Activation of the pentose phosphate pathway in macrophages is crucial for granuloma formation in sarcoidosis

肉芽腫形成に特異的な代謝経路の発見 --ペントースリン酸回路の制御による新規治療--. 京都大学プレスリリース. 2023-12-01.More than skin-deep: Kyoto researchers discover metabolic pathway specific to granuloma formation in patients. 京都大学プレスリリース. 2023-12-07.Sarcoidosis is a disease of unknown etiology in which granulomas form throughout the body and is typically treated with glucocorticoids, but there are no approved steroid-sparing alternatives. Here, we investigated the mechanism of granuloma formation using single-cell RNA-Seq in sarcoidosis patients. We observed that the percentages of triggering receptor expressed on myeloid cells 2–positive (TREM2-positive) macrophages expressing angiotensin-converting enzyme (ACE) and lysozyme, diagnostic makers of sarcoidosis, were increased in cutaneous sarcoidosis granulomas. Macrophages in the sarcoidosis lesion were hypermetabolic, especially in the pentose phosphate pathway (PPP). Expression of the PPP enzymes, such as fructose-1, 6-bisphosphatase 1 (FBP1), was elevated in both systemic granuloma lesions and serum of sarcoidosis patients. Granuloma formation was attenuated by the PPP inhibitors in in vitro giant cell and in vivo murine granuloma models. These results suggest that the PPP may be a promising target for developing therapeutics for sarcoidosis

乳房外パジェット病における潜在的腫瘍進展の三次元的解析:組織学的境界の可視化とその臨床的境界との比較検討

京都大学0048新制・課程博士博士(医学)甲第20245号医博第4204号新制||医||1020(附属図書館)京都大学大学院医学研究科医学専攻(主査)教授 松田 道行, 教授 羽賀 博典, 教授 鈴木 茂彦学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDFA

Combined multiphoton imaging and biaxial tissue extension for quantitative analysis of geometric fiber organization in human reticular dermis

刺しゅう枠で皮膚の線維構造を解明 --コラーゲンと弾性線維の網目構造--. 京都大学プレスリリース. 2019-07-24.I see the pattern under your skin. 京都大学プレスリリース. 2019-08-01.The geometric organization of collagen fibers in human reticular dermis and its relationship to that of elastic fibers remain unclear. The tight packing and complex intertwining of dermal collagen fibers hinder accurate analysis of fiber orientation. We hypothesized that combined multiphoton microscopy and biaxial extension could overcome this issue. Continuous observation of fresh dermal sheets under biaxial extension revealed that the geometry of the elastic fiber network is maintained during expansion. Full-thickness human thigh skin samples were biaxially extended and cleared to visualize the entire reticular dermis. Throughout the dermis, collagen fibers straightened with increased inter-fiber spaces, making them more clearly identifiable after extension. The distribution of collagen fibers was evaluated with compilation of local orientation data. Two or three modes were confirmed in all superficial reticular layer samples. A high degree of local similarities in the direction of collagen and elastic fibers was observed. More than 80% of fibers had directional differences of ≤15°, regardless of layer. Understanding the geometric organization of fibers in the reticular dermis improves the understanding of mechanisms underlying the pliability of human skin. Combined multiphoton imaging and biaxial extension provides a research tool for studying the fibrous microarchitecture of the skin

Transient elevation of cytoplasmic calcium ion concentration at a single cell level precedes morphological changes of epidermal keratinocytes during cornification

Epidermal keratinocytes achieve sequential differentiation from basal to granular layers, and undergo a specific programmed cell death, cornification, to form an indispensable barrier of the body. Although elevation of the cytoplasmic calcium ion concentration ([Ca²⁺]i) is one of the factors predicted to regulate cornification, the dynamics of [Ca²⁺]i in epidermal keratinocytes is largely unknown. Here using intravital imaging, we captured the dynamics of [Ca²⁺]i in mouse skin. [Ca²⁺]i was elevated in basal cells on the second time scale in three spatiotemporally distinct patterns. The transient elevation of [Ca²⁺]i also occurred at the most apical granular layer at a single cell level, and lasted for approximately 40 min. The transient elevation of [Ca²⁺]i at the granular layer was followed by cornification, which was completed within 10 min. This study demonstrates the tightly regulated elevation of [Ca²⁺]i preceding the cornification of epidermal keratinocytes, providing possible clues to the mechanisms of cornification

Resolvin E1 inhibits dendritic cell migration in the skin and attenuates contact hypersensitivity responses

魚油に多く含まれるオメガ3脂肪酸が皮膚アレルギー反応を抑制する機序の解明. 京都大学プレスリリース. 2015-10-06.Resolvin E1 (RvE1) is a lipid mediator derived from ω3 polyunsaturated fatty acids that exerts potent antiinflammatory roles in several murine models. The antiinflammatory mechanism of RvE1 in acquired immune responses has been attributed to attenuation of cytokine production by dendritic cells (DCs). In this study, we newly investigated the effect of RvE1 on DC motility using two-photon microscopy in a contact hypersensitivity (CHS) model and found that RvE1 impaired DC motility in the skin. In addition, RvE1 attenuated T cell priming in the draining lymph nodes and effector T cell activation in the skin, which led to the reduced skin inflammation in CHS. In contrast, leukotriene B4 (LTB4) induced actin filament reorganization in DCs and increased DC motility by activating Cdc42 and Rac1 via BLT1, which was abrogated by RvE1. Collectively, our results suggest that RvE1 attenuates cutaneous acquired immune responses by inhibiting cutaneous DC motility, possibly through LTB4-BLT1 signaling blockade