987 Cytosolic nucleic acid induced signaling events in keratinocytes

Abstract

TGFb is essential the epidermal retention resident memory T cells and Langerhans cells, but the source of TGFb that is important for these functions is unknown. Since the majority of cells in epidermis are keratinocytes (KC), we hypothesized that TGFb from KC might be important for skin homeostasis and the maintenance of skin immune cells. To examine this, we generated K14CreER T2 TGFb fl YFP mice which enables tamoxifen inducible specifically ablation of TGFb in KC. Systemic application of tamoxifen was lethal likely due to esophageal inflammation. Topical application of 4-hydroxytamoxifen (4-OHT) once a day for 2 days was well tolerated. We confirmed the deletion of TGFb in bulge, isthumus and interfollicular keratinocytes based on YFP expression and TGFb mRNA 28 and 84 days post 4-OHT treatment. Mice with KC specific deletion of TGFb developed acanthosis without observable skin inflammation, implicating a TGFb autocrine/paracrine suppression of KC proliferation. We also found that ablation of TGFb in KC has no effect on the numbers of epidermal-resident Langerhans cell, ab T cells and Innate lymphoid. A modest decrease in DETC was observed. In dermis, we did not find any alteration in numbers of DC subsets, ab T cells or dermal gd T cells. Thus, under homeostatic conditions deletion of TGFb in KC enhances epidermal acanthosis but has limited effect on cutaneous residence of most immune cells. 983Pluripotent stem cell model of Nakajo-Nishimura syndrome untangles proinflammatory pathways mediated by oxidative stress Nakajo-Nishimura syndrome (NNS) is an immunoproteasome-associated autoinflammatory disorder caused by a mutation of the PSMB8 gene. Although dysfunction of the immunoproteasome causes various cellular stresses attributed to the overproduction of inflammatory cytokines and chemokines in NNS, the underlying mechanisms of the autoinflammation are still largely unknown. To investigate and understand the mechanisms and signal pathways in NNS, we established a panel of isogenic pluripotent stem cell (PSC) lines with PSMB8 mutation. Activity of the immunoproteasome in PSMB8-mutant PSC-derived myeloid cell lines (MT-MLs) was reduced even without stimulation compared to non-mutant-MLs. Additionally, MT-MLs showed an overproduction of inflammatory cytokines and chemokines, with elevated reactive oxygen species (ROS) and phosphorylated p38 MAPK levels. Treatment with p38 MAPK inhibitor and anti-oxidants decreased the abnormal production of cytokines and chemokines. The current PSC model revealed a specific ROS-mediated inflammatory pathway, providing a platform for the discovery of alternative therapeutic options for NNS and related immunoproteasome disorders. 984Superoxide dismutase 3 controls Th2 cytokine-mediated allergic inflammation through inhibition of periostin S Sah, C Nguyen and T Kim The Catholic University of Korea, Seoul, Republic of Korea Superoxide dismutase 3 (SOD3), an antioxidant enzyme that plays an important role in regulation of inflammation. However, the role of SOD3 and the mechanism(s) b...