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Summary: T helper type 17 lymphocytes (Th17 cells) infiltrate the central nervous system (CNS), induce inflammation and demyelination and play a pivotal role in the pathogenesis of multiple sclerosis. Sialomucin CD43 is highly expressed in Th17 cells and mediates adhesion to endothelial selectin (E‐selectin), an initiating step in Th17 cell recruitment to sites of inflammation. CD43−/− mice have impaired Th17 cell recruitment to the CNS and are protected from experimental autoimmune encephalomyelitis (EAE), the mouse model of multiple sclerosis. However, E‐selectin is dispensable for the development of EAE, in contrast to intercellular and vascular cell adhesion molecules (ICAM‐1 and VCAM‐1). We report that CD43−/− mice have decreased demyelination and T‐cell infiltration, but similar up‐regulation of ICAM‐1 and VCAM‐1 in the spinal cord, compared with wild‐type (WT) mice, at the initiation of EAE. CD43−/− Th17 cells have impaired adhesion to ICAM‐1 under flow conditions in vitro, despite having similar expression of LFA‐1, the main T‐cell ligand for ICAM‐1, as WT Th17 cells. Regardless of the route of integrin activation, CD43−/− Th17 cell firm arrest on ICAM‐1 was comparable to that of WT Th17 cells, but CD43−/− Th17 cells failed to optimally apically migrate on immobilized ICAM‐1‐coated coverslips and endothelial cells, and to transmigrate under shear flow conditions in an ICAM‐1‐dependent manner. Collectively, these findings unveil novel roles for CD43, facilitating adhesion of Th17 cells to ICAM‐1 and modulating apical and transendothelial migration, as mechanisms potentially responsible for Th17 cell recruitment to sites of inflammation such as the CNS. [ABSTRACT FROM AUTHOR]

R1616 --> Percutaneous coronary interventions (PCI) are commonly used to improve blood flow in Peripheral Artery Disease. Complications of PCI are delayed re‐endothelialization and endothelial cell (EC) dysfunction leading to adverse clinical outcomes. Stimulator of Interferon Genes (STING), canonically activated downstream of the cGAS enzyme, is a signaling hub molecule modulating immune responses triggered by self‐derived and/or foreign DNA. We hypothesized that EC‐intrinsic STING regulates re‐endothelialization in response to vascular injury. We modeled PCI in WT, STING‐/‐, and in a newly generated inducible vascular EC‐ specific mouse (VECad5Cre‐ERT2STINGfl/fl mice: EC‐STING‐/‐) using the wire induced carotid injury model. We used Evans Blue Dye injection post injury to identify the areas denuded of EC and quantified the % of non‐blue (re‐endothelialized) area. We found that WT mice had complete re‐endothelialization five days post injury (95.16 ± 2.77 %). In contrast, injured carotid arteries in STING‐/‐ mice exhibited a decrease in re‐endothelialization at the same timepoint (43.57 ± 9.79%). Moreover, EC‐STING‐/‐ mice recapitulated the delayed re‐endothelialization (10.45 ± 1.56% in Tamoxifen treated mice to induce excision of STING in EC, compared to 40 ± 1.28% observed in vehicle treated VECad5Cre‐ERT2STINGfl/fl control mice 5 days post scratch) in the injured arteries, supporting a role of EC STING in re‐endothelialization post injury. To further investigate this EC‐specific effect of STING mechanistically in vitro, we performed scratch assays on WT and STING mouse heart EC (MHEC) monolayers, as well as on human EC monolayers lacking STING after CRISPR knock down and imaged wound healing in real time by IncuCyte. WT MHEC and HUVEC completely covered the scratch area within 24 hours, and 4 hours, respectively, whereas both EC lacking STING were delayed healing the scratch. Additionally, we found that the healing response was independent of cGAS, since cGAS KD HUVEC had similar post‐ scratch recovery time as control HUVEC. Ongoing experiments investigate the mechanisms involved in this novel STING dependent, cGAS‐independent pathway of EC response to injury, as well as the consequences of EC‐STING in adverse chronic vascular remodeling. [ABSTRACT FROM AUTHOR]