Botulinum Toxins Could Soothe Inflammation

Although the potent neurotoxins secreted by the bacterium Clostridium botulinum can cause paralysis and death, doctors sometimes inject tiny doses of the toxins under the skin. They do so to treat muscle spasms, relieve migraine headaches, and—perhaps most famously—smooth away wrinkles. Now researchers report that redirecting the toxins from nerve cells to immune cells could combat chronic inflammation (Biochemistry, DOI: 10.1021/bi201490t).

Botulinum toxins work by slipping into neurons and cleaving proteins called SNAREs. During nerve cell firing, these proteins help the cells release neurotransmitters. When botulinum toxins inactivate the SNAREs, nerve cells can no longer signal muscle cells to contract.

Other cell types also use SNAREs to secrete signaling molecules. For example, immune cells called macrophages promote inflammation by secreting a cytokine called TNF-α. Felix Yeh, Edwin Chapman, and their colleagues at the University of Wisconsin, Madison, wondered if they could use botulinum toxins’ SNARE-chopping ability to control the release of this signal. “We chose macrophages because chronic inflammation is a driving force behind many diseases, such as cancer, diabetes, rheumatoid arthritis, and atherosclerosis,” he says.

The challenge, Yeh says, was to force the toxins to target macrophages. To do so, the researchers incubated macrophages with botulinum B, one of seven botulinum neurotoxins, and an antibody that recognizes the toxin. They knew that the antibodies would bind to receptors on the surface of macrophages, which would then help pull the antibody and the bound toxin into the cell. Once inside the macrophages, the toxin could cleave SNAREs. As a result, they found, treated macrophages released about 50% less TNF-α than untreated cells.

Next the researchers tested if the toxins could disrupt inflammation. They injected mice with a chemical that causes inflammation and then injected the toxin and antibody into the animals’ body cavities. To prevent botulinum B from paralyzing the mice, the researchers first cut off the portion of the toxin that targets it to neurons. They found that after they treated the mice with the combination of the modified toxin and the antibody, the number of macrophages that came to the site of inflammation dropped by around 35%. When macrophages release TNF-α, they attract other macrophages, causing further inflammation. The mouse experiment suggests that by blocking TNF-α release, the toxin could help break the cycle of chronic inflammation, the researchers say.

Thomas Binz, a physiological chemist at Hannover Medical School, in Germany, calls the approach “a smart new idea that potentially allows treatment of chronic inflammation.” However, he says that the researchers still need to work out the mechanistic details. “It’s unclear why the toxin/antibody mixture interferes with TNF-α release but not with that of other cytokines,” he says.