How skin cells team up to fight pathogens

SFamily protects our bodies from the dangers of the world, but sometimes, with a nick or a bump, that barrier is broken. This is when nociceptor neurons sensitive to pain and itch kick in, transmitting threat signals to the central nervous system, while dendritic cells eliminate pathogens by secreting cytokines and coordinating local inflammation, while also playing a role in adaptive immunity.

But this work isn’t done in isolation: dendritic cells (DCs) and nociceptors are entangled in a powerful partnership, and a new study published March 31 in Science describes three unique ways these intertwined cells communicate to fine-tune the fight against invaders.

In the early 2010s, clinicians observed that people with psoriasis, an autoimmune inflammatory skin condition, who also had nerve damage, did not suffer from the disease’s hallmark skin lesions in the injured area. When the nerve heals, however, the lesions reappear. Lorena Riol-Blanco and Ulrich von Andrian, immunology researchers at Harvard University, were intrigued, and in 2014 their team discovered for the first time that DCs interact with nociceptors. They discovered that this relationship is necessary for an inflammatory response: DCs sit on the axons of nociceptors and need a signal from them to make the cytokine interleukin (IL)-23, which is the main motor of inflammation of the skin in psoriasis.

The precise nature of this relationship, however, eluded them. “We didn’t know what language was spoken there,” says von Andrian The scientist. Answering “the question ‘How exactly does it work?’ was a five-year process.

Since the 2014 research used live mice, postdoctoral researcher Pavel Hanc, von Andrian and their team could not determine with certainty which of the different cell types was involved in nociceptor-DC communication. To narrow it down, the researchers first wanted to determine if the nociceptors were talking directly to the DCs, or if there was an unknown third cell relaying the message. They set up a co-culture system with neurons from the dorsal root ganglia (including nociceptors) and dendritic cells from the bone marrow. The team then treated the cultured cells with a compound that causes psoriasis-like inflammatory disease in mice and found that the DCs produce more cytokines in the presence of the neurons – no other cell type was needed.

Next, they looked at what happened when neurons and dendritic cells shared the same culture medium but were separated by a filter that prevented them from touching. They found that the DCs were “actively trying to squeeze through these filter holes to find the neurons,” says von Andrian. The researchers reasoned, he adds, that there must be some sort of “find me” signal coming from the nociceptor. So they used multiplexed assays to identify several known chemoattractants in the nociceptor-conditioned medium, and when they depleted one of the most abundant, a chemokine called CCL2, migration of DCs to the nociceptor-conditioned medium was considerably decreased. Nociceptors release CCL2 in greater quantities when stimulated (in vivo, this stimulation would feel like pain or an itch). Nociceptors taken from mice genetically engineered to lack CCL2 did not attract DCs as well as those from wild-type mice.

Microscopy image showing two dendritic cells (green) communicating with a nociceptor neuron (purple).

Microscopy image showing two dendritic cells (green) communicating with a nociceptor neuron (purple).


“The concept of neurons calling and holding DCs in place through the release of CCL2 is well done and novel, so it’s very exciting,” says Caroline Sokol, a neuroimmunologist at Massachusetts General Hospital who has not worked on the study.

The team also analyzed the DC transcriptome in the presence or absence of nociceptors and found that 983 genes showed altered expression patterns between the two conditions. They found that a neuropeptide called CGRP released by nociceptor neurons induces a transcriptional program responsible for most of the gene expression changes in DCs that allow them to fight off pathogens. One of the most important changes is that CGRP triggers DCs to produce pro-IL-1beta, which is the biologically inactive precursor to an important cytokine that DC stores for use in inflammation and d other cellular activities.

“[Dendritic cells are] a sort of sentinel guard sitting in our barrier tissues on the lookout for any invading pathogens,” says von Andrian. “So we interpret this CGRP signal from the nociceptors as a kind of ‘get ready’ signal” that primes the DCs so that they are ready to be activated, he explains.

Using calcium imaging, the team found a third communication pathway between DCs and nociceptors. They knew that cells had to physically touch each other for DCs to produce cytokines. To see if the cells communicated via this touch, they first treated the nociceptors in contact with the DCs with capsaicin (the fiery component of chili peppers that activates nociceptors to induce the sensation of pain). This led to a rapid increase in intracellular calcium in both the neuron and the adjoining DC; this did not occur when DCs alone were treated with capsaicin. The team determined that the neuron’s action potential extends to the DC in contact with the neuron, opening channels in the DC that allow calcium to enter the cell, causing the membrane to temporarily depolarize. When accompanied by a microbial immune stimulus directly to the DC, this increased calcium inside the cell has downstream effects that lead to an increased cytokine response. So essentially that third signal is “go,” says von Andrian.

Sokol says “They’ve done a really nice job here, and it begs other researchers to look at the same kind of output but with really diverse real-world DC subsets that can respond to a whole host of different neuropeptides. .”

This work could eventually lead to better drugs to treat inflammatory diseases, says von Andrian, who has been involved in several companies (none of which have to do with nociceptors). But he also says he finds it fascinating to understand how dendritic cells and nociceptors work together as a neuro-immune unit in skin and mucous membranes. “They just use different ways to probe our bodies for the presence of injuries or infections,” he says. “So teleologically, it makes perfect sense that these systems evolved together and were sort of in cahoots to do the best job possible of protecting us.”

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