C-Jun Protein Linked to Psoriasis

The “c-Jun” protein in dendritic cells has an important role in psoriasis skin inflammation, 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 Activator Protein 1 (AP-1) family of 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 psoriasis development and inflammation are incompletely understood, the study’s lead author Philipp Novoszel, PhD, told Dermatology Times ®. 

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

The investigators identified elevated c-Jun values in human psoriasis skin and studied c-Jun’s role by deactivating the gene in dendritic cells. C-Jun deactivation reduced epidermal thickening and decreased immune cell infiltration, according to the study.

The study’s findings describe a previously unknown pro-inflammatory role of c-Jun in dermal dendritic cells, which occurs on a molecular level, through control of IL-23.

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

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

Board-certified dermatologist and rheumatologist Saakshi Khattri, MD, director of the Center for Connective Tissue Diseases at the Icahn School of Medicine at Mount Sinai, New York, New York, said these results make sense and hold promise.

While she is not a study author, Khattri’s take away from the study is that c-JUN/AP-1 might play a role in the pathogenesis of psoriasis lesions.

“We already know role of IL-23 in psoriasis and have therapies out there that block IL-23, so to have a novel pathway (c-Jun) with a therapeutic possibility of ameliorating psoriasis by blocking c-Jun pathway and thereby IL-23 seems exciting,” she told Dermatology Times ®. “I think this is an important study for dermatologists who are interested in basic science or translational research, as this is a new pathway that needs further study to see if this could translate into a new therapy for psoriasis.”

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

“We have many treatment options for psoriasis that target different pathways, and recent therapies in addition to ones currently being investigated are looking at PASI 100 which is complete clearance,” Khattri said. “With regard to gaps, the main concern that exists is loss of efficacy—whether primary or secondary—of biologics, and then a subsequent need to switch. So, it would be good to move towards precision and personalized medicine, [helping us determine] which biologic for which patient ensures clearance and prevents loss of efficacy.”

Unravelling the molecular and cellular processes in blood, tissue and genetics can be one way to address the issue around precision and personalized medicine, Khattri said. 

“Another gap is when it comes to psoriatic arthritis, we all know that approximately 30% of patients with psoriasis will have psoriatic arthritis. While we are looking at PAS I90 AND PASI 100 in skin, we are still at [American College of Rheumatology 20] ACR20 as our primary end point in psoriatic arthritis trials,” Khattri said. 

Psoriasis was originally considered to be a disease arising from abnormalities in epidermal cells, or keratinocytes. But studies have shown that a dysfunctional interplay between immune cells and keratinocytes promote a skin inflammation characterized by epidermal thickening, scaling, etc., clinically classified as psoriasis. Moreover, mouse genetics and genome sequencing have unveiled the complex genetic underlying of psoriasis, according to Novoszel.

“We think that psoriasis should not be viewed as a singular disease, but as a continuous spectrum of dysregulated cellular states in the skin,” Novoszel said. “Future work, employing modern molecular technologies, like single cell sequencing are going to unravel such heterogeneity in patients and allow for more tailored, patient specific therapies.”

Disclosures:

The study’s authors declared no conflicts. Khattri consults for and receives an honorarium 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. Psoriatic skin inflammation is promoted by c-Jun/AP-1-dependent CCL2 and IL-23 expression in dendritic cells. EMBO Mol Med. 2021;13(4):e12409. doi:10.15252/emmm.202012409