The accumulation of cellular and molecular debris in the extracellular compartment must be precisely regulated to preserve tissue integrity. We are interested in discovering the pathways that regulate the removal of matrix molecules (collagen) and cellular debris (apoptotic cells) under normal and pathological conditions. Our long-term objective is to understand how these fundamental pathways maintain tissue homeostasis by regulating the constituents of the extracellular compartment.
Collagen homeostasis is a dynamic process with exquisite control of collagen production and degradation maintaining normal tissue architecture. With injury, both collagen production and degradation are increased with the balance between these two opposing processes determining whether tissue fibrosis occurs. From this perspective, the development of fibrotic disease can be viewed as a failure of collagen degradation. While many of the pathways that lead to increase collagen production have been characterized, very little is known about the pathways that regulate removal of collagen from the extracellular matrix. We have recently found that the extracellular glycoprotein Mfge8 is used by macrophages to resorb collagen from areas of tissue fibrosis. Mfge8 knockout (KO) mice develop an exaggerated fibrotic response to lung injury and have a defect in collagen degradation in vivo. Mfge8 binds collagen directly and Mfge8 KO macrophages have impaired uptake of collagen. This pathway is the first evidence that removal and cellular internalization of collagen is a biologically important mechanism in diminishing the severity of the fibrotic response to injury. We plan to build on these observations by focusing on 3 fundamental questions: How is collagen internalized by cells? Which cell types remove collagen under homeostatic and pathological conditions? What are the molecules involved in collagen binding, uptake and degradation? A better understanding of the pathways that regulate collagen turnover should provide new therapeutic targets for the treatment of fibrotic disease.
Orderly apoptotic cell clearance is a fundamental process that has implications for many basic biological processes including morphogenesis, tissue remodeling, and the regulation of immunity. Clearance of apoptotic cells actively suppresses inflammation by preventing cell necrosis and by stimulating production of anti-inflammatory cytokines. Apoptosis is an ongoing process in the lung where epithelial cell turnover is repeatedly induced by exposure to inhaled toxins. With lung injury, the volume of cells undergoing apoptosis increases due to accelerated apoptosis of resident parenchymal cells and apoptosis of infiltrating inflammatory cells. The immune-modulatory effect of apoptotic cells may be particularly important in the lung both in maintaining the characteristic immune tolerant environment and accelerating resolution of injury-induced inflammation. Most, if not all cells are capable of ingesting apoptotic cells. There is increasing evidence that nonprofessional phagocytes (such as epithelial cells) play a critical role in this process. We have shown that in the involuting mammary gland, epithelial cells are the dominant phagocyte and use an Mfge8-dependent pathway to clear the vast majority of apoptotic cells.
We are interested in delineating the role of apoptotic cell clearance in modulating the immune environment of the lung with an emphasis on differentiating the role of professional and nonprofessional phagocytes in this process. We have focused our studies on answering the following questions: How does apoptotic cell clearance modulate the response to deleterious stimuli? What are the roles of professional and nonprofessional phagocytes in apoptotic cell clearance under homeostatic and disease conditions? What are the pathways of apoptotic cell clearance and how are they different and nonprofessional phagocytes as compared with professional phagocytes?
Atabai K, Jame S, Azhar N, Kuo A, Lam M, McKleroy W, DeHart G, Rahman S, Xia D, Melton A, Wolters P, Werb Z, and Sheppard D. Mfge8 diminishes the severity of tissue fibrosis in mice by binding and targeting collagen for uptake by macrophages. J Clin Invest. 2009 Dec;119(12):3713-22. PMID: 19884654.
Nandrot EF, Anand M, Almeida D, Atabai K, Sheppard D, Finnemann SC. Essential role for MFG-E8 as ligand for avb5 integrin in diurnal retinal phagocytosis. Proc Natl Acad Sci (USA) 2007; 104:1205-10. PMID:17620600.
Atabai K, Sheppard D, and Werb Z. Roles of the Innate Immune System in Mammary Gland Remodeling during Involution. J Mammary Gland Biol. Neoplasia, 2007, Mar;12(1):37-45. PMID: 17286210.
Atabai K, Fernández R, Huang X, Ueki I, Kline A, Li Y, Sadatmansoori S, Smith-Steinhardt C, Zhu W, Pytela R, Werb Z, Sheppard D. Mfge8 Is Critical for Mammary Gland Remodeling during Involution. Mol Biol Cell. 2005 Sep 29. PMID:16195353.
Atabai K, Ishigaki M, Geiser T, Ueki I, Matthay MA, Ware LB. Keratinocyte growth factor can enhance alveolar epithelial repair by nonmitogenic mechanisms. Am J Physiol Lung Cell Mol Physiol. 2002 Jul;283(1):L163-9.