Microbiota-Induced Immune Activation Promotes Sensory Neuron Regeneration
Post by Leanna Kalinowski
The takeaway
Our skin microbiota, such as the bacteria Staphylococcus aureus, produce an accumulation of immune cells that accelerate sensory neuron regeneration following skin injury.
What's the science?
Barrier tissues, such as our skin, play an important role in both nervous and immune system functions. Our skin contains sensory nerve fibers that are involved in touch, pain, and temperature perception, along with being home to many bacteria, fungi, and viruses that compose the skin microbiota. Following infection or injury, it is important for rapid immune system activation to protect and restore all tissue components, including the sensory nerves. However, the exact role that the microbiota plays in activating the immune system for sensory nerve regeneration is unknown. This week in Cell, Enamorado and colleagues explored the role of microbiota-induced immune activation in sensory neuron regeneration following skin injury.
How did they do it?
The researchers first studied the relationship between the microbiota, immune system, and sensory neuron regeneration during homeostasis (i.e., when there was no skin injury). First, mice received either a topical application or intradermal injection of Staphylococcus aureus (S. aureus) bacteria, which is a microbiota that is commonly found on human skin. When S. aureus is applied topically, it produces an accumulation of T helper 17 cells (Th17) that help produce interleukin 17 (IL-17) and boost future immune system response. On the other hand, when S. aureus is injected intradermally, it causes a pathogenic effect that produces T helper 1 cells (Th1) that actively fight against infection. Following the administration of S. aureus, Th17, and Th1 cells were then collected and sequenced using RNA-seq. Next, to visualize where T cells were located relative to sensory neurons, the researchers topically applied S. aureus to mice engineered for sensory neuron visualization and imaged them using two-photon microscopy.
To test whether S. aureus-induced T cells could contribute to sensory nerve regeneration, the researchers deployed a model of skin injury that causes axonal damage. Mice that previously received topical administration of S. aureus had a small piece of ear skin removed with a small punch biopsy, after which the injury site was imaged under a microscope to visualize Th17 cells.
Finally, the researchers attempted to uncover the immune mechanism that underlies the relationship between the microbiota (i.e., S. aureus) and neuronal regeneration. First, they again deployed the above model of skin injury, this time in mice engineered to block the IL-17a response, after which the injury site was imaged under a microscope to visualize Th17 cells. Then, they isolated sensory neurons in vitro (i.e., in a petri dish), treated them with IL-17A, and sequenced them using RNA-seq.
What did they find?
From the first set of experiments, the researchers found several relevant genes that were upregulated in Th17 cells (i.e., from topical S. aureus) compared to Th1 (i.e., from injected S. aureus) cells. Most notably, several of these genes are responsible for tissue repair (e.g., Tgfb1, Vegfa, Pdgfb, Furin, Mmp10, and Areg), while others are responsible for neuronal interaction and regeneration (e.g., Neu3, Lif, Marveld1, Ramp1, Ramp3, Ccr4, and Tnfsf8). Further, the researchers also found a significant accumulation of Th17 cells that were located close to sensory neurons within the skin. Together, this shows that S. aureus leads to an accumulation of Th17 cells, located in close proximity to sensory neurons, with upregulated genes that are responsible for neuronal regeneration.
From the second experiment, the researchers found that mice who received topical S. aureus had an increased number of Th17 cells accumulating near the injury site compared to controls. This was associated with an increased area and volume of nerve fibers surrounding the injury site, suggesting that the immune response to topical S. aureus enhances neuronal regeneration.
From the final set of experiments, the researchers first found that topical S. aureus does not accelerate neuron regeneration in mice with a blocked IL-17a response. Further, they found that genes implicated in neuronal maintenance, response, and function were unregulated in isolated sensory neurons treated with IL-17A. Together, this suggests a crucial role for IL-17A in promoting sensory neuron regeneration.
What's the impact?
Results from this study show that immunity from the microbiota that live on our skin (e.g., S. aureus) can rapidly jump-start a response to tissue damage by promoting the repair of sensory neurons - an effect that is mediated by IL-17A. Further exploring these relationships may help pave the way for future therapeutic approaches to facilitating sensory neuronal recovery after a skin injury, such as psoriasis.