Role of KLF6 in myeloid cell biology

描述(申请人提供)：临床、病理和实验研究支持巨噬细胞在多种急性(如感染、败血症)和慢性炎症(如肥胖和胰岛素抵抗)中发挥重要作用。最初的炎症反应是由促炎刺激激活的巨噬细胞(经典激活的M1巨噬细胞)协调的。相反，炎症过程的分解阶段是由交替激活的M2巨噬细胞进行的。经典激活的M1型巨噬细胞和交替激活的M2型巨噬细胞之间的平衡失调可能会导致各种人类疾病和炎症性疾病。因此，更好地了解这一现象具有相当大的科学和治疗意义。Kruppel样因子是锌指转录因子家族的一个亚类，它调节关键的细胞过程，如发育、分化、增殖和细胞程序性死亡。然而，KLF6在髓系细胞生物学中的作用是完全未知的。我们迄今的研究表明，(A)KLF6在人类败血症患者的髓系细胞中表达上调；(B)获得和功能丧失的研究表明，KLF6促进巨噬细胞M1极化，同时抑制M2极化；(C)KLF6髓系缺陷增加感染后宿主死亡率；(D)髓系KLF6缺乏减轻高脂饮食诱导的肥胖和糖耐量异常。为了更好地了解KLF6在巨噬细胞极化和功能中的确切作用，提出了以下三个目标。在目标1中，我们将研究KLF6在促炎(M1)巨噬细胞极化和功能中的作用。在目的2中，我们将评估KLF6的S抑制抗炎(M2)巨噬细胞极化的能力和功能。在目标3中，我们将阐明髓系KLF6在肥胖和代谢综合征发展中的作用。总的来说，这些研究将确定KLF6介导的巨噬细胞极化的分子基础以及炎症性疾病和紊乱的功能后果。这些研究的结果将为针对广泛的人类慢性和急性炎症性疾病的治疗的新疗法提供基础。

DESCRIPTION (provided by applicant): Clinical, pathologic and experimental studies support an important role for the macrophages in a broad spectrum of acute (e.g. infections, sepsis) and chronic inflammatory conditions (e.g. obesity and insulin resistance). The initial inflammatory response is orchestrated by macrophages activated by pro-inflammatory stimuli (classically activated M1 macrophages). In contrast, the resolution phase of the inflammatory process is conducted by alternatively activated M2 macrophages. The perturbation in balance between the classically activated M1-type and alternatively activated M2-type macrophages can contribute to various human diseases and inflammatory disorders. Therefore a better understanding of this phenomenon is of considerable scientific and therapeutic interest. Kruppel-like factors are a subclass of the zinc-finger family of transcription factors that regulate key cellular processes such as development, differentiation, proliferation and programmed cell death. However, the role of KLF6 in myeloid cell biology is completely unknown. Our studies to date indicate that, (a) KLF6 expression is elevated in myeloid cells derived from human septic patients; (b) gain and loss-of-function studies revealed that KLF6 promote macrophage M1 polarization while suppressing M2 polarization; (c) Myeloid deficiency of KLF6 enhanced host mortality following infection; (d) Deficiency of myeloid KLF6 attenuated high fat diet induced obesity and glucose intolerance. To better understand the precise role of KLF6 in macrophage polarization and function, following three aims are proposed. In Aim 1, we will investigate KLF6 contribution to pro-inflammatory (M1) macrophage polarization and functions. In Aim 2, we will evaluate KLF6's ability to suppress anti-inflammatory (M2) macrophage polarization and functions. In Aim 3, we will elucidate the role of myeloid KLF6 in development of obesity and metabolic syndrome. Collectively, these studies will define the molecular basis for KLF6-mediated macrophage cell polarization and the functional consequences in inflammatory disease and disorders. The results of these studies will provide the foundation for novel therapies directed at the treatment of a broad spectrum of human chronic and acute inflammatory disease conditions.