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年中急剧上升，美国糖尿病协会现在报告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-1RA平衡，对T2D生物行为并发症的发展和持续至关重要。我们已经证明，在糖尿病小鼠模型中，神经免疫激活的严重程度增加和恢复延迟是由于IL-12反调节失败，可以通过IL-1受体拮抗剂（IL-1RA）给予纠正。关键的是，我们已经证明糖尿病小鼠处于“IL-4抵抗状态”，并且IL-4是脂多糖（LPS）依赖性IL- 1RA上调的关键。因此，本研究项目的目的是检验T2D中神经免疫系统的激活是由关键的基于细胞因子的反调节抗炎途径的衰减而加剧的假设。该项目的长期目标是制定策略来消除和/或改善糖尿病促炎状态的发展，并防止其对大脑和行为的不利影响。为了支持这些目标，我们实验室令人兴奋的新初步数据揭示了IL-4对LPS诱导的生物行为恢复的重要性，因为与野生型小鼠相比，IL-4敲除（KO）小鼠明显增加了LPS诱导的疾病，恢复速度较慢。此外，我们还发现了一种在小鼠中诱导IL-4表达的创新方法，该方法也增强了巨噬细胞的替代激活。我们发现，给小鼠喂食富含可溶性纤维的饮食会导致大脑、脾脏和胃肠道（GI）中IL-4的显著上调，促进巨噬细胞IL-1RA的产生，并使小鼠对lps诱导的社交退缩产生显著的抵抗力。重要的是，IL-4 KO小鼠并没有从这种饮食中获益。总之，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，我们将确定哪些疾病症状是由IL-4控制的。在目标#2中，我们将确定依赖于IL-4的疾病恢复是否依赖于IL-4驱动巨噬细胞替代激活表型的能力，以及它是否由IL-4依赖的IL-1/IL-1RA平衡调节介导。在目标#3中，我们将确定可溶性纤维是否可用于阻止疾病和/或改善疾病恢复，并确定它是否适用于小鼠T2D模型。需要这些研究来确定减轻T2D患者痛苦的新靶点。

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.