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Programmed necrosis, such as necroptosis and pyroptosis, is a highly pro-inflammatory cellular event that is associated with chronic inflammation. Although there are various triggers of pyroptosis and necroptosis in autoimmune tissue inflammation and subsequent lytic forms of cell death release abundant inflammatory mediators, including damage-associated molecular patterns and IL-1β, capable of amplifying autoimmune Th17 effector functions, it remains largely unclear whether the programs play a crucial role in the pathogenesis of autoimmune arthritis. We herein report that Gasdermin D (Gsdmd) and receptor interacting serine/threonine kinase 3 (Ripk3)—key molecules of pyroptosis and necroptosis, respectively—are upregulated in inflamed synovial tissues, but dispensable for IL-1β production and the development of IL-17-producing T helper (Th17) cell-mediated autoimmune arthritis in SKG mice. Gsdmd−/−, Ripk3−/−, or Gsdmd−/−Ripk3−/− SKG mice showed severe arthritis with expansion of arthritogenic Th17 cells in the draining LNs and inflamed joints, which was comparable to that in wild-type SKG mice. Despite the marked reduction of IL-1β secretion from Gsdmd−/− or Ripk3−/− bone marrow-derived DCs by canonical stimuli, IL-1β levels in the inflamed synovium were not affected in the absence of Gsdmd or Ripk3. Our results revealed that T cell-mediated autoimmune arthritis proceeds independently of the pyroptosis and necroptosis pathways. [ABSTRACT FROM AUTHOR]

Acidic hydrothermal degradation of glucose was examined in the presence of HCl, H2SO4, and H3PO4 with pH varying from 1.5 to 2.5 and reaction time varying from 1 to 10 min at 523 K, to investigate the effect of different acid catalysts and acid concentration on the production of 5-hydroxymethyl-2-furaldehyde (HMF) and levulinic acid from glucose. At lower acidities of pH 2.5, a considerably higher amount of HMF was produced. The increase in acid concentration accelerated the conversion of HMF to levulinic acid. The order for the production of HMF using the three acids is in the sequence of H3PO4 > H2SO4 > HCl. On the contrary, the order for production of levulinic acid follows HCl > H2SO4 > H3PO4. In the experimental conditions used in this study, the highest yield of levulinic acid is about 55%, which was obtained at pH 1.5 for 5 min in the case of HCl as an acid catalyst, and the total highest yields of HMF and levulinic acid are about 50%, which occurred at pH 2.0 for 5 min in the case of H3PO4 as an acid catalyst. [ABSTRACT FROM AUTHOR]

During thymic negative selection, autoreactive thymocytes carrying T cell receptor (TCR) with overtly strong affinity to self-MHC/self-peptide are removed by Bim-dependent apoptosis, but how Bim is specifically regulated to link TCR activation and apoptosis induction is unclear. Here we identify a murine T cell-specific genomic enhancer EBAB (Bub1-Acoxl-Bim), whose deletion leads to accumulation of thymocytes expressing high affinity TCRs. Consistently, EBAB knockout mice have defective negative selection and fail to delete autoreactive thymocytes in various settings, with this defect accompanied by reduced Bim expression and apoptosis induction. By contrast, EBAB is dispensable for maintaining peripheral T cell homeostasis via Bim-dependent pathways. Our data thus implicate EBAB as an important, developmental stage-specific regulator of Bim expression and apoptosis induction to enforce thymic negative selection and suppress autoimmunity. Our study unravels a part of genomic enhancer codes that underlie complex and context-dependent gene regulation in TCR signaling. Autoreactive T cells are deleted in the thymus via thymic negative selection and Bim-mediated apoptosis. Here the authors identify a cis-acting enhancer, EBAB, that is essential for proper Bim expression and apoptosis induction, and show that EBAB deficiency specifically impairs thymic negative selection without affecting peripheral T cell homeostasis. [ABSTRACT FROM AUTHOR]