Regulation of macrophage dynamics and adipose stromal cells by laminins during adipose tissue remodelling in obesity

肥胖脂肪组织重塑过程中层粘连蛋白对巨噬细胞动力学和脂肪基质细胞的调节

• 批准号: 431551011
• 负责人: Professorin Dr. Lydia Sorokin
• 金额: --
• 依托单位: National Natural Science Foundation of China
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/431551011?language=en
• 关键词: Regulation; macrophage; dynamics; adipose; stromal

Obesity can induce an insulin resistant state in adipose tissue, liver and skeletal muscle and is strongly related to type 2 diabetes. During obesity, adipose tissue expansion is an ongoing process, characterized by hyperplasia and hypertrophy of adipocytes, accumulation of macrophages and other immune cells, and aberrant extracellular matrix deposition. Such an inflammatory state disrupts homeostasis, impairs adipocyte function and leads to insulin resistance. The Chinese partner has shown that both infiltration of blood monocytes and an unusual IL-4/STAT6 driven proliferation of tissue resident macrophages result in macrophage accumulation in obese adipose tissue. Blocking monocyte infiltration reduces obesity and resistance to insulin, suggesting different roles for tissue resident and infiltrating macrophages. While others have described distinct populations of macrophages associated with adipose tissue, the Chinese partner has shown a close association between adipose tissue macrophages (ATM) and a novel CD45negCD31negICAM-1+ population of adipose stromal cells, which represent committed preadipocytes, and localise peri-vascularly. Preliminary studies show that elimination of ICAM-1+ expression in stromal cells promotes adipocyte hyperplasia in mice on a high fat diet (HFD), suggesting that it is not ATMs alone but rather their cross-talk with ICAM+ stromal cells that is critical for fat homeostasis.Each adipocyte is encased in its own basement membrane (BM), which the German partner has shown contains mainly laminin 411, produced by stromal cells of the fat anlage. Genetic elimination of laminin 411 (Lama4-/-) reduces fat development and confers resistance to HFD induced obesity and insulin resistance. Single cell RNA analysis of wild type (WT) adipose tissue has revealed high expression of laminin 411 in the CD45negCD31negICAM-1+ adipose stromal cells. Significantly higher numbers of these cells occur Lama4-/- mice compared to WT littermates and ATMs are reduced. This suggests a central role for ICAM-1+ stromal cells in obesity and implicates laminin 411 in regulating these cells either directly and/or by altering ATM number or function. However, the relationship between laminin 411, the ICAM-1+ adipose stromal cells and ATMs remains unclear.We hypothesize that interactions between ICAM-1+ adipose stromal cells and macrophages are critical to remodelling of fat tissue during obesity and that these cell populations are regulated by laminin 411. We will investigate1. The role of ICAM-1 in lineage specification of committed preadipocytes and how this is affected by laminin 411 and macrophages;2. The contribution of tissue resident versus infiltrating macrophages to obesity and whether laminins affect macrophage infiltration or their polarization/phenotype;3. The molecular nature of interactions between ICAM-1+ adipose stromal cells and macrophage populations and whether this is affected by laminins.

肥胖可在脂肪组织、肝脏和骨骼肌中诱导胰岛素抵抗状态，并且与2型糖尿病密切相关。在肥胖期间，脂肪组织扩张是一个持续的过程，其特征在于脂肪细胞的增生和肥大、巨噬细胞和其他免疫细胞的积聚以及异常的细胞外基质沉积。这种炎症状态破坏体内平衡，损害脂肪细胞功能并导致胰岛素抵抗。中国合作伙伴已经表明，血液单核细胞的浸润和组织驻留巨噬细胞的不寻常的IL-4/STAT 6驱动的增殖都导致了肥胖脂肪组织中巨噬细胞的积聚。阻断单核细胞浸润减少肥胖和胰岛素抵抗，表明组织驻留和浸润巨噬细胞的不同作用。虽然其他人已经描述了与脂肪组织相关的不同巨噬细胞群体，但中国合作伙伴已显示脂肪组织巨噬细胞（ATM）与脂肪基质细胞的新型CD 45 + CD 31 + ICAM-1+群体之间存在密切联系，这些细胞代表定向前脂肪细胞，并定位于血管周围。初步研究表明，基质细胞中ICAM-1+表达的消除促进了高脂饮食（HFD）小鼠的脂肪细胞增生，这表明对于脂肪稳态至关重要的不是ATM本身，而是它们与ICAM+基质细胞的相互作用。每个脂肪细胞都被包裹在自己的基底膜（BM）中，其中德国合作伙伴已经表明主要含有层粘连蛋白411，由脂肪原基的基质细胞产生。层粘连蛋白411（Lama 4-/-）的遗传消除减少脂肪发育并赋予对HFD诱导的肥胖和胰岛素抗性的抗性。野生型（WT）脂肪组织的单细胞RNA分析揭示了层粘连蛋白411在CD 45 + CD 31 + ICAM-1+脂肪基质细胞中的高表达。与WT同窝仔相比，Lama 4-/-小鼠中出现的这些细胞的数量显著更高，并且ATM减少。这表明ICAM-1+基质细胞在肥胖中的核心作用，并暗示层粘连蛋白411直接和/或通过改变ATM数量或功能来调节这些细胞。然而，层粘连蛋白411，ICAM-1+脂肪基质细胞和ATMs之间的关系仍然不清楚，我们假设ICAM-1+脂肪基质细胞和巨噬细胞之间的相互作用是至关重要的，在肥胖症的脂肪组织重塑，这些细胞群是由层粘连蛋白411调节。我们将调查1。ICAM-1在定向前脂肪细胞谱系特化中的作用以及层粘连蛋白411和巨噬细胞如何影响这一作用;2.组织驻留与浸润巨噬细胞对肥胖的贡献以及层粘连蛋白是否影响巨噬细胞浸润或其极化/表型;3. ICAM-1+脂肪基质细胞和巨噬细胞群体之间相互作用的分子性质，以及这是否受到层粘连蛋白的影响。