Accumulation of macrophages in affected tissues is a common feature of chronic inflammatory diseases of the kidney, liver, adipose tissue and cardiovascular system that are the leading cause of morbidity and mortality worldwide. In mouse models of obesity and atherosclerosis, interference with inflammatory macrophage accumulation can reduce adipose tissue inflammation and insulin resistance, and progression of lesions of atherosclerosis. Recent findings suggest that local macrophage proliferation, rather than monocyte recruitment, is the key event for macrophage accumulation, but mechanisms initiating the macrophage proliferative response are poorly understood. This proposal will address this knowledge gap specifically in human leukocytes by building on novel observations made by our laboratory in mouse models that identify proteolytic cleavage of the cell surface form of macrophage colony-stimulating factor (csCSF-1), a potent stimulant of monoycte and macrophage proliferation, as a major event controlling proliferation of macrophages recruited to inflammatory sites. Further, our studies in mice identified macrophages and neutrophils as major sources of csCSF-1, which has previously been attributed to mesenchymal and epithelial cells. We propose two specific aims 1. To characterize cellular sources, intracellular localization and mechanisms controlling release of csCSF-1 from human leukocytes, including the role of the transmembrane protease ADAM17 and other enzymes; 2. To develop an antibody to the cleavage site in human csCSF-1 and test its efficacy in blocking inflammatory macrophage proliferation in a novel ?humanized myeloid csCSF-1? mouse model. Thus our proposed studies will clarify molecular mechanisms in human leukocytes controlling macrophage proliferation, and have the potential to develop strategies to interfere with macrophage accumulation, a major factor driving chronic inflammatory disease.
This proposal will determine the contribution of different human blood cells to the release of a major stimulant of inflammatory leukocyte accumulation in chronic inflammatory diseases, including obesity and atherosclerosis. An antibody to block the release of the human stimulant will also be developed and tested. Thus, the proposed studies have the potential to identify new strategies to prevent the buildup of leukocytes within fat tissue and blood vessels, and thus target chronic inflammatory diseases that remain the leading cause of morbidity and mortality worldwide.
|Tang, Jingjing; Frey, Jeremy M; Wilson, Carole L et al. (2018) Neutrophil and macrophage cell surface CSF-1 shed by ADAM17 drives mouse macrophage proliferation in acute and chronic inflammation. Mol Cell Biol :|