Paxbp1 is indispensable for the survival of CD4 and CD8 double-positive thymocytes.

The lifespan of double-positive (DP) thymocytes is critical for intrathymic development and shaping the peripheral T cell repertoire. However, the molecular mechanisms that control DP thymocyte survival remain poorly understood. Paxbp1 is a conserved nuclear protein that has been reported to play important roles in cell growth and development. Its high expression in T cells suggests a possible role in T cell development. Here, we observed that deletion of Paxbp1 resulted in thymic atrophy in mice lacking Paxbp1 in the early stages of T cell development. Conditional loss of Paxbp1 resulted in fewer CD4+CD8+ DP T cells, CD4 and CD8 single positive (SP) T cells in the thymus, and fewer T cells in the periphery. Meanwhile, Paxbp1 deficiency had limited effects on the CD4-CD8- double negative (DN) or immature single-positive (ISP) cell populations. Instead, we observed a significant increase in the susceptibility of Paxbp1-deficient DP thymocytes to apoptosis. Consistent with this, RNA-Seq analysis revealed a significant enrichment of the apoptotic pathway within differentially expressed genes in Paxbp1-deficient DP cells compared to control DP cells. Together, our results suggest a new function for Paxbp1, which is an important mediator of DP thymocyte survival and critical for proper thymic development.

The Crucial Roles and Research Advances of cGAS-STING Pathway in Cutaneous Disorders.

The cGAS-STING signaling pathway senses the presence of cytosolic DNA, induces strong type I interferon responses, and enhances inflammatory cytokine production, placing it as an important axis in infection, autoimmunity, and tumor immunity. Recent studies have shown that the abnormalities and/or dysfunctions of cGAS-STING signaling are closely related to the pathogenesis of skin diseases and/or cancers. Additionally, a variety of new therapeutics targeting the cGAS-STING signaling are in development for the treatment of skin disorders. However, the precise molecular mechanisms of cGAS-STING-mediated cutaneous disorders have not been fully elucidated. In this review, we will summarize the regulatory roles and mechanisms of cGAS-STING signaling in skin disorders and recent progresses of cGAS-STING-related drugs as well as their potential clinical applications.

Human Umbilical Cord-Derived Mesenchymal Stem Cells Alleviate Psoriasis Through TNF-α/NF-κB/MMP13 Pathway.

Psoriasis is a chronic, immune-mediated disease that affects 2-3% of the global population. Recently, mesenchymal stem cells (MSCs) have been used to alleviate psoriasis. However, the therapeutic mechanisms of MSCs remain unclear. Matrix metalloproteinase-13 (MMP13), a member of the MMPs family, is the key enzyme in the cleavage of type II collagen and plays a pivotal role in extracellular matrix (ECM) remodeling. Here, it was found that Mmp13 was upregulated in the skin lesions of an imiquimod-induced mouse model, which was downregulated after intravenous infusion of human umbilical cord MSCs (hUC-MSCs). Knockdown of MMP13 inhibited the proliferation of keratinocytes and arrested the cell cycle in G1 stage. In addition, hUC-MSCs were co-cultured with THP-1 or PMA-stimulated THP-1 directly in vitro to simulate the fate of systematically infused hUC-MSCs. The level of TNF-α was decreased in the supernatant of co-cultured hUC-MSCs and THP-1 or PMA-stimulated THP-1. Moreover, it was identified that TNF-α upregulated MMP13 through the NF-κB pathway in keratinocytes. In conclusion, we propose that systematically infused hUC-MSCs exert a therapeutic effect on psoriasis through the TNF-α/NF-κB/MMP13 pathway.