Figure 2. Neuroimmune interactions in skin infection and psoriasis.

Several pathogens, such as Candida albicans, Staphylococcus aureus, and Streptococcus pyogenes have been determined to interact with sensory nerves in the skin to drive neuro-immune modulation. Pathogenic activation of sensory nerves leads to release of neuropeptides that modulate immune cells during infection, affecting infection and disease outcome. a) The pathogenic yeast, C. albicans, activates sensory nerves during epicutaneous infection to release the neuropeptide CGRP, which augments the release of IL-23 from CD301b⁺ dermal dendritic cells (dDCs). IL-23 then drives IL-17 release from γδ T-cells, which mediates resistance against C. albicans due to induction of polymorphonuclear neutrophil (PMN) recruitment and expression of antimicrobial peptides (AMPs) [24]. In a mouse model of psoriasis, a similar neuroimmune interaction was found: sensory nerves mediate IL-23 release from dDCs which mediate IL-17 release by γδ T-cells that contribute to psoriatic inflammation and plaque formation [23]. A similar neuro-immune mechanism operates during psoriasis-like inflammation. b) S. pyogenes and S. aureus are two bacterial pathogens known to cause painful and invasive skin infections such as abscesses, cellulitis, and necrotizing fasciitis. These pathogens directly activate sensory nerves via pore-forming toxins to produce pain and to release CGRP from their nerve terminals. In S. pyogenes infection, CGRP prevents the recruitment of neutrophils (PMNs) and the subsequent killing of the bacteria, worsening the infection outcome and bacterial clearance [53]. In S. aureus infection, nociceptor release of CGRP decreases TNFα production from macrophages and lymph node hypertrophy, subsequently decreasing bacterial killing [50].