Brain Immune Interactions In Type 2 Diabetes

描述(由申请人提供)：2型糖尿病(T2D)的患病率在过去20年里急剧上升，美国糖尿病协会现在报告称，有2080万美国人患有这种疾病。正如我们已经展示和回顾的，炎症，特别是IL-12/IL-1RA平衡，对T2D生物行为并发症的发生和持续至关重要。我们已经证明，糖尿病小鼠模型的严重程度增加和从神经免疫激活中恢复的延迟是由于IL-12反向调节失败，可以通过给予IL-1受体拮抗剂(IL-1RA)来纠正。重要的是，我们已经证明糖尿病小鼠处于“IL-4抵抗状态”，并且IL-4是依赖脂多糖(LPS)上调IL-1RA的关键。因此，本研究项目的目的是验证一种假说，即T2D中神经免疫系统的激活是由于关键的基于细胞因子的反调节抗炎通路的减弱而加剧的。该项目的长期目标是制定策略，以消除和/或改善糖尿病前炎症状态的发展，并防止其对大脑和行为的不利影响。为了支持这些目标，来自我们实验室的令人兴奋的新的初步数据揭示了IL-4对从内毒素中恢复生物行为的重要性，因为与野生型小鼠相比，IL-4基因敲除(KO)小鼠显著增加了内毒素诱导的疾病并且恢复得更慢。此外，我们还发现了一种诱导小鼠IL-4表达的创新方法，这种方法还可以增强巨噬细胞的选择性激活。我们发现，给小鼠喂食富含可溶性纤维的食物会导致脑、脾和胃肠道(GI)中IL-4的显著上调，促进巨噬细胞产生IL-1RA，并使小鼠对内毒素诱导的社交退缩产生戏剧性的抵抗。重要的是，IL-4KO小鼠不会从这种饮食中受益。总之，这些发现首次显示了IL-4对疾病和疾病康复的潜在后果。他们还提供了对IL-4如何调节神经免疫和疾病相关行为的洞察。在目标1中，我们将确定IL-4控制哪些疾病症状。在目标2中，我们将确定IL-4依赖的疾病康复是否依赖于IL-4驱动巨噬细胞选择性激活表型的能力，以及它是否通过IL-4依赖的对IL-1/IL-1RA平衡的调节来介导。在目标3中，我们将辨别可溶性纤维是否可以用来阻止疾病和/或改善疾病恢复，并确定它是否适用于T2D小鼠模型。需要这些研究来确定减轻T2D患者痛苦的新目标。公共卫生相关性：在过去20年中，2型糖尿病(T2D)的患病率急剧上升。正如我们已经展示和回顾的，炎症，特别是IL-12/IL-1RA平衡，对于T2D生物行为并发症的发生和持续是必不可少的。至关重要的是，我们已经证明糖尿病小鼠处于“IL-4抵抗状态”，而IL-4是依赖脂多糖(LPS)上调IL-1RA的关键，也是巨噬细胞选择性激活表型的主要调节因子。因此，一个重要而富有成效的新研究领域是研究T2D中神经免疫系统的激活是否因关键的反调节抗炎途径的减弱而加剧，并开发策略以消除和/或减轻糖尿病前炎症状态的发展。我们的目标的成功完成将为改善T2D引发的不良生物行为提供具体的目标。

DESCRIPTION (provided by applicant): The prevalence of type 2 diabetes (T2D) has risen dramatically in the last 20 years with the American Diabetes Association now reporting that 20.8 million Americans suffer from this disease. As we have shown and reviewed, inflammation, especially IL-12/IL-1RA balance, is vital to the development and persistence of biobehavioral complications in T2D. We have demonstrated that increased severity and delayed recovery from neuroimmune activation in mouse models of diabetes is due to a failure in IL-12 counter-regulation and can be rectified by IL-1 receptor antagonist (IL-1RA) administration. Critically, we have shown that diabetic mice are in a "state of IL-4 resistance" and that IL-4 is key to lipopolysaccharide (LPS)-dependent up-regulation of IL- 1RA.Therefore, the objective of this research project is to examine the hypothesis that activation of the neuroimmune system in T2D is exacerbated by attenuation of crucial cytokine-based counter-regulatory anti-inflammatory pathways. The long-term goal of this project is to develop strategies to abrogate and/or ameliorate the development of the diabetic proinflammatory state and prevent its adverse impact on the brain and behavior. In support of these aims, exciting new preliminary data from our laboratory reveal the importance of IL-4 to biobehavioral recovery from LPS because IL-4 knockout (KO) mice have significantly increased LPS-induced sickness and slower recovery when compared to wild type mice. In addition, we have discovered an innovative way to induce IL-4 expression in mice that, also, augments macrophage alternative activation. We have discovered that feeding mice a diet enriched in soluble fiber causes marked up-regulation of IL-4 in the brain, spleen and gastrointestinal (GI), boosts macrophage production of IL-1RA and affords mice dramatic resistance to LPS-induced social withdrawal. Importantly, IL-4 KO mice do not gain the benefit of this diet. Altogether, these findings are the first to show the potential consequence of IL-4 to sickness and sickness recovery. They also provide insight into how IL-4 would modulate neuroimmunity and sickness-associated behaviors. In Objective #1, we will determine what sickness symptoms are controlled by IL-4. In Objective #2, we will ascertain if IL-4-dependent recovery from sickness is reliant on the ability of IL-4 to drive the macrophage alternative activation phenotype and if it is mediated by IL-4-dependent regulation of IL-1/IL-1RA balance. In Objective #3, we will discern whether soluble fiber can be used to block sickness and/or improve sickness recovery and establish if it will work in mouse models of T2D. These studies are needed to identify new targets for the alleviation of suffering in those afflicted by T2D. PUBLIC HEALTH RELEVANCE: The prevalence of type 2 diabetes (T2D) has risen dramatically in the last 20 years. As we have shown and reviewed, inflammation, especially IL-12/IL-1RA balance, is essential to the development and persistence of biobehavioral complications in T2D. Critically, we have demonstrated that diabetic mice are in a "state of IL-4 resistance" and IL-4 is key to lipopolysaccharide (LPS)-dependent up-regulation of IL-1RA and a major regulator of the macrophage alternative activation phenotype. Therefore, a vital and fruitful new area of research is investigating if activation of the neuroimmune system in T2D is exacerbated by attenuation of crucial counter-regulatory anti-inflammatory pathways and developing strategies to abrogate and/or mitigate the development of the diabetic proinflammatory state. Successful completion of our objectives will provide specific targets for ameliorating adverse biobehaviors triggered in T2D.