May 11, 2001 CHAPEL HILL - Along with derailing the body's rapid disposal of dying cells, defective functioning of a gene identified at the University of North Carolina at Chapel Hill also may contribute to tissue inflammation and the development of autoimmune diseases such as systemic lupus erythematosus.
A report of the new findings appears in the May 10 issue of Nature, the international science journal.
The report focuses on the function of a gene called Mer, which is expressed as a receptor on monocytes and macrophages, scavenger cell that circulate throughout the body or reside in tissue and ingest dead tissue and degenerated cells. Together with the genes Axl and Tyro3, Mer comprises a family of molecules known as receptor tyrosine kinases, which serve multiple functions in different tissues.
Scientists at the UNC School of Medicine's Lineberger Comprehensive Cancer Center led by director H. Shelton Earp III, MD cloned human and mouse Mer in 1995. This achievement led to their development of a Mer knockout mouse, a strain of mice defective in Mer function, which would provide insights to the function of Mer.
UNC researchers have been studying the role of Mer in cancer development because Mer, like Axl, is found on cancer cells. After further study, it appears that Mer is also an important player in phagocytosis, the rapid clearance from tissue of dying, or apoptotic, cells. Phagocytosis of other particles and bacteria occur by other mechanisms independent of Mer.
"This paper details the knockout mouse research and describes the basic mechanisms involved in the clearing of apoptotic cells particularly by macrophages," said study co-author Glenn K. Matsushima, PhD, a molecular neuroimmunologist at the UNC Neuroscience Center. "We show that mutating this receptor prohibits the ingestion of apoptotic cells."
In the study led by Rona S. Scott, PhD, of Matushima's lab, thymus cells that had been made apoptotic by treatment with the corticosteroid dexamethasone were placed in culture dishes with macrophages taken from the knockout mice and normal mice. After about an hour in the dishes, it was clear that macrophages from normal "wild type" mice had ingested apoptotic cells while macrophages carrying defective Mer ingested far fewer.
To make the mutation, Earp, Beverly Koller, PhD and graduate assistant researcher Todd D. Camenisch, had deleted the molecule's cytoplasmic tail. Thus, without Mer, macrophages apparently can still recognize and bind apoptotic cells but cannot ingest them.
"So the signal to ingest is missing due to the deletion of the receptor's cytoplasmic tail," Matsushima explained. "And because of this inability to quickly clear apoptotic cells, the cells eventually degenerate, releasing their internal components."
The consequences can eventually play out as an autoimmune response. The body sees this spilled material from its own cells as foreign and makes antibodies to it. "By not clearing this material as rapidly as you should, you end up developing antibodies against 'self material' that you shouldn't have," Earp said.
In terms of possible adverse effects, Earp, Matsushima and co-authors collaborated with researchers at the Salk Institute, La Jolla, California. There, "triple knockout studies" involving all three genes - Axl, Mer and Tyro3 - resulted in animals with several abnormalities that included blindness, neurological abnormalities and enlarged spleen, all due to increased numbers of apoptotic cells. Other studies implicate Mer defects in the development of retinal degeneration typical of retinitis pigmentosa, an eye disorder associated with atrophy of the retina's inner layer. In animal studies, a failure of retinal pigment epithelial cells to clear outer segments of cells that had been shed resulted in the death of photoreceptors. "Indeed, preliminary studies indicate our mice carrying the defective Mer show retinal degeneration," Matsushima said.
Moreover, "some human patients with retinitis pigmentosa have been shown to contain mutations in the Mer gene," the Nature authors stated.
There is also a possible link to the autoimmune disorder systemic lupus erythematosus. "It has been reported that some patients with SLE have deficits in their macrophages and their ability to clear cells," said Matsushima. Such a deficiency suggests that the mer knockout mouse may be a suitable animal model for studying SLE, the study authors stated. Still, a defective Mer gene in SLE patients has not been identified.
Mer might also be involved in dampening the body's inflammatory response. "We believe Mer is involved in down-regulating pro-inflammatory cytokines. And the process of clearing apoptotic cells is a signal to down-regulate inflammation," Matsushima said.
"It's very exciting to see a real physiologic function for this molecule emerge from research and to show it may be important in diseases of immune origin," Earp said.
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