Clinical, pathologic, and experimental studies support an important role for the macrophage in a broad spectrum of acute (e.g. pathogen infection, sepsis) and chronic inflammatory conditions (e.g. insulin resistance, atherosclerosis and tumorigenesis). Recent studies have defined distinct subsets of macrophages that subserve specific functions that critically regulate the inflammatory response. Macrophage phenotypes exist across an M1 to M2 polarization state in which M1 cells are operationally defined as """"""""classically activated"""""""" proinflammatory macrophages, while M2 cells constitute the """"""""alternatively activated"""""""" anti-inflammatory macrophage population. Despite the acknowledged importance of these two macrophage subsets, the molecular mechanisms that govern subset selection remain poorly understood. Members of the Kruppel-like family (KLF) of zinc finger class of transcription factors have been shown to critically regulate cellular growth and differentiation. Results of studies conducted under the auspices of this grant identified KLF4 as a novel and critical regulator of monopoiesis. In this application we focus on the role of KLF4 in macrophage subset selection and function. Preliminary studies in macrophage cell lines and primary cells (mouse and human) indicate that KLF4 expression is induced by M2 stimuli (e.g. IL-4 and IL-13) and reduced by M1 stimuli (e.g. LPS +INFg). Using gain and loss-of-function approaches, our studies on macrophage gene expression and effector functions strongly indicate that KLF4 polarizes macrophages towards an antiinflammatory M2 phenotype. Finally, our studies place KLF4 at an upstream level within the transcriptirs of the Kruppel-like family (KLF) of zinc finger class of transcription factors have been shown to critically regulate cellular growth and differentiation. Results of stu the transcriptional hierarchy regulating IL-4 induced M2a polarization.
In Aim 2, we will define the effect of reduced KLF4 expression on M2 effector functions ex vivo and in vivo.
The macrophage is a critical regulator of the body's response to acute and chronic inflammation. Recent studies from our group have identified a factor that regulates key aspects of macrophage biology. This proposal seeks to understand the mechanisms underlying the function of this factor with the goal of developing novel therapies for the treatment of inflammatory disease states.
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