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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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Leukocyte rolling fractions in skin venules of control and RTX-treated mice analyzed by intravital microscopyCombined results are shown for 26 venules from 5 control mice and for 20 venules from 4 RTX-treated mice. Data are expressed as mean ± SEM of four experiments.
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Figure 5: Leukocyte rolling fractions in skin venules of control and RTX-treated mice analyzed by intravital microscopyCombined results are shown for 26 venules from 5 control mice and for 20 venules from 4 RTX-treated mice. Data are expressed as mean ± SEM of four experiments.

Mentions: Following sympathetic denervation, IMQ-induced ear swelling was reduced compared to controls (Extended Data Fig. 1c); however, the inflammatory infiltrate was increased, while IL-17A, IL-17F, IL-22 and IL-23-p40 production remained unchanged (Extended Data Fig. 1d–i). Thus, sympathetic innervation exerts little or no direct local control over the inflammatory skin response. The observed changes were likely due to cardiovascular effects and/or global immune dysregulation following systemic sympathectomy (Supplementary Information)5. By contrast, in RTX-treated mice both ear swelling and inflammatory infiltrates in IMQ-exposed ears were profoundly reduced (Fig. 1b–e; Extended Data Fig. 4a–d). RTX treatment did not alter the systemic supply of inflammatory cells (Extended Data Fig. 4e–f)18. Moreover, intravital microcopy of ear skin revealed similar leukocyte rolling in RTX-treated and control mice (Extended Data Fig. 5), indicating that the absence of nociceptors did not affect the baseline adhesiveness of dermal microvessels19. More likely, ablation of TRPV1+ sensory nerves reduced IMQ-induced inflammation via local, extravascular mechanisms. However, the attenuated inflammatory response was not limited to the skin, as the IMQ-induced enhancement in cellularity of the draining auricular lymph node (LN) was also blunted by RTX (Fig. 1f).


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)

Leukocyte rolling fractions in skin venules of control and RTX-treated mice analyzed by intravital microscopyCombined results are shown for 26 venules from 5 control mice and for 20 venules from 4 RTX-treated mice. Data are expressed as mean ± SEM of four experiments.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 5: Leukocyte rolling fractions in skin venules of control and RTX-treated mice analyzed by intravital microscopyCombined results are shown for 26 venules from 5 control mice and for 20 venules from 4 RTX-treated mice. Data are expressed as mean ± SEM of four experiments.
Mentions: Following sympathetic denervation, IMQ-induced ear swelling was reduced compared to controls (Extended Data Fig. 1c); however, the inflammatory infiltrate was increased, while IL-17A, IL-17F, IL-22 and IL-23-p40 production remained unchanged (Extended Data Fig. 1d–i). Thus, sympathetic innervation exerts little or no direct local control over the inflammatory skin response. The observed changes were likely due to cardiovascular effects and/or global immune dysregulation following systemic sympathectomy (Supplementary Information)5. By contrast, in RTX-treated mice both ear swelling and inflammatory infiltrates in IMQ-exposed ears were profoundly reduced (Fig. 1b–e; Extended Data Fig. 4a–d). RTX treatment did not alter the systemic supply of inflammatory cells (Extended Data Fig. 4e–f)18. Moreover, intravital microcopy of ear skin revealed similar leukocyte rolling in RTX-treated and control mice (Extended Data Fig. 5), indicating that the absence of nociceptors did not affect the baseline adhesiveness of dermal microvessels19. More likely, ablation of TRPV1+ sensory nerves reduced IMQ-induced inflammation via local, extravascular mechanisms. However, the attenuated inflammatory response was not limited to the skin, as the IMQ-induced enhancement in cellularity of the draining auricular lymph node (LN) was also blunted by RTX (Fig. 1f).

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