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Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation.

Riol-Blanco L, Ordovas-Montanes J, Perro M, Naval E, Thiriot A, Alvarez D, Paust S, Wood JN, von Andrian UH - Nature (2014)

Bottom Line: Upon selective pharmacological or genetic ablation of nociceptors, DDCs failed to produce IL-23 in imiquimod-exposed skin.Consequently, the local production of IL-23-dependent inflammatory cytokines by dermal γδT17 cells and the subsequent recruitment of inflammatory cells to the skin were markedly reduced.These findings indicate that TRPV1(+)Nav1.8(+) nociceptors, by interacting with DDCs, regulate the IL-23/IL-17 pathway and control cutaneous immune responses.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA [2].

ABSTRACT
The skin has a dual function as a barrier and a sensory interface between the body and the environment. To protect against invading pathogens, the skin harbours specialized immune cells, including dermal dendritic cells (DDCs) and interleukin (IL)-17-producing γδ T (γδT17) cells, the aberrant activation of which by IL-23 can provoke psoriasis-like inflammation. The skin is also innervated by a meshwork of peripheral nerves consisting of relatively sparse autonomic and abundant sensory fibres. Interactions between the autonomic nervous system and immune cells in lymphoid organs are known to contribute to systemic immunity, but how peripheral nerves regulate cutaneous immune responses remains unclear. We exposed the skin of mice to imiquimod, which induces IL-23-dependent psoriasis-like inflammation. Here we show that a subset of sensory neurons expressing the ion channels TRPV1 and Nav1.8 is essential to drive this inflammatory response. Imaging of intact skin revealed that a large fraction of DDCs, the principal source of IL-23, is in close contact with these nociceptors. Upon selective pharmacological or genetic ablation of nociceptors, DDCs failed to produce IL-23 in imiquimod-exposed skin. Consequently, the local production of IL-23-dependent inflammatory cytokines by dermal γδT17 cells and the subsequent recruitment of inflammatory cells to the skin were markedly reduced. Intradermal injection of IL-23 bypassed the requirement for nociceptor communication with DDCs and restored the inflammatory response. These findings indicate that TRPV1(+)Nav1.8(+) nociceptors, by interacting with DDCs, regulate the IL-23/IL-17 pathway and control cutaneous immune responses.

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Gating strategy for T cell subsets and myeloid cells from digested ear skina, The ear skin of mice challenged for 3 days with IMQ was digested as described in methods and, after doublet exclusion and gating on defined FSC-A, SSC-A parameters, infiltrating myeloid cells were gated as CD45+ I-Ab (Class-II)−, CD11b+ CD11c−, and then subdivided into inflammatory monocytes and neutrophils based on Ly6C and Ly6G staining. b, The ear skin of naïve mice was digested as described in methods and, after doublet exclusion and gating on defined FSC-A, SSC-A parameters, cutaneous T cells were gated on CD45+, Thy1+, and then divided into subsets based on staining for δ-TCR and β-TCR.
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Figure 3: Gating strategy for T cell subsets and myeloid cells from digested ear skina, The ear skin of mice challenged for 3 days with IMQ was digested as described in methods and, after doublet exclusion and gating on defined FSC-A, SSC-A parameters, infiltrating myeloid cells were gated as CD45+ I-Ab (Class-II)−, CD11b+ CD11c−, and then subdivided into inflammatory monocytes and neutrophils based on Ly6C and Ly6G staining. b, The ear skin of naïve mice was digested as described in methods and, after doublet exclusion and gating on defined FSC-A, SSC-A parameters, cutaneous T cells were gated on CD45+, Thy1+, and then divided into subsets based on staining for δ-TCR and β-TCR.

Mentions: To dissect the roles of sympathetic fibers and nociceptors in the IMQ-model, mice were treated systemically with either 6-hydroxydopamine (6OHDA) or resiniferatoxin (RTX) to ablate TH+ sympathetic neurons or TRPV1+nociceptors, respectively (Extended Data Figs. 1&2)11,17. Subsequently, IMQ was applied topically to one ear and the ensuing inflammatory response was assessed based on the change in ear thickness, size of the myeloid infiltrate (Extended Data Fig. 3a) and tissue contents of inflammatory cytokines.


Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation.

