Environmental Factor, May 2010, National Institute of Environmental Health Sciences
Stanford Scientist Discusses Macrophage Activation
By Thaddeus Schug
On April 20, Ajay Chawla, M.D., Ph.D., visited NIEHS to discuss his research, which involves determining the role of nuclear receptors in macrophage activation and inflammatory disease. Chawla, an endocrinologist and assistant professor of medicine at Stanford University, presented a seminar titled "PPAR Regulation of Macrophage Activation in Health and Disease," as part of the Laboratory of Signal Transduction Seminar Series.
Chawla(https://bms.ucsf.edu/directory/faculty/ajay-chawla-md-phd) began his talk by telling his at-capacity audience, "Chronic inflammation is an underlying factor in the development of several pathological disorders including obesity-associated metabolic disease, heart disease, atherosclerosis, and autoimmune disease. Macrophages, which are white blood cells and part of the innate immune system, play key roles in regulating the body's inflammatory response to pathogens, cellular debris, and environmental stimuli."
Chawla's group has identified a signaling pathway that determines whether macrophages become classically activated (M1) and prone to inflammation, or alternatively activated (M2) and therefore more involved with tissue repair.
PPARs control macrophage activation
According to Chawla, the lipid-sensing nuclear receptor, PPAR delta, controls the phenotypic switch between M1 and M2 activation in the macrophage. "We used a bone marrow transplant trick commonly used by immunologists, to show that PPAR delta-deficient hepatic macrophages were less prone to alternative activation. Loss of PPAR delta in macrophages resulted in liver dysfunction and whole-body insulin resistance in the mice."
Chawla explained that, in addition to impairments in activation status, PPAR delta-deficient macrophages display disrupted fatty acid metabolism. He noted that M1 macrophages tend to migrate to and take residence in white adipose tissue (WAT). High levels of WAT macrophages further predispose mice to chronic inflammation, obesity, and disrupted insulin signaling.
Disruptions in macrophage activation cause autoimmune disease
Shifting gears, Chawla observed, "Macrophages are also known as the scavenger cells of the immune system." They are responsible for disposing of dead cells or cells undergoing programmed cell death called apoptosis. He added, "If you don't clear the dying cells, then they can provide antigens against ourselves, leading to development of autoimmune diseases such as lupus." It is estimated that lupus affects 1.5 to 2 million people in the United States.
When macrophages consume dying cells, certain genes, called opsonins, are activated to assist in debris clearance. Chawla discovered that PPAR delta appears to control expression levels of opsonins and is therefore essential in arranging the timely disposal of dying cells. PPAR delta-deficient macrophages are unable to efficiently clear apoptotic cells, resulting in buildup of modified lipids and dangerous antigens.
Chawla said that PPAR agonists, or drugs that are traditionally used to treat diabetes and metabolic disorders, also aid macrophages in debris clearance. Chawla's findings provide both a better understanding of the cause of autoimmune disease and potential for development of drugs or screening procedures used for disease prevention.
Citation: Mukundan L, Odegaard JI, Morel CR, Heredia JE, Mwangi JW, Ricardo-Gonzalez RR, et al(http://www.ncbi.nlm.nih.gov/pubmed/19838202) . 2009. PPAR-delta senses and orchestrates clearance of apoptotic cells to promote tolerance. Nat Med 15(11):1266-1272.
(Thaddeus Schug, Ph.D., is a postdoctoral research fellow in the NIEHS Laboratory of Signal Transduction.)
Summer of Discovery Student Joins Lab at Stanford
Following two successful internships at NIEHS, former Summer of Discovery student Ashwin Peres-da-Silva has joined the lab of Ajay Chawla at Stanford Medical School. Peres-da-Silva participated in the NIEHS program during his junior and senior years, 2008-2009, while a student at the North Carolina School of Science and Math. Peres-da-Silva conducted research in the in the laboratory of Mammalian Aging Group Principal Investigator Xiaoling Li, Ph.D.(http://www.niehs.nih.gov/research/atniehs/labs/lst/mammalian/index.cfm)
Peres-da-Silva's project involved determining the role of the SIRT1 gene in regulation of macrophage biology. Together with his mentor, Thaddeus Schug, he learned bone marrow cell harvesting and cell culture techniques that he continues to employ in his new lab at Stanford.
Chawla noted that Peres-da-Silva has done very well in his lab and that the experience that he obtained at NIEHS has made him a well-equipped scientist. Peres-da-Silva was recently awarded a Stanford University Vice Provost for Undergraduate Education Major Grant, which will allow him to continue his research through the summer of 2010.