Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM, 87131, USA.
Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM, 87131, USA.
Sci Rep. 2018 Jun 11;8(1):8905. doi: 10.1038/s41598-018-27278-4.
Allergic asthma and obesity are major public health problems in the world. Recent Meta-analysis studies implicated a positive relationship between serum leptin, which is elevated in obese individuals, and the risk of asthma. However, it is not well understood how obesity-associated elevation of leptin increases the risk of asthma. In the current study, we have found that leptin induces the unfolded protein response factor XBP1s in an mTOR- and MAPK-dependent manner in pro-allergic TH2 cells; in vivo, mice fed with high fat diet had increased serum leptin as observed in human obese population and exacerbated asthmatic symptoms, associated with increased XBP1s expression in splenic CD4 T cells. XBP1s is required for leptin-mediated pro-allergic TH2 cell survival and cytokine production. Our results reveal a previously unappreciated insight that obesity-associated hyperleptinemia contributes to enhanced pro-allergic lymphocyte responses through induction of XBP1s, leading to exacerbation of allergic asthma.
过敏性哮喘和肥胖是全球主要的公共卫生问题。最近的荟萃分析研究表明，血清瘦素与哮喘风险之间存在正相关关系，而肥胖个体的血清瘦素水平升高。然而，人们尚不清楚肥胖相关的瘦素升高如何增加哮喘的风险。在本研究中，我们发现瘦素通过 mTOR 和 MAPK 依赖的方式诱导变应原性 TH2 细胞中的未折叠蛋白反应因子 XBP1s；在体内，给予高脂肪饮食的小鼠表现出与人肥胖人群中观察到的血清瘦素增加，并伴有哮喘症状加重，与脾 CD4 T 细胞中 XBP1s 表达增加相关。XBP1s 是瘦素介导的变应原性 TH2 细胞存活和细胞因子产生所必需的。我们的结果揭示了一个以前未被认识到的见解，即肥胖相关的高瘦素血症通过诱导 XBP1s 促进增强的变应原性淋巴细胞反应，导致过敏性哮喘加重。