Riol-Blanco L, Ordovas-Montanes J, Perro M, Naval E, Thiriot A, Alvarez D, Paust S, Wood JN, von Andrian UH - Nature (2014)

Gating strategy for T cell subsets and myeloid cells from digested ear skina, The ear skin of mice challenged for 3 days with IMQ was digested as described in methods and, after doublet exclusion and gating on defined FSC-A, SSC-A parameters, infiltrating myeloid cells were gated as CD45+ I-Ab (Class-II)−, CD11b+ CD11c−, and then subdivided into inflammatory monocytes and neutrophils based on Ly6C and Ly6G staining. b, The ear skin of naïve mice was digested as described in methods and, after doublet exclusion and gating on defined FSC-A, SSC-A parameters, cutaneous T cells were gated on CD45+, Thy1+, and then divided into subsets based on staining for δ-TCR and β-TCR.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4127885&req=5

Figure 3: Gating strategy for T cell subsets and myeloid cells from digested ear skina, The ear skin of mice challenged for 3 days with IMQ was digested as described in methods and, after doublet exclusion and gating on defined FSC-A, SSC-A parameters, infiltrating myeloid cells were gated as CD45+ I-Ab (Class-II)−, CD11b+ CD11c−, and then subdivided into inflammatory monocytes and neutrophils based on Ly6C and Ly6G staining. b, The ear skin of naïve mice was digested as described in methods and, after doublet exclusion and gating on defined FSC-A, SSC-A parameters, cutaneous T cells were gated on CD45+, Thy1+, and then divided into subsets based on staining for δ-TCR and β-TCR.
Mentions: To dissect the roles of sympathetic fibers and nociceptors in the IMQ-model, mice were treated systemically with either 6-hydroxydopamine (6OHDA) or resiniferatoxin (RTX) to ablate TH+ sympathetic neurons or TRPV1+nociceptors, respectively (Extended Data Figs. 1&2)11,17. Subsequently, IMQ was applied topically to one ear and the ensuing inflammatory response was assessed based on the change in ear thickness, size of the myeloid infiltrate (Extended Data Fig. 3a) and tissue contents of inflammatory cytokines.

Bottom Line: Upon selective pharmacological or genetic ablation of nociceptors, DDCs failed to produce IL-23 in imiquimod-exposed skin.Consequently, the local production of IL-23-dependent inflammatory cytokines by dermal γδT17 cells and the subsequent recruitment of inflammatory cells to the skin were markedly reduced.These findings indicate that TRPV1(+)Nav1.8(+) nociceptors, by interacting with DDCs, regulate the IL-23/IL-17 pathway and control cutaneous immune responses.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA [2].

ABSTRACT
The skin has a dual function as a barrier and a sensory interface between the body and the environment. To protect against invading pathogens, the skin harbours specialized immune cells, including dermal dendritic cells (DDCs) and interleukin (IL)-17-producing γδ T (γδT17) cells, the aberrant activation of which by IL-23 can provoke psoriasis-like inflammation. The skin is also innervated by a meshwork of peripheral nerves consisting of relatively sparse autonomic and abundant sensory fibres. Interactions between the autonomic nervous system and immune cells in lymphoid organs are known to contribute to systemic immunity, but how peripheral nerves regulate cutaneous immune responses remains unclear. We exposed the skin of mice to imiquimod, which induces IL-23-dependent psoriasis-like inflammation. Here we show that a subset of sensory neurons expressing the ion channels TRPV1 and Nav1.8 is essential to drive this inflammatory response. Imaging of intact skin revealed that a large fraction of DDCs, the principal source of IL-23, is in close contact with these nociceptors. Upon selective pharmacological or genetic ablation of nociceptors, DDCs failed to produce IL-23 in imiquimod-exposed skin. Consequently, the local production of IL-23-dependent inflammatory cytokines by dermal γδT17 cells and the subsequent recruitment of inflammatory cells to the skin were markedly reduced. Intradermal injection of IL-23 bypassed the requirement for nociceptor communication with DDCs and restored the inflammatory response. These findings indicate that TRPV1(+)Nav1.8(+) nociceptors, by interacting with DDCs, regulate the IL-23/IL-17 pathway and control cutaneous immune responses.

Show MeSH
Related in: MedlinePlus