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Greg E. Lemke

 

Greg E. Lemke

Greg E. Lemke

Professor
Molecular Neurobiology Laboratory

"A biological system without the ability to be shut off is akin to the 'Sorcerer's Apprentice,' who set in motion a chain of events over which he had no control. Our work has revealed that TAM receptors ensure that the innate immune response to invading pathogens is strong enough to defeat these threats, but not so strong as to endanger the host."

Antigen-presenting cells or APCs, which provide the body's first line of defense against disease-causing bacteria and viruses, are constantly on the prowl in search of pathogens. When they encounter foreign invaders, they unleash a "cytokine storm"—a wave of chemical messengers that jumpstart the T and B cell response. When the invaders have been successfully vanquished, the APCs need to shut down; otherwise, a chronic inflammation ensues, overwhelming the regulatory mechanisms that normally distinguish "self" from "non-self," leading to autoimmune diseases such as lupus and rheumatoid arthritis.

In their latest study, Lemke and his team explored how the so-called TAM receptors (Tyro3, Axl, Mer) in mice stop the immune system from mounting an out-of-control, destructive inflammatory response against invading pathogens. When receptors studded on the surface of patrolling APCs encounter a pathogen, the cells release an initial burst of cytokines, which is then amplified in a second stage via a feed-forward loop working through cytokine receptors. But this same activation pathway trips the fuse that is designed to prevent the inflammatory response from spiraling out of control.

The researchers found that an essential stimulator of inflammation—the type 1 interferon receptor (IFNAR)— turns on the expression of Axl, a TAM receptor. Axl and IFNAR then physically bind together and activate SOCS genes, whose products are potent inhibitors of pro-inflammatory signaling pathways. Without TAM receptors, they discovered, the APCs never shut down after their initial activation, but remain in a state of red-alert.

Knowing how important TAM receptors are to the control of inflammation in mice will not only aid our understanding of human immune system disorders but might enable researchers to manipulate the switch in ways that could be clinically beneficial. For example, a drug that inhibited TAMs in the short term could be given along with a therapeutic vaccine in order to help the body mount a better immune response. Conversely, it may be possible to engage the TAMs early in an immune reaction to treat chronic autoimmune diseases such as lupus.

Lab Photo

Left to right:
Joe Hash, Jochem Bernink, Patrick Burrola, Becky Hensley, Nick Bevins, Greg Lemke, Michael Reber, Carla Rothlin, Christian Bose, Tal Burstyn-Cohen.
Not pictured: Thomas Vacik

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Greg E. Lemke

Faculty

Greg E. Lemke

Greg E. Lemke

Professor
Molecular Neurobiology Laboratory

Our laboratory is interested in the signal transduction molecules that mediate cellular interactions during development of the mammalian nervous and immune system. We employ several experimental models, most of them in the mouse, which exploit both cell culture and molecular genetics.

Over the last several years, we have focused in particular on three receptor protein-tyrosine kinase signaling systems: the ErbB receptors and their ligands of the neuregulin family, the Eph receptors and their ephrin ligands, and the Tyro 3 family receptors and their ligands Gas6 and protein S. We have investigated the roles that these proteins play in neural and immune development by engineering and then analyzing knock-out and knock-in mutations in their corresponding genes in the chick and mouse.

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