What Do We Know?

What we know: Cytokine signaling is a driver for pathogenic skin inflammation seen in psoriasis. This revelation has led to biologic treatment discovery and hope for people living with psoriasis. Furthermore, it has also led to the identification of skin-resident T cell populations that support recurrent disease.

What we do not know: The ‘how’ and ‘why’ of pathogenic pathways, including why these pathways are restrained between flares, or how the initial inflammatory activation is amplified in immune cells to such a level that skin lesions develop.

Working across the globe, Jeffrey Cheng, M.D., Ph.D., and Raymond Cho, M.D., Ph.D., both associate professors of dermatology at the University of California, San Francisco, along with a larger group of researchers, began to ask why those mechanisms failed to restrain the inflammation observed in conditions and diseases such as psoriasis. Using data from single-cell sequencing, they identified the ZIST program. Dr. Cho explains that ZIST is “a set of inflammation-suppressive genes that are turned off in the T cells that most robustly drive psoriasis.” More specifically, this research has identified “many inflammation-suppressing genes that we noted earlier as downregulated in psoriatic T cells were found in this set, including ZFP36, SOCS1, SOCS3, CCL22, and CD69, as well as the global quiescence enforcers BTG139 and TXNIP40. We thus termed these genes, which appear coherently suppressed in the highest cytokine-expressing single Th17/Tc17 cells, the ZFP36L2 inflammation-suppressive transcriptional program, or ZIST.”

It is well understood that Th17/Tc17 cytokines play a central role in psoriasis development. Dr. Cho shares that “these regulators appear to normally suppress Th17/Tc17 transcript levels and translation to protein, making their absence a key pro-inflammatory state.”

According to this research recently published in Cell Reports Medicine, “Our findings reveal that ZIST inflammation-suppressive transcripts exist in a single-cell continuum. This gradient is then coordinately shifted downward in psoriatic lesions, relieving suppression of inflammation, and driving cytokine expression in the most ZIST-depressed subpopulation. In fact, we find that IL17F and IL26 expression emerges only in those psoriatic T cells whose ZIST expression is depressed below the range observed in normal control samples, underscoring the tight link between this gradient and pathogenic inflammation.” [1]

“While there is no question the Th17/Tc17 axis is the primary driver of most psoriasis, we are continuing to make key discoveries about how this axis is imperfectly restrained in psoriasis lesions,” shares Dr. Cho.

The National Psoriasis Foundation (NPF) is proud to help support this important research. Dr. Cheng is a NPF Discovery Grant recipient. “The overarching goal of my NPF discovery grant work was to use new single cell profiling approaches (with an emphasis on highly multiplexed immunofluorescence) to provide insight into molecular drivers of psoriasis. In parallel, we utilized the complementary method of single cell RNA-sequencing on psoriatic skin samples which allowed us to identify this ZIST suppressive program in psoriatic T cells,” Dr. Cheng says.