The genesis of cutaneous neurogenic inflammation is a multi-step process requiring dendritic cell aggregation.

Cutaneous inflammation involving neuroimmune interactions can be initiated by both neurons and immune cells, making it complicated to parse the mechanisms of neurogenic inflammation. 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 type 2 dendritic cell (DC2) aggregation that required substance P-Mrgprb2-dependent mast cell activation and mast cell-derived chemokine CCL2. Spatial transcriptomic analysis revealed that DC aggregation allowed the second nociceptor stimulation to efficiently activate DCs via the neuropeptide calcitonin gene-related peptide α (CGRPα). Thus, early neurogenic inflammation is a two-step process: substance P induces Mrgprb2-dependent mast cell activation and formation of DC aggregates that allow for efficient subsequent CGRPα-mediated DC activation. These data reveal a multi-cell, dynamic mechanism underlying neurogenic inflammation.