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Dynamic duo takes out the cellular trash

In most of the tissues of the body, specialized immune cells are entrusted with the task of engulfing the billions of dead cells that are generated every day. When these garbage disposals don’t do their job, dead cells and their waste products rapidly pile up, destroying healthy tissue and leading to autoimmune diseases such as lupus and rheumatoid arthritis.

Now, Salk scientists have discovered how two critical receptors on these garbage-eating cells identify and engulf dead cells in very different environments, as detailed in the journals Nature Immunology and eLife this past September.

“To target these receptors as treatments for autoimmune disease and cancer, it’s important to know exactly which receptor is doing what. And these discoveries tell us that,” says senior author of the work Greg Lemke, Salk professor of molecular neurobiology and the holder of Salk’s Françoise Gilot-Salk Chair.

The garbage-disposing cells, known as macrophages, have arrays of receptors on their surface, two of which–called Mer and Axl–are responsible for recognizing dead cells in normal environments and inflamed environments, respectively. Mer operates as a “steady-asshe- goes” receptor, clearing out dead cells in healthy tissues on a daily basis. Axl, in contrast, acts as an “all-hands-on-deck” receptor, kicking macrophages into action in inflammatory settings that result from infection or tissue trauma. These inflamed environments have many more dead cells.

“We thought Axl and Mer were doing the same job, and they are: they both recognize a so-called ‘eat me’ signal displayed on the surface of dead cells. But it turns out that they work in very different settings,” says Lemke, whose lab first discovered the two receptors–which, along with a third, make up the TAM family–two decades ago. The receptors have since become a growing focus for cancer and autoimmune research, as well as research in other areas.

In the new work, the researchers found multiple critical differences between Axl and Mer.

Greg Lemke, Erin Lew, Anna Zagórska and Paqui Gonzalez of the Molecular Neurobiology Laboratory

From left: Greg Lemke, Erin Lew, Anna Zagórska and Paqui Gonzalez of the Molecular Neurobiology Laboratory

“The results were very striking,” says Anna Zagórska, first author of the Nature Immunology paper, which detailed Axl and Mer’s two different roles. “In response to many different pro-inflammatory stimuli, Axl was upregulated and Mer was not. In contrast, immunosuppressive corticosteroids, which are widely used to suppress inflammation in people, upregulated Mer and suppressed Axl.”

“Understanding how these two receptors act differently–one during inflammation and one during homeostasis–will allow us to design targeted therapies for a number of autoimmune diseases,” says Erin Lew, first author of the eLife paper, which demonstrated how the two receptors use different molecules–called ligands–to become activated. For both receptors, their ligands must bind to the ‘eat me’ signal on the surface of dead cells and simultaneously to the receptors to activate the garbage-disposing mechanism of the cell.

The work further details how Axl’s ligand, once engaged, is quickly cleaved from the surface of the macrophage. Levels of the free-floating Axl in the blood have turned out to be an accurate, general biomarker for inflammation, quickly showing up in the circulation after tissue trauma or injury.

Next, the researchers are looking into each receptor’s activity in more detail. The team is finding that these receptors are unusual in that they have a three-step binding procedure, whereas most cell receptors bind in one step. Exploring and understanding this process will help to lead to more targeted therapeutics for cancers and other diseases in which the receptors are thought to act.