Inflammasomes form as the result of the intracellular presence of danger-associated molecular patterns and mediate the release of active IL-1β, which influences a variety of inflammatory responses. Excessive inflammasome activation results in severe inflammatory conditions, but physiological IL-1β secretion is necessary for intestinal homeostasis. Here, we have described a mechanism of NLRP3 inflammasome regulation by tyrosine phosphorylation of NLRP3 at Tyr861. We demonstrated that protein tyrosine phosphatase non-receptor 22 (PTPN22), variants in which are associated with chronic inflammatory disorders, dephosphorylates NLRP3 upon inflammasome induction, allowing efficient NLRP3 activation and subsequent IL-1β release. In murine models, PTPN22 deficiency resulted in pronounced colitis, increased NLRP3 phosphorylation, but reduced levels of mature IL-1β. Conversely, patients with inflammatory bowel disease (IBD) that carried an autoimmunity-associated PTPN22 variant had increased IL-1β levels. Together, our results identify tyrosine phosphorylation as an important regulatory mechanism for NLRP3 that prevents aberrant inflammasome activation.

The gut microbiota is crucial for our health, and well-balanced interactions between the host’s immune system and the microbiota are essential to prevent chronic intestinal inflammation, as observed in inflammatory bowel diseases (IBD). A variant in protein tyrosine phosphatase non-receptor type 22 (PTPN22) is associated with reduced risk of developing IBD, but promotes the onset of autoimmune disorders. While the role of PTPN22 in modulating molecular pathways involved in IBD pathogenesis is well studied, its impact on shaping the intestinal microbiota has not been addressed in depth. Here, we demonstrate that mice carrying the PTPN22 variant (619W mice) were protected from acute dextran sulfate sodium (DSS) colitis, but suffered from pronounced inflammation upon chronic DSS treatment. The basal microbiota composition was distinct between genotypes, and DSS-induced dysbiosis was milder in 619W mice than in WT littermates. Transfer of microbiota from 619W mice after the first DSS cycle into treatment-naive 619W mice promoted colitis, indicating that changes in microbial composition enhanced chronic colitis in those animals. This indicates that presence of the PTPN22 variant affects intestinal inflammation by modulating the host’s response to the intestinal microbiota.

Protein tyrosine phosphatases (PTPs) are key regulators of intracellular signaling cascades involved in cell growth, proliferation, differentiation, inflammation, and cancer. PTPN23, a non-receptor PTP, is involved in endosomal sorting and thereby regulates the internalization of growth factor receptors, such as the epidermal growth factor receptor (EGFR). PTPN23 has been proposed to exert tumor-suppressive effects in several epithelial cancers, including breast and lung cancer. PTPN23 is ubiquitously expressed in the body; however, it is particularly highly expressed in the intestine, where it plays an essential role in maintaining intestinal homeostasis. Despite these observations, its involvement in colorectal carcinoma (CRC) remains largely unexplored. To investigate the function of PTPN23 in CRC, we generated PTPN23-overexpressing CRC cell lines and evaluated their effects in vitro and in subcutaneous tumor models. Our in-vitro findings demonstrate that PTPN23 overexpression resulted in reduced proliferation levels and follow-up experiments showed suppression of colorectal cancer growth and proliferation in experimental CRC models. These effects were accompanied by changes in EGFR-associated signaling; however, the underlying mechanism, including a potential role of EGFR trafficking, remains to be established through direct experimental validation. Together, these findings expand current knowledge of PTPN23 in colorectal cancer and provide a basis for future studies addressing its biological function and therapeutic relevance.

T-cells are major therapeutic targets in cancer and immune-mediated diseases. Their development and differentiation require highly dynamic receptor turnover. Protein tyrosine phosphatase non-receptor type 23 (PTPN23) encodes a ubiquitously expressed pseudophosphatase involved in trafficking and internalization of specific cell receptors. Although PTPN23 has essential functions in several cell types, its role in T-cells remains unknown. We therefore investigated the role of PTPN23 in T-cells. We generated transgenic mice lacking PTPN23 specifically in T-cells (PTPN23-CD4-Cre). Flow cytometry, single-cell RNA sequencing (scRNA-seq), and proteomic analysis were performed in lymphoid and mucosal organs. PTPN23-CD4-Cre mice exhibited a significant reduction in total T-cell numbers in lymphoid organs, accompanied by increased proportions and numbers of γδ T-cells and markedly reduced naïve T-cells. Similar findings were made in mucosal organs, with γδ T-cell levels rising as age increased. In vitro functional assays revealed that residual PTPN23-CD4-Cre T-cells display an altered cytokine profile enriched for inflammatory mediators, a finding that was accompanied by proteomic and phosphoproteomic alterations consistent with changes in T-cell differentiation and inflammatory programs. scRNA-seq analysis showed altered representation of thymocytes along a shared developmental trajectory, with enrichment of PTPN23-deficient T-cells at earlier developmental states. Our study identifies PTPN23 as a previously unrecognized player of T-cell development, differentiation, and immune homeostasis.