How Do Sensory Neurons Sense Danger Signals?. Issue 10 (October 2020) - Donnelly, Christopher R.
Abstract : Sensory neurons are activated by physical and chemical stimuli, eliciting sensations such as temperature, touch, pain, and itch. From an evolutionary perspective, sensing danger is essential for organismal survival. Upon infection and injury, immune cells respond to pathogen/damage-associated molecular patterns (PAMPs/DAMPs) through pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs), and produce inflammatory mediators that activate sensory neurons through neuro–immune interactions. Sensory neurons also express TLRs and other PRRs that directly sense danger signals after injury or during infection, leading to pain, itch, or analgesia. In addition to slow-acting canonical TLR signaling, TLRs function uniquely in sensory neurons through non-canonical coupling to ion channels, enabling rapid modulation of neuronal activity. We discuss how sensory neurons utilize TLRs and other PRR pathways to detect danger signals in their environment. Highlights: The detection of potentially hazardous stimuli is a fundamental property of both immune cells and peripheral sensory neurons. To detect danger signals, both cell types utilize specialized pattern recognition receptors (PRRs) that recognize pattern‐associated molecular patterns (PAMPs) from invading pathogens and damage‐associated molecular patterns (DAMPs) from damaged host cells. Sensory neurons express DAMP/PAMP-sensing toll‐like receptors (TLRs) that signal non-canonically through coupling to ion channels to effect rapid modulation of sensory neuron excitability. TLRs can also alter neuronal excitability via a slower MyD88-mediated canonical pathway. DAMP and PAMP-mediated modulation of peripheral sensory neuron excitability can evoke pain, itch, or analgesia. Databases emerging from RNA-Seq profiling of peripheral sensory neurons indicate that they express many additional PRRs beyond TLRs.