun / AP-1 protein in skin inflammation following [toll-like receptor 7] activation using human psoriatic skin, dendritic cells and genetically engineered mouse models, ”the authors wrote.

The underlying genetic causes that predispose to the development of psoriasis and inflammation are not fully understood, study lead author Philipp Novoszel, PhD, told Dermatology Times ®.

“In our study, we show that a specific transcription factor, c-Jun, is pro-inflammatory, expressed prominently in dendritic cells of psoriatic lesions and essential for the expression of interleukin-23 (IL- 23), a key cytokine in psoriasis. pathogenesis. Therefore, our results pave the way for a new therapeutic option in psoriasis based on inhibition of the c-Jun signaling pathway, ”said Novoszel, project scientist in the European Council-funded research laboratory. research of Dr Maria Sibilia at the Cancer Institute. Research, Vienna Medical University, Austria.

The researchers identified high values ​​of c-Jun in human psoriasis skin and studied the role of c-Jun in disabling the gene in dendritic cells. According to the study, disabling C-Jun reduced epidermal thickening and immune cell infiltration.

The results of the study describe a previously unknown pro-inflammatory role of c-Jun in dermal dendritic cells, which occurs at the molecular level, through the control of IL-23.

Inhibition with a small molecule inhibitor of the JNK / c-Jun signaling axis improves skin inflammation in a mouse model of psoriasis, similar to inhibition of IL-23 with a blocking antibody, according to Novoszel.

“Such biologics are very popular in the modern treatment of psoriasis, but [are] dear, ”he wrote. “Our therapeutic option could therefore offer a cheaper alternative, but more data in humans is needed. For a dermatologist, we provide a better molecular understanding of one of the central effector molecules of psoriasis, the cytokine IL-23, its regulation by transcription factors and signaling pathways.

Certified dermatologist and rheumatologist Saakshi Khattri, MD, director of the Center for Connective Tissue Diseases at the Icahn School of Medicine in Mount Sinai, New York, New York, said the results were logical and promising.

Although not an author of the study, Khattri retained from the study that c-JUN / AP-1 could play a role in the pathogenesis of psoriasis lesions.

“We already know the role of IL-23 in psoriasis and we have therapies that block IL-23, in order to have a new path (c-Jun) with a therapeutic possibility of improving psoriasis by blocking the c-Jun pathway and therefore IL-23 seems exciting, ”she told Dermatology Times ®. “I think this is an important study for dermatologists interested in basic science or translational research because it is a new path that needs further study to see if this could translate into a new therapy for psoriasis. “

There are many treatment options for patients with psoriasis, but gaps in treatment exist, according to Khattri.

“We have many treatment options for psoriasis that target different pathways, and recent therapies, in addition to those currently under investigation, are looking at PASI 100 which is complete elimination,” Khattri said. “In terms of the gaps, the main concern that exists is the loss of efficacy – whether primary or secondary – of biologics, and then a subsequent need for change. So, it would be good to move towards precision and personalized medicine, [helping us determine] which biological product for which patient ensures elimination and prevents loss of efficacy.

Unraveling molecular and cellular processes in blood, tissue, and genetics may be one way to solve the problem of precision and personalized medicine, Khattri said.

“Another shortcoming is that when it comes to psoriatic arthritis, we all know that about 30% of psoriasis patients will suffer from psoriatic arthritis. As we look at PAS I90 AND PASI 100 in the skin, we are still at [American College of Rheumatology 20] ACR20 as the primary endpoint in psoriatic arthritis trials, ”said Khattri.

Psoriasis was originally thought to be a disease resulting from abnormalities in epidermal cells, or keratinocytes. But studies have shown that a dysfunctional interaction between immune cells and keratinocytes promotes skin inflammation characterized by epidermal thickening, scaling, etc., clinically classified as psoriasis. What’s more, mouse genetics and genome sequencing have exposed the underlying genetic complexity of psoriasis, according to Novoszel.

“We believe that psoriasis should not be viewed as a singular disease, but as a continuous spectrum of deregulated cellular conditions in the skin,” Novoszel said. “Future work, using modern molecular technologies, such as single cell sequencing, will unravel such heterogeneity in patients and allow more tailored and patient-specific therapies. “

Disclosures:

The study authors declared no conflicts. Khattri consults and receives honoraria from Eli Lilly and Company, Janssen, Novartis, Ichnos Sciences, UCB and Pfizer. She does research for Novartis and Pfizer.

Reference:

1. Novoszel P, Holcmann M, Stulnig G, et al. Inflammation of psoriatic skin is promoted by the expression of c-Jun / AP-1 dependent CCL2 and IL-23 in dendritic cells. EMBO Mol Med. 2021; 13 (4): e12409. doi: 10.15252 / emmm.202012409


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