Brain Immune Interactions In Type 2 Diabetes

描述（由申请人提供）：2型糖尿病（T2 D）的患病率在过去20年中急剧上升，美国糖尿病协会目前报告有2080万美国人患有这种疾病。正如我们所展示和回顾的，炎症，特别是IL-12/IL-1 RA平衡，对T2 D生物行为并发症的发展和持续至关重要。我们已经证明，在小鼠糖尿病模型中，神经免疫激活的严重程度增加和恢复延迟是由于IL-12反调节的失败，并且可以通过IL-1受体拮抗剂（IL-1 RA）给药来纠正。关键的是，我们已经发现糖尿病小鼠处于“IL-4抵抗状态”，并且IL-4是脂多糖（LPS）依赖性上调IL-1 RA的关键。因此，本研究项目的目的是检验以下假设：T2 D中神经免疫系统的激活由于关键的基于精氨酸的反调节抗炎通路的减弱而加剧。该项目的长期目标是制定消除和/或改善糖尿病促炎状态发展的策略，并防止其对大脑和行为的不良影响。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LPS恢复生物行为的重要性，因为与野生型小鼠相比，IL-4敲除（KO）小鼠显著增加了LPS诱导的疾病和较慢的恢复。此外，我们还发现了一种创新的方法来诱导小鼠中IL-4的表达，这种方法也增强了巨噬细胞的替代激活。我们已经发现，给小鼠喂食富含可溶性纤维的饮食会导致脑、脾和胃肠道（GI）中IL-4的显著上调，促进巨噬细胞产生IL-1 RA，并使小鼠对LPS诱导的社交退缩具有显著的抵抗力。重要的是，IL-4 KO小鼠没有从这种饮食中获益。总而言之，这些发现首次显示了IL-4对疾病和疾病恢复的潜在影响。他们还提供了IL-4如何调节神经免疫和疾病相关行为的见解。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依赖性疾病恢复是否依赖于IL-4驱动巨噬细胞替代活化表型的能力，以及它是否由IL-1/IL-1 RA平衡的IL-4依赖性调节介导。在目标#3中，我们将辨别可溶性纤维是否可以用于阻断疾病和/或改善疾病恢复，并确定它是否会在T2 D小鼠模型中起作用。需要这些研究来确定减轻T2 D患者痛苦的新目标。公共卫生相关性：2型糖尿病（T2 D）的患病率在过去20年中急剧上升。正如我们所展示和回顾的那样，炎症，特别是IL-12/IL-1 RA平衡，对T2 D生物行为并发症的发展和持续至关重要。重要的是，我们已经证明糖尿病小鼠处于“IL-4抵抗状态”，IL-4是IL-1 RA的脂多糖（LPS）依赖性上调的关键，并且是巨噬细胞替代活化表型的主要调节剂。因此，一个重要且富有成效的新研究领域正在研究T2 D中神经免疫系统的激活是否因关键的反调节抗炎途径的衰减而加剧，并制定消除和/或减轻糖尿病促炎状态发展的策略。成功完成我们的目标将为改善T2 D引发的不良生物行为提供具体目标。

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.