記述言語：英語   出版者・発行元：Nature Communications  

The root of asthma can be linked to early life, with prenatal environments influencing risk. We investigate the effects of maternal asthma on the offspring’s lungs during fetal and adult life. Adult offspring of asthmatic mothers show an increase in lung group 2 innate lymphoid cell (ILC2) number and function with allergen-induced lung inflammation. Offspring of asthmatic mothers show phenotypic alteration of their lung ILC2s during fetal life, with increased expression of genes related to activation and glucocorticoid signaling. Furthermore, these offspring carry overlapping chromatin-accessible altered regions, including glucocorticoid receptor-binding regions in their lung ILC2s both at the fetal stage and adulthood, suggesting persistent prenatal epigenetic changes. Moreover, maternal exposure to glucocorticoids has similar effects on fetal lung ILC2s and contributes to allergen-induced lung inflammation during adulthood. Thus, asthma during pregnancy may have long-term effects on lung ILC2s in the offspring from the embryonic period, contributing to an increased risk of developing asthma.

DOI： 10.1038/s41467-025-55941-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： https://doi.org/10.1038/s41467-025-55941-8

記述言語：英語   出版者・発行元：Journal of Neuroinflammation  

T cells play an important role in the acquired immune response, with regulatory T cells (Tregs) serving as key players in immune tolerance. Tregs are found in nonlymphoid and damaged tissues and are referred to as “tissue Tregs”. They have tissue-specific characteristics and contribute to immunomodulation, homeostasis, and tissue repair through interactions with tissue cells. However, important determinants of Treg tissue specificity, such as antigen specificity, tissue environment, and pathology, remain unclear. In this study, we analyzed Tregs in the central nervous system of mice with ischemic stroke and experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. The gene expression pattern of brain Tregs in the EAE model was more similar to that of ischemic stroke Tregs in the brain than to that of spinal cord Tregs. In addition, most T-cell receptors (TCRs) with high clonality were present in both the brain and spinal cord. Furthermore, Gata3+ and Rorc+ Tregs expressed TCRs recognizing MOG in the spinal cord, suggesting a tissue environment conducive to Rorc expression. Tissue-specific chemokine/chemokine receptor interactions in the spinal cord and brain influenced Treg localization. Finally, spinal cord- or brain-derived Tregs had greater anti-inflammatory capacities in EAE mice, respectively. Taken together, these findings suggest that the tissue environment, rather than pathogenesis or antigen specificity, is the primary determinant of the tissue-specific properties of Tregs. These findings may contribute to the development of novel therapies to suppress inflammation through tissue-specific Treg regulation.

DOI： 10.1186/s12974-024-03144-1

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記述言語：英語   出版者・発行元：Inflammation and Regeneration  

Background: Alzheimer’s disease (AD) is one of the neurodegenerative diseases and characterized by the appearance and accumulation of amyloid-β (Aβ) aggregates and phosphorylated tau with aging. The aggregation of Aβ, which is the main component of senile plaques, is closely associated with disease progression. AppNL-G-F mice, a mouse model of AD, have three familial AD mutations in the amyloid-β precursor gene and exhibit age-dependent AD-like symptoms and pathology. Gut-brain interactions have attracted considerable attention and inflammatory bowel disease (IBD) has been associated with a higher risk of dementia, especially AD, in humans. However, the underlying mechanisms and the effects of intestinal inflammation on the brain in AD remain largely unknown. Therefore, we aimed to investigate the effects of intestinal inflammation on AD pathogenesis. Methods: Wild-type and AppNL-G-F mice at three months of age were fed with water containing 2% dextran sulfate sodium (DSS) to induce colitis. Immune cells in the brain were analyzed using single-cell RNA sequencing (scRNA-seq) analysis, and the aggregation of Aβ protein in the brain was analyzed via immunohistochemistry. Results: An increase in aggregated Aβ was observed in the brains of AppNL-G-F mice with acute intestinal inflammation. Detailed scRNA-seq analysis of immune cells in the brain showed that neutrophils in the brain increased after acute enteritis. Eliminating neutrophils by antibodies suppressed the accumulation of Aβ, which increased because of intestinal inflammation. Conclusion: These results suggest that neutrophils infiltrate the AD brain parenchyma when acute colitis occurs, and this infiltration is significantly related to disease progression. Therefore, we propose that neutrophil-targeted therapies could reduce Aβ accumulation observed in early AD and prevent the increased risk of AD due to colitis.

DOI： 10.1186/s41232-023-00257-7

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記述言語：英語   出版者・発行元：Frontiers in Immunology  

Regulatory T cells (Tregs) are normally born in the thymus and activated in secondary lymphoid tissues to suppress immune responses in the lymph node and at sites of inflammation. Tregs are also resident in various tissues or accumulate in damaged tissues, which are now called tissue Tregs, and contribute to homeostasis and tissue repair by interacting with non-immune cells. We have shown that Tregs accumulate in the brain during the chronic phase in a mouse cerebral infarction model, and these Tregs acquire the characteristic properties of brain Tregs and contribute to the recovery of neurological damage by interacting with astrocytes. However, the mechanism of tissue Treg development is not fully understood. We developed a culture method that confers brain Treg characteristics in vitro. Naive Tregs from the spleen were activated and efficiently amplified by T-cell receptor (TCR) stimulation in the presence of primary astrocytes. Furthermore, adding IL-33 and serotonin could confer part of the properties of brain Tregs, such as ST2, peroxisome proliferator-activated receptor γ (PPARγ), and serotonin receptor 7 (Htr7) expression. Transcriptome analysis revealed that in vitro generated brain Treg-like Tregs (induced brain Tregs; iB-Tregs) showed similar gene expression patterns as those in in vivo brain Tregs, although they were not identical. Furthermore, in Parkinson’s disease models, in which T cells have been shown to be involved in disease progression, iB-Tregs infiltrated into the brain more readily and ameliorated pathological symptoms more effectively than splenic Tregs. These data indicate that iB-Tregs contribute to our understanding of brain Treg development and could also be therapeutic for inflammatory brain diseases.

DOI： 10.3389/fimmu.2022.960036

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記述言語：日本語   出版者・発行元：(有)科学評論社  

記述言語：日本語   出版者・発行元：(株)先端医学社  

中枢神経系疾患においても間質細胞の一つである免疫細胞が関与している.中枢神経系疾患のなかでも劇的な炎症応答と組織修復が起こる急性虚血性脳梗塞時の免疫細胞の役割について,理解が進んできている.虚血によって脳組織が壊死に陥ると,さまざまな免疫細胞が脳内に浸潤してきて自然免疫応答が起こる.その後もさまざまな免疫細胞は細胞種や特徴を変化させながら持続的に脳内に存在しており,獲得免疫応答も発動する.本稿では,このような脳梗塞時の間質細胞,とくに免疫細胞の経時的な変化と役割について概説する.(著者抄録)