Fast and Furious: Neurons driving skin inflammation

       IL-23 is heretodimeric cytokine made of p40 and p19 subunits. IL-23 is produced by dendritic cells and can drive psoriasis-like skin inflammation characterized by epidermal hyperplasia. The therapeutic antibodies targeting p40 subunit of IL-23 has been shown to reduce psoriatic skin inflammation and represent one of the most successful example of translation of basic immunological knowledge to medicine.

     Immune system does not operate in isolation. It functions are primarily influenced by microbiota and surrounding tissues. This new paper from Nature addressed the role of skin neurons in driving psoriasis-like skin inflammation. The authors reveal new role of nociceptors (neurons sensing pain, heat, itch) in transmitting signals to local immune cells.

      This work (1) led by Urlich H. von Andrian studied the effect of imiquimod (IMQ) on psoriasis-like skin inflammation in mice. In general, IMQ is more known for its activation of Toll-like receptor 7 (TLR-7) and its analogs are used as an anti-viral topical medicine.

      First, the authors showed that application of IMQ on mouse ear induced skin swelling, cell infiltration and production of IL-23, IL-17, IL-17F, IL-22. Cellular analysis revealed that main cell population responsible for IL-17, IL-17F, IL-22 production were skin gamma-delta T cells.

     Second, the authors showed IMQ effect on IL-17, IL-17F, IL-22 production was mediated through IL-23 since this effect was lost in IL-23R-GFP mice lacking functional IL-23 receptor.

    Third, pharmacological inactivation of nociceptors with resiniferatoxin specifically reduced IMQ induced cell infiltration and abolished production of IL-23, IL-17, IL-17F, IL-22. However, application of IL-23 induced IL-17, IL-17F, IL-22 production even in presence of pharmacological inactivation of nociceptors implying that nociceptors effect was exclusively IL-23 mediated.

    To definitely address the role of nociceptors in IMQ induced psoriasis-like skin inflammation, the authors used mice genetically modified to deplete nociceptors, Nav1.8-diphtheria toxin (DTA). IMQ application on Nav1.8-DTA mice confirmed that IMQ effect was mediated through nociceptors.

    In summary, the authors proposed a neuroimmune model on initiation of psoriasis-like skin inflammation: activation of nociceptors triggers IL-23 production from local dendritic cells that in turn activates skin gamma-delta T cells producing IL-17, IL-17F, IL-22 leading to recruitment of cell infiltration in the affected skin.

   This model primarily addressed the role of innate immune system in initiation of skin inflammation. It is interesting that the authors totally ignored to mention if TLR7 played any role in this process. It is not clear either how can IMQ directly activate nociceptors.

David