Journal of leukocyte biology
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Burn patients with concomitant pulmonary Pseudomonas aeruginosa (PA) infection have mortality rates as high as 50%, despite antibiotic therapy. Sphingosine is generated from ceramide via ceramidase and has been reported to have antimicrobial properties. We observed a reduction in sphingosine and a concurrent increase in ceramide in bronchial epithelial cells after burn injury. ⋯ We further observed that sphingosine directly kills PA. Together, these results demonstrate that reduction in sphingosine is associated with an increased susceptibility to pulmonary infection after burn injury. Restoration of sphingosine levels through direct sphingosine administration or conversion of the increased ceramide to sphingosine by neutral ceramidase reduces mortality and mitigates pulmonary infection after burn injury.
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T cells kill microbial-infected and malignant cells by detection of nonself antigens with the TCR. Tumor reactivity can be encoded genetically by introducing a chimeric antigen receptor (CAR) into T cells. CARs are composed of an antigen-binding domain and an intracellular T cell activation domain. ⋯ It is currently managed conservatively but can be treated with cytokine-directed therapy or with high-dose steroids. Current efforts are dedicated to confirming the clinical efficacy and managing toxicities in multicenter Phase II trials. We present a thorough overview of the preclinical and clinical development of CAR T cell therapy that will highlight important areas for the basic researcher to investigate in the laboratory and contribute to this exciting field.
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Myeloid-derived suppressor cells (MDSCs) are immature cells that do not differentiate into mature myeloid cells. Two major populations of PMN-MDSCs (Ly6GhighLy6ClowGr1highCD11b+) and MO-MDSCs (Ly6G-Ly6ChighGr-1intCD11b+) have an immune suppressive function. Interferon regulatory factor 4 (IRF4) has a role in the negative regulation of TLR signaling and is associated with lymphoid cell development. ⋯ Notably, treatment with IL-4, an upstream regulator of IRF4, induced IRF4 expression in the bone marrow cells, and consequently, IL-4-induced IRF4 expression resulted in a decrease in PMN-MDSC numbers. Finally, we confirmed that IRF4 expression in MDSCs can modulate their activity to inhibit T cell proliferation through IL-10 production and ROS generation, and myeloid-specific deletion of IRF4 leads to the increase of MDSC differentiation. Our present findings indicate that IRF4 reduction induced by tumor formation can increase the number of MDSCs, and increases in the IRF4 expression in MDSCs may infringe on the immune-suppressive function of MDSCs.