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.
Infection, sepsis, obesity, metabolic syndrome and its complication such as diabetes significantly contribute to the health care financial burden and are the major leading causes of mortality and morbidity in the United States. There is an increasing appreciation that inflammatory cells including macrophages can significantly alter these acute and chronic pathophysiological processes and this study addresses role of KLF6 in transcription regulation of macrophage polarization and function. Our studies to date indicated that KLF6 expression is altered in human septic patients suggesting that an understanding of its biology may potently impact human disease and therapeutic approaches for numerous pathological processes including, but not limited to, infection, sepsis and metabolic syndrome.