In a study published in the journal Immunity, Sakeen Kashem and colleagues report that in the murine skin, interleukin (IL)-23, derived from CD301b+ DCs drives IL-17A production by γδ T cells, and this cytokine network is required to establish resistance to cutaneous candidiasis.
Production of IL-17 by tissue-resident lymphocytes is mediated by pro-inflammatory cytokines such as IL-23. IL-23 signaling plays a critical role against mucocutaneous candidiasis as shown by the fact that humans with IL-23R signaling defects are prone to CMC and mice with IL-23 deficiencies are susceptible to oral and cutaneous candidiasis.
Interleukin-23 is a major pro-inflammatory cytokine that drives IL-17 production by tissue-resident lymphocytes. Recent research indicates that the IL-23→IL-17 axis plays a crucial role in chronic inflammation and several autoimmune diseases.
In the new Immunity study Sakeen Kashem and colleagues from the University of Minnesota, Minneapolis, MN, USA examined the cellular sources of IL-17 and the inflammatory cascade that mediated resistance to cutaneous C. albicans infection in naive mice.
The authors provide evidence that sensory nociceptive neurons are able to directly ‘sense’ fungal agents such as Candida albicans.
They found that IL-23 from CD301b+ dDCs that includes the CD11b+ dDC subset drove expansion and IL-17 production by dermal γδ T cells, resulting in protection from C. albicans.
Thus, they provide evidence that the resistance to C. albicans skin infection requires IL-17A and identifies dermal γδ T cells as the dominant and primary source of this cytokine. IL-23 derived from CD301+ dDCs was required for proliferation and IL-17A production by dermal γδ T cells.
Furthermore, the study shows that calcitonin gene related peptide (CGRP), released from TRPV1-positive fibers is able to up-regulate IL-23 production by CD301b+ DCs, which in turn drives IL-17 production by γδ T cells.
Thus, Kashem et al., provide a model where pain-sensing neurons, neuropeptides such as CGRP, skin innate and immune cells, and cytokines as IL-23 and IL-17 are involved in a local neural-immune response delivering resistance to skin infections such as candidiasis.
In conclusion, the authors elucidated a mechanism of innate host defense against C. albicans infection in the skin that involves pain-sensing neurons, dermal dendritic cells, and dermal γδ T cells as well as the soluble factors CGRPα, IL-23, and IL-17.
The study may have important implications for autoimmune diseases in the skin, and/or the development of new antimicrobial/antifungal therapeutic strategies.