Finding a dimmer switch for IBD?
Date: January 3, 2011
Quelling chronic inflammation is in the back of Shukti Chakravarti’s mind as she maps a new path that appears to refine the intestine’s innate immune response—a route that may one day add sensitivity to inflammatory bowel disease (IBD) therapy.
Chakravarti, a cell biologist, has long focused on the basic science of proteins in the extracellular matrix (ECM)—the non-cell “stuff” comprising most of the cornea, cartilage and lining of the gut. For her, one protein called lumican has become singular. She’s shown, for example, how lumican engineers the cornea’s transparency by directing the way collagen molecules orient themselves.
But when she came to Hopkins in 2000, Chakravarti signed on to a broader view of ECM proteins, one that suggests they also regulate immune response and inflammation. “What we’re now finding about lumican,” she says, “is amazing.”
Lumican sits on inflammatory cells, neutrophils and macrophages, helping them recognize bacterial pathogens. The molecule may not be one of the “big dogs,” like the well-known Toll-like receptors on cell membranes. Their “bark,” upon recognizing pathogenic bacteria in the gut, sounds the alarm that results in inflammation. Lumican’s effect, however, is more subtle, Chakravarti’s found: It’s the collar on the “big dog,” regulating the Toll-like receptors’ ability to detect a pathogen. And now work in Chakravarti’s lab suggests a lumican role in IBD.
Earlier, her group developed a mouse model of chronic colitis by introducing a low-dose irritant into the animals’ colons. The model mirrors Crohn’s disease, with its transmural inflammation and cobblestone tissues. But to discover lumican’s role, the researchers used the intestinal irritant instead on knockout mice—those genetically manipulated not to make lumican.
“What we saw,” says Chakravarti, “is that in early-stage colitis, inflammation doesn’t develop properly without lumican. That, surprisingly, makes damage worse in the mice.” What gets muted without the molecule, she says, is the short-term inflammation that allows recovery—the acute response that brings the cleanup of cell debris and release of cytokines that actually help healing.
Knockout mice also have a hard time gaining lost body weight, a hallmark of IBD.
“So we think lumican adds another layer of control by modifying inflammatory response,” Chakravarti explains. “And we’re finding that it isn’t alone, that its relatives do similar things.” Chakravarti hopes her studies will prompt others to look for mutations in lumican or genes for similar-acting matrix proteins as risk factors for IBD.
“We also hope,” she adds, “that this work will lead to therapies that can help the early inflammation while damping the continued flareup that’s a problem.”