The genesis of cutaneous neurogenic inflammation is a multi-step process requiring DC aggregation

Optogenetic activation of Trpv1-expressing nociceptors drives Type-17 inflammation in the absence of other inflammatory triggers. We found that two rounds of nociceptor activation were required for Il23a expression and maximal expression of Il1b and Il6, key drivers of Type-17 inflammation.

The first round of nociceptor activation triggered transient DC2 aggregation that required Substance P/Mrgprb2-dependent mast cell activation and mast cell-derived CCL2. Spatial transcriptomic analysis revealed that DC aggregation allowed the second nociceptor stimulation to efficiently activate DC via CGRPalpha. Thus, early neurogenic inflammation is a 2-step process: Substance P induces Mrgprb2-dependent mast cell activation and formation of DC aggregates that allow for efficient subsequent CGRPalpha-mediated DC activation.