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Receptor-interacting protein kinase 1 (RIPK1) regulates cell death and inflammation. Here, we show that T cell–specific RIPK1 deficiency in mice leads to the premature senescence of T cells and induces various age-related diseases, resulting in premature death. RIPK1 deficiency causes higher basal activation of mTORC1 (mechanistic target of rapamycin complex 1) that drives enhanced cytokine production, induction of senescence-related genes, and increased activation of caspase-3/7, which are restored by inhibition of mTORC1. Critically, normal aged T cells exhibit similar phenotypes and responses. Mechanistically, a combined deficiency of RIPK3 and caspase-8 inhibition restores the impaired proliferative responses; the elevated activation of Akt, mTORC1, extracellular signal–regulated kinase, and caspase-3/7; and the increased expression of senescence-related genes in RIPK1-deficient CD4 T cells. Last, we revealed that the senescent phenotype of RIPK1-deficient and aged CD4 T cells is restored in the normal tissue environment. Thus, we have clarified the function of RIPK3 and caspase-8 in inducing CD4 T cell senescence, which is modulated by environmental signals.

Pulmonary fibrosis (PF) is characterised by inflammation and collagen deposition in the alveolar interstitium, leading to dyspnoea and death. However, the comprehensive pathogenesis of PF remains unclear due to the lack of spontaneous fibrosis mouse models. Here, we found that Ifngr1-/-Rag2-/- mice, lacking the mechanisms to suppress group 2 and 3 innate lymphoid cells (ILC2s and ILC3s), developed severe PF spontaneously. In Ifngr1-/-Rag2-/- mice, Il1rl1hiIl13hi-ILC2 subpopulation was increased at disease-onset phase before collagen production began. Further, defects in ILCs or IL-33, the strong ILC2 activator, prevented PF development. ILC2s directly induce collagen production by fibroblasts in vitro, and fibroblasts started to produce IL-33 in the chronic phase, presumably forming a positive feedback loop between fibroblasts and ILC2s leading to irreversible fibrosis. Moreover, the increased IL1RL1 and IL13 and decreased IFNGR1 expression levels in ILC2s from human idiopathic PF patients highlight the significance of the novel mouse model in fibrosis research.

A total synthesis of garcinone A, a natural xanthone possessing a 2,4-diisoprenylated structure, was accomplished by utilizing a readily available 1,3-difluoroxanthone derivative as the key intermediate through the installation of two isoprenyl side chains by an SNAr reaction with the alkoxide of 1,1-dimethylallyl alcohol followed by a Claisen rearrangement. The strategy also permitted the selective installation of mutually different allylic moieties at the C2 and C4 positions.

The SNAr reaction of 1-fluoroxanthone derivatives with alkoxide of 1,1-dimethylallyl alcohol cleanly afforded the corresponding ethers, which have thus far been unavailable. The obtained ethers underwent the Claisen rearrangement at room temperature by treatment with silica gel in toluene. This two-step protocol provides expeditious and high-yield access to xanthones possessing isoprenyl or the related allylic side chain at the C2 position.

Group 2 innate lymphoid cells (ILC2s) are type 2 cytokine-producing cells that have important roles in helminth infection and allergic inflammation. ILC2s are tissue-resident cells, and their phenotypes and roles are regulated by tissue-specific environmental factors. While the role of ILC2s in the lung, intestine and bone marrow has been elucidated in many studies, their role in adipose tissues is still unclear. Here, we report on the role of ILC2-derived bone morphogenetic protein 7 (BMP7) in adipocyte differentiation and lipid accumulation. Co-culture of fat-derived ILC2s with pluripotent mesenchymal C3H10T1/2 cells and committed white preadipocyte 3T3-L1 cells resulted in their differentiation to adipocytes and induced lipid accumulation. Co-culture experiments using BMP7-deficient ILC2s revealed that BMP7, produced by ILC2s, induces differentiation into brown adipocytes. Our results demonstrate that BMP7, produced by ILC2s, affects adipocyte differentiation, particularly in brown adipocytes.

Group 2 innate lymphoid cells (ILC2s) are tissue-resident cells that play different roles in different organs by sensing surrounding environmental factors. Initially, it was thought that ILC2s in bone marrow (BM) are progenitors for systemic ILC2s, which migrate to other organs and acquire effector functions. However, accumulating evidence that ILC2s differentiate in peripheral tissues suggests that BM ILC2s may play a specific role in the BM as a unique effector per se. Here, we demonstrate that BM ILC2s highly express the receptor activator of nuclear factor κB ligand (RANKL), a robust cytokine for osteoclast differentiation and activation, and RANKL expression on ILC2s is up-regulated by interleukin (IL)-2, IL-7 and all-trans retinoic acid (ATRA). BM ILC2s co-cultured with BM-derived monocyte/macrophage lineage cells (BMMs) in the presence of IL-7 induce the differentiation of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts in a RANKL-dependent manner. In contrast, BM ILC2s stimulated with IL-33 down-regulate RANKL expression and convert BMMs differentiation into M2 macrophage-like cells rather than osteoclasts by granulocyte macrophage colony-stimulating factor (GM-CSF) and IL-13 production. Intravital imaging using two-photon microscopy revealed that a depletion of ILC2s prominently impaired in vivo osteoclast activity in an IL-7 plus ATRA-induced bone loss mouse model. These results suggest that ILC2s regulate osteoclast activation and contribute to bone homeostasis in both steady state and IL-33-induced inflammation.

Medical aromatherapy aimed at enhancing the prevention and symptomatic treatment of disease is widely used in nursing and the nursing field. It is important that the specific fragrance and its application are selected only after the absorption and mechanism of action of its essential oil are understood. Because it acts on the hippocampus and autonomic nervous system, fragrance stimulation has been considered a complementary and alternative medical therapy for dementia, sleeplessness and sleep disturbance, all of which are related to aging. The in vivo role of free radicals in the development of various diseases has recently been identified. A recent study reported that fragrance use enhanced the elimination of free radicals, and wide application of this modality in complementary and alternative medicine is expected.

Group 2 innate lymphoid cells (ILC2 cells) are type 2 cytokine-producing cells of the innate immune system with important roles in helminth infection and allergic inflammation. Here we found that tissue-resident ILC2 cells proliferated in situ without migrating during inflammatory responses. Both type I and type II interferons and interleukin 27 (IL-27) suppressed ILC2 function in a manner dependent on the transcription factor STAT1. ILC2-mediated lung inflammation was enhanced in the absence of the interferon-γ (IFN-γ) receptor on ILC2 cells in vivo. IFN-γ effectively suppressed the function of tissue-resident ILC2 cells but not that of inflammatory ILC2 cells, and IL-27 suppressed tissue-resident ILC2 cells but not tissue-resident TH2 cells during lung inflammation induced by Alternaria alternata. Our results demonstrate that suppression mediated by interferon and IL-27 is a negative feedback mechanism for ILC2 function in vivo.

To express the cbhI gene, encoding Aspergillus aculeatus cellobiohydrolase I (CBHI), in Aspergillus oryzae, a plasmid was constructed. The strain that displayed the strongest CBHI activity among the transformants produced about 941 mg/l in liquid culture. It was confirmed by a PCR method that the plasmid was integrated at the niaD locus.