Immunity system complexity: skin protections (Introduction)

by David Turell , Tuesday, July 04, 2023, 15:16 (298 days ago) @ David Turell

Immune cells and pain neurons act together:

https://www.the-scientist.com/news-opinion/how-cells-in-the-skin-team-up-to-fight-patho...

"Skin shields our bodies from the world’s dangers, but sometimes, with a nick or a bump, that barrier is breached. That’s when pain- and itch-sensing nociceptor neurons jump to action, 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 is not 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.

"...their team discovered for the first time that DCs interact with nociceptors. They found that this relationship is necessary for an inflammatory response: DCs sit on nociceptor axons and require a signal from them to make the cytokine interleukin (IL)-23, which is the master driver of psoriasis skin inflammation.

***

“'The concept of neurons calling and keeping the DCs in place through CCL2 release is well-done and new, so that is very exciting,” says Caroline Sokol, a neuroimmunologist at Massachusetts General Hospital who didn’t work on the study.

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

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

"Using calcium imaging, the team found a third way that DCs and nociceptors communicate. They knew that the cells had to physically touch each other for DCs to produce cytokines. To see whether the cells communicated via this touch, they first treated the nociceptors in contact with 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 abutting DC; this did not occur when DCs alone were treated with capsaicin. The neuron’s action potential, the team determined, extended to the DC in contact with the neuron, opening channels in the DC that allow calcium to stream into the cell, causing temporary membrane depolarization. When accompanied by a microbial immune stimulus directly on the DC, this increased calcium inside the cell has downstream effects that lead to an enhanced cytokine response. So, essentially, this third signal is “go,” says von Andrian."

Comment: This degree of complexity must be designed all at once.