Serpine1 plays a critical role in Th17 cell differentiation and psoriasis pathogenesis

Keywords

• Psoriasis

• Serpine1

• Th17 differentiation

• Autoimmunity

• Inflammation

Main Findings

Psoriasis is an autoimmune disease with unknown etiology that manifests in dry, inflamed patches of skin on patients, with an estimated 125 million people suffering globally. While Th17 cells are well-established as important mediators of autoimmunity and have been shown to play a notable role in psoriasis pathogenesis, the mechanisms governing their dysregulated differentiation remain unclear. In this promising study, Saimaier et al. revealed a previously unrecognized role for Serpine1, the gene encoding plasminogen activator inhibitor-1 (PAI-1), as a critical regulator of Th17 cell differentiation and a key contributor to psoriasis pathogenesis.

Through transcriptomic profiling of murine CD4+ T cell subsets stimulated with different cytokines in vitro, the authors identified Serpine1 as a highly expressed gene, specifically in Th17 cells, relative to other CD4⁺ T cell subsets. Notably, Serpine1 expression appeared to be regulated by Th17-associated transcription factors, STAT3, BATF, and IRF4 (as deletion of these factors reduced Serpine1 mRNA expression in Th17 cells), but was surprisingly not affected by deletion of RORγt, the master regulator of Th17 cells.

Both genetic knockout of Serpine1⁻/⁻ mice and pharmacological inhibition, with PAI-1 inhibitors Tiplaxtinin or TM(TM5441), impaired Th17 polarization in vitro. Importantly, both genetic deletion and pharmacologic suppression did not impact Treg differentiation and only mildly reduced Th1 cell differentiation.

Using an imiquimod (IMQ)-induced mouse model of psoriasis, Serpine1 knockout mice showed attenuated disease severity by exhibiting reduced epidermal thickness and decreased cytokines specifically related to psoriatic lesions (especiallyIL-17, IL-6, and IL-23). Treatment with Tiplaxtinin of IMQ-induced psoriasis also reduced skin thickness, supporting the use of Serpine1 as a therapeutic target. Additionally, the authors observed a reduction in CD4+ T cells within splenocyte populations of Serpine1-/- psoriatic mice, while Th17 cell levels remained unchanged. Conversely, both draining lymph nodes (DLNs) and mesenteric lymph nodes (MLNs) exhibited decreased Th17 cell populations. These cell counts support the indication that Serpine1deletion mitigates IMQ-induced psoriasis inflammation.

Collectively, this study is the first to establish Serpine1 as a Th17-intrinsic factor directly involved in Th17 differentiation and finds certain evidence for regulation of autoimmune inflammation in the context of psoriasis. While these findings are promising, several questions remain. The long-term intrinsic effects of Serpine1deletion, in the context of altered immune responses of different subsets or tissues, are not yet known.

Limitations & Suggestions

• The number of mice used per experiment, as well as their distribution across experimental groups, is not clearly indicated in the text. This affects the reproducibility and statistical validation of the findings, particularly in establishing clear associations between declaring certain genotypes or spontaneous activity. If the sample size is insufficient in achieving statistical validation, repeating the study under the same conditions could strengthen the validity of the results.

• Furthermore, the authors did not specify their methods of gene screening or preliminary analysis that guided their selection of Serpine1 as the gene of interest. Thus, it is unclear whether other factors, whether intrinsic or extrinsic (through unique protein expression or secreted proteins), could similarly induce elevated Serpine1 expression that is observed in Th17 cells. Future studies might explore whether supplementing naïve CD4+ T cell subsets with various Th17-specific cytokines in vitro, such as the psoriatic specific cytokines examined previously (IL-17, IL-6, and/or IL-23), while inhibiting Serpine1, could recapitulate the unique cell differentiation that was observed in this study.

• While the authors briefly mentioned the importance of screening existing drugs to assess for therapeutic efficacy and variability in autoimmune responses, the study does not adequately address these same potential risks associated with Serpine1 manipulation. Specifically, pharmacological inhibition of PAI-1, using inhibitors Tiplaxtinin and TM, has the risk of disrupting the fibrinolytic system and impairing fibrin breakdown function. This should be considered for therapeutic translation and mentioned in the text.

• In addition to investigating mRNA expression levels and histopathologic changes in the skin of the Serpine1-/- mice, it would be important to investigate the immune cell populations of the skin through flow cytometry. Similar to the author’s flow cytometric analysis of the spleen and lymph nodes, extending this analysis to the skin to investigate reduced Th17 subsets would be informative, as the skin is the primary affected organ in psoriasis.

• Lastly, the psoriasis examined in this study is induced by IMQ. While this is an established mouse model for psoriasis, different forms and subtypes of psoriasis may be driven by distinct immune responses, adaptive vs innate, and the results are difficult to generalize across all disease subtypes. Without this distinction, it is unclear if the observed results can be broadly applicable. Given the accessibility of human single-cell RNA sequencing (scRNA-seq) data from human psoriasis samples, the authors could investigate for evidence of Serpine1 expression patterns observed in their mouse models in human context. Future studies could utilize the available public transcriptomic data to validate the relevance of Serpine1 expression in human disease. Specifically, investigating immune cell subsets, most notably Th17 cells, could support the novel potential of Serpine1 as a therapeutic target for psoriasis.

Significance/Novelty

• The authors identified Serpine1 as a novel regulatory factor for Th17 cell differentiation, a role that has not been previously reported. They further revealed Serpine1 as highly expressed in Th17 cells, revealing its cell-intrinsic function. This advances mechanistic understanding into how Serpine1 influences autoimmune inflammation at the cellular level.

• The authors evaluate the therapeutic potential of pharmacologic inhibition using PAI-1 inhibitors (Tiplaxtinin and TM). These findings suggest that the protein inhibition can be targeted to modulate Th17-driven inflammation in psoriasis.

• By targeting Serpine1, the authors address a gap in current treatment options, particularly for Th17-mediated disease. Therefore, their findings may have broader implications for other autoimmune disorders characterized by Th17-driven pathology, including Multiple sclerosis and IBD, potentially expanding the audiences able to be treated.

Credit

Reviewed by Michelle Montoya as part of a cross-institutional journal club between the Max-Delbrück Center Berlin, the Ragon Institute Boston (Mass General, MIT, Harvard), the University of Virginia, the Medical University of Vienna and other life science institutes in Vienna. The author declares no conflict of interests in relation to their involvement in the review.