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April 23, 2014
It’s a phenomenon familiar to doctors treating patients in the clinic or scientists searching case reports in the medical literature. When the web of nerves underneath the skin is broken by surgery or injury, the red, sometimes painful, scales of psoriasis fade away—but the lesions return when nerves heal and feeling is restored.
Scientists have long wondered about that severed connection. What else are those nerves doing, beyond sending the brain one-way messages that say hot or cold or itchy?
Now, researchers led by Lorena Riol-Blanco and Jose Ordovas-Montanes, both members of Ulrich von Andrian’s lab at Harvard Medical School, have discovered a detailed answer to that question, showing how specific sensory neurons drive specialized immune cells to provoke the inflammation that is the hallmark of psoriasis. Working with a model of the disease in mice, they have revealed how this neuroimmune crosstalk bypasses components of the larger immune system—conventional T cells and lymph nodes that had been previously assumed to play a role—when nerve cells take control, signaling nearby immune cells to mount a local immune response.
“Anecdotal evidence suggested that the sensations from the peripheral nervous system were actually controlling the immune responses,” Riol-Blanco, a postdoctoral scientist, said about neurons distant from the brain. “Now we can pinpoint the specific sensory fibers that are talking to immune cells.”
These findings are reported in Nature.
The skin itself serves as both a barrier to invading threats and a boundary between the body and the environment that senses harm. The research team discovered that just beneath the skin’s surface, specialized immune cells called dermal dendritic cells are closely interwoven with sensory neurons. The dendritic cells produce interleukin-23, a molecule that can set off a cascade of inflammation—a helpful response when infection is the foe but a harmful reaction in autoinflammatory diseases such as psoriasis.
While peripheral nerves are composed of several types of sensory neurons, specific nerve cells transmit sensations to the brain that are perceived as pain, itch or uncomfortable temperature. How they work with neighboring dendritic cells is what the team teased out. To understand those cellular mechanisms, the team studied mice treated with a drug that induces local inflammation mimicking psoriasis.
First, the scientists needed to address the involvement of players in the systemic immune response: lymph nodes, which swell in the presence of infection, and T cells, the immune cells typically called into action when a threat is detected. Blocking these immune elements had no effect on inflammation in the mice. The lymph nodes seemed completely irrelevant, lending strength to the idea that the immune response was strictly local.
The scientists also asked whether the sensory nerve cells were interacting with T cells further downstream in the inflammatory cascade. That was not the case. Dendritic cells act like “generals” in the skin, talking to a specialized subset of skin resident T cell “soldiers” involved in the inflammatory fight; they accomplish this by dispatching interleukin-23 molecules that send the inflammatory message down the chain of command and induce the pathological changes. In a series of experiments, the scientists identified the specific pain-sensitive neurons that are essential to driving interleukin-23 production and, hence, the ensuing inflammatory response by nearby dendritic cells.
“When you got rid of this particular subset of sensory nerves, there was a dramatic reduction in inflammation,” Ordovas-Montanes, a graduate student at HMS, said. “What makes this really exciting is that you have something that could be local in the control of these key inflammatory cytokines. We want to investigate what the nerves are relaying to the dendritic cells to see if that’s a signal you could interrupt in a more specific fashion in the skin” without affecting overall immune function.
This discovery opens new avenues for the treatment of inflammatory disease in the skin and perhaps the gut, the scientists said, but much more work needs to be done to determine the precise molecular details of the neuroimmune conversation. Their findings pinpoint pain-sensing neurons as regulators of a clinically relevant cytokine that has been linked to several autoimmune and autoinflammatory diseases.
“We know there is a critical instructive communication between the nerves and the dendritic cells, but we don’t know what the language is,” said von Andrian, the Edward Mallinckrodt Professor of Immunopathology at HMS. “We need to understand the language and then we can hopefully devise an approach to rephrase these instructions pharmacologically in a way that this misinformation provided by the nerves to the dendritic cells is rectified.”