Netrin-1 in obesity-associated inflammation and metabolic dysfunction

肥胖及其合并症，如胰岛素抵抗、2型糖尿病和心血管疾病，在过去几十年中急剧增加，是对全球健康的主要威胁。肥胖的慢性炎症是由脂肪组织中促炎单核细胞的积累和滞留介导的。在瘦鼠和人的脂肪组织中，巨噬细胞主要是抗炎交替激活的m2巨噬细胞，通过分泌IL-10来维持脂肪细胞的胰岛素敏感性，而肥胖的脂肪组织中主要是促炎M1巨噬细胞，导致局部和全身慢性炎症的发生和持续。这些活跃保留的M1巨噬细胞是肥胖及其代谢后遗症之间的关键致病环节。神经元引导蛋白netrin-1在中枢神经发育过程中对轴突生长锥的生物学作用取决于其结合的受体。在之前的工作中，我们和其他人能够证明netrin-1影响外周的炎症过程，在急性和慢性炎症中具有不同的作用。最近的研究报道，netrin-1通过Unc5b阻断巨噬细胞对趋化因子的反应，阻碍巨噬细胞从脂肪组织中分泌，提高肥胖慢性炎症中的巨噬细胞存活率。因此，我建议明确netrin-1和Unc5b诱导肥胖巨噬细胞的机制。此外，我的目标是了解netrin-1和Unc5b维持肥胖相关慢性炎症和代谢功能障碍的机制。为此，我计划测试肥胖中巨噬细胞特异性netrin-1和/或Unc5b是否促进巨噬细胞潴留，改变巨噬细胞极化和代谢，维持代谢功能障碍和全身性炎症。了解netrin-1在肥胖中维持肥胖炎症的机制和关键途径，可能会开辟新的治疗方案，这些治疗方案将通过在已经肥胖的慢性炎症小鼠中删除巨噬细胞特异性netrin-1来进一步测试。

Obesity and its comorbidities, such as insulin resistance, type 2 diabetes and cardiovascular diseases, have dramatically increased over the past decades and are major threats to global health. Chronic inflammation in obesity is mediated by accumulation and retention of proinflammatory monocytes in the adipose tissue. While in lean mice and humans adipose tissue macrophages are mainly anti-inflammatory alternatively activated M2-macrophages, which maintain the insulin sensitivity of adipocytes by the secretion of IL-10, adipose tissue of obese is dominated by pro-inflammatory M1 macrophages contributing to the onset and the persistence of local and systemic chronic inflammation. These actively retained M1 macrophages are a key pathogenic link between obesity and its metabolic sequels. The neuronal guidance protein netrin-1 has dichotomous biological effects on the axonal growth cones in the developing central nervous development depending on the receptor it binds. In previous work we and others were able to demonstrate that netrin-1 impacts inflammatory processes in the periphery with divergent effects in acute and chronic inflammation. Recent work reported that netrin-1 blocks macrophage response to chemokines via Unc5b hindering macrophage egress from adipose tissue and enhancing macrophage survival in chronic inflammation in obesity. Therefore, I propose to identify the mechanisms causing netrin-1 and Unc5b induction on macrophages in obesity. Furthermore, I aim to understand the mechanisms by which netrin-1 and Unc5b sustain obesity related chronic inflammation and metabolic dysfunction. For this, I plan to test whether macrophage specific netrin-1 and/or Unc5b in obesity promote macrophage retention, alter macrophage polarization and metabolism and sustain metabolic dysfunction and systemic inflammation. Understanding mechanisms and identifying crucial pathways by which netrin-1 sustains obesity inflammation in obesity might open novel therapeutics options therapeutic which will be further tested by deleting macrophage specific netrin-1 in already obese mice with established chronic inflammation.