Hyperoxia is frequently used for treating acute respiratory failure, but it can cause acute lung injury. Nucleotide-binding domain and leucine-rich-repeat-containing family member X1 (NLRX1) is localized in mitochondria and related to reactive oxygen species production, inflammation, and apoptosis, which are the features of hyperoxic acute lung injury (HALI). However, the contribution of NLRX1 in HALI has not been addressed, so we designed to demonstrate the role of NLRX1 in hyperoxia. A murine model of HALI was generated in wild-type mice (WT) and NLRX1−/− mice by exposing them to over 95% oxygen for 72 h. As a result, NLRX1 expression was elevated in mice exposed to hyperoxia. In acute lung injury, levels of inflammatory cells, protein leakage, cell cytotoxicity, and pro-inflammatory cytokines were diminished in NLRX1−/− mice compared to WT mice. In survival test, NLRX1−/− mice showed alleviated mortality under hyperoxic conditions, and apoptotic cell death and caspase expression and activity were reduced in NLRX1−/− mice. Furthermore, levels of MAPK signaling proteins ERK 1/2, JNK, and p38 were decreased in NLRX1-deficient mice than in WT mice exposed to hyperoxia. This study reveals that the genetic deficiency of NLRX1 dampens hyperoxia-induced apoptosis, suggesting NLRX1 acts as a pivotal regulator of HALI.
Hyperoxia is frequently used for treating acute respiratory failure, but it can cause acute lung injury. Nucleotide-binding domain and leucine-rich-repeat-containing family member X1 (NLRX1) is localized in mitochondria and involved in production of reactive oxygen species, inflammation, and apoptosis, which are the features of hyperoxic acute lung injury (HALI). The contribution of NLRX1 to HALI has not previously been addressed. Thus, to investigate the role of NLRX1 in hyperoxia, we generated a murine model of HALI in wild-type (WT) and NLRX1−/− mice by exposure to > 95% oxygen for 72 h. As a result, NLRX1 expression was elevated in mice exposed to hyperoxia. In acute lung injury, levels of inflammatory cells, protein leakage, cell cytotoxicity, and pro-inflammatory cytokines were diminished in NLRX1−/− mice compared to WT mice. In a survival test, NLRX1−/− mice showed reduced mortality under hyperoxic conditions, and apoptotic cell death and caspase expression and activity were also lower in NLRX1−/− mice. Furthermore, levels of the MAPK signaling proteins ERK 1/2, JNK, and p38 were decreased in NLRX1-deficient mice than in WT mice exposed to hyperoxia. The study shows that a genetic deficit in NLRX1 can suppress hyperoxia-induced apoptosis, suggesting that NLRX1 acts as a pivotal regulator of HALI.
Purpose The prevalence of food allergy, triggered by T-helper type 2 (Th2) cell-mediated inflammation, is increasing worldwide. Interleukin (IL)-18 plays an important role in inflammatory diseases by binding with the IL-18 receptor. IL-18/IL-18 receptor α (IL-18Rα) is a cofactor for immunoglobulin E (IgE) production and Th2 cell development. Studies have not investigated the association between the IL-18/IL-18Rα signaling pathway and food allergy. Here, we investigated the role of IL-18Rα in food allergy induction and development. Methods Wild-type (WT) and IL-18Rα-null mutant (IL-18Rα −/− ) C57BL/6 mice were sensitized and challenged using ovalbumin (OVA) for food allergy induction. Food allergy symptoms, T cell-mediated immune responses, and signal transducer and activator of transcription (STAT)/suppressors of cytokine signaling (SOCS) pathways were analyzed in mice. Results IL-18Rα expression was increased in WT mouse intestines after OVA treatment. Food allergy-induced IL-18Rα −/− mice showed attenuated systemic food allergic reactions, OVA-specific IgE and mouse mast cell protease-1 production, inflammatory cell infiltration, and T cell activation. Ex vivo experiments showed that cell proliferation and Th2 cytokine production were lower in IL-18Rα −/− mouse splenocytes than in WT mouse splenocytes. IL-18Rα blockade in WT splenocytes attenuated cell proliferation and Th2 cytokine production. Moreover, STAT3 phosphorylation was reduced in IL-18Rα −/− mice, and SOCS3 and SOCS1 activation were diminished in IL-18Rα −/− intestinal T cells. Conclusions IL-18Rα regulates allergic reactions and immune responses by regulating T cell responses in food allergies. Moreover, IL-18Rα is involved in the STAT/SOCS signaling pathways. Targeting IL-18Rα signaling might be a novel therapeutic strategy for food allergy.
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