Peripheral Nerves Sense Infection Drive IL-23

New Evidence that Peripheral Nerves Sense Infection and Drive IL-23 Production by Skin Dendritic Cells

Peripheral Nerves Sense Infection Drive IL-23

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.

Candida albicans is a common, highly morbid pathogen at barrier sites such as the skin and oral cavity in the setting of immunosuppression. Thus, patients with defective T helper 17 (Th17) cell immunity such as AIDS or hyper-IgE syndrome are prone to develop chronic mucocutaneous candidiasis (CMC). Mice with defective Th17 cell type responses are also more susceptible to both oral and cutaneous candidiasis.

It is becoming increasingly clear that innate sources of IL-17 are crucial for host defense against C. albicans at barrier site. In the skin, dendritic epidermal T cells (DETCs), dermal γδ T cells, CD4+ and CD8+ αβ T cells, and innate lymphoid cells (ILCs) all can produce IL-17. IL-17 from dermal γδ T cells is required for immunity against BCG, Staphylococcus aureus, and vaccinia virus and for autoimmune inflammation.

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.

A recent Nature study provided new insights into the connection between the peripheral nervous system, nociception and innate immunity. It indicated that TRPV1 (transient receptor potential vanilloid 1) sensory nerves trigger IL-23 output in psoriasis-like inflammation, and that dendritic cells (DCs) are in direct contact with sensory nerves. In this IL-23-mediated imiquimod-induced skin inflammation model, sensory neurons induced and controled IL-23 production by nearby DCs.

Peripheral Nerves Sense Infection Drive IL-23In 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.

Source: Immunity, 2015, 43:515-26. doi: 10.1016/j.immuni.2015.08.016
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