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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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Dermal DCs (DDCs) are found in close apposition to NaV1.8+ nociceptors in skin, NaV-DTA mice express reduced levels of key nociceptor markers, yet nociceptor deletion does not grossly affect the peripheral neural network in skina, Representative confocal micrographs of CD11c-YFP mice stained for β3-tubulin, Lyve-1 (collecting lymphatics), and CD31 (blood and lymphatic endothelial cells). b, 3D quantification of DDC proximity to peripheral nerves in naïve and 6 hours post-IMQ treatment binned into contact (<0 um), proximal (0–7 um) and distal (>7 um) fractions as explained in the methods (n of DCs = 200). c, Total RNA from dorsal root ganglia (DRGs) (C1–C4) of littermate control and NaV1.8-DTA mice was isolated and levels of mRNA for trpv1 (TRPV1), scn10a (NaV1.8), tac1 (Substance P) and trpa1 (TRPA1) were determined relative to gapdh. This demonstrates the efficacy of the NaV1.8-DTA system and combined with the original reference characterizing the pain phenotype of these mice illustrates that a subset of peptidergic TRPV1+ nerve fibers is spared. d, Representative confocal micrograph of whole mount ear skin of Vehicle- and RTX-treated mice showing preserved nerve scaffold and e, representative confocal micrographs of whole mount ear skin of Control and NaV1.8-DTA mice showing preserved nerve scaffold. While DRGs showed a loss of the hallmark ion channels of these nerve subsets (Extended Data Fig. 1c and Extended Data Fig. 9c), surprisingly we still observed that RTX mice and NaV1.8-DTA mice maintain a meshwork of nerves in the skin.
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Figure 9: Dermal DCs (DDCs) are found in close apposition to NaV1.8+ nociceptors in skin, NaV-DTA mice express reduced levels of key nociceptor markers, yet nociceptor deletion does not grossly affect the peripheral neural network in skina, Representative confocal micrographs of CD11c-YFP mice stained for β3-tubulin, Lyve-1 (collecting lymphatics), and CD31 (blood and lymphatic endothelial cells). b, 3D quantification of DDC proximity to peripheral nerves in naïve and 6 hours post-IMQ treatment binned into contact (<0 um), proximal (0–7 um) and distal (>7 um) fractions as explained in the methods (n of DCs = 200). c, Total RNA from dorsal root ganglia (DRGs) (C1–C4) of littermate control and NaV1.8-DTA mice was isolated and levels of mRNA for trpv1 (TRPV1), scn10a (NaV1.8), tac1 (Substance P) and trpa1 (TRPA1) were determined relative to gapdh. This demonstrates the efficacy of the NaV1.8-DTA system and combined with the original reference characterizing the pain phenotype of these mice illustrates that a subset of peptidergic TRPV1+ nerve fibers is spared. d, Representative confocal micrograph of whole mount ear skin of Vehicle- and RTX-treated mice showing preserved nerve scaffold and e, representative confocal micrographs of whole mount ear skin of Control and NaV1.8-DTA mice showing preserved nerve scaffold. While DRGs showed a loss of the hallmark ion channels of these nerve subsets (Extended Data Fig. 1c and Extended Data Fig. 9c), surprisingly we still observed that RTX mice and NaV1.8-DTA mice maintain a meshwork of nerves in the skin.

Mentions: Having identified DDCs as the principal source of IMQ-induced IL-23, we sought to characterize the spatial relationship between DDCs and cutaneous nerves. Remarkably, confocal microscopy of skin whole mounts revealed that at steady state ~75% of DDCs were either in direct contact or in close proximity to sensory nerves (Fig. 4b–d; Extended Data Fig. 9a). Interactions were apparent along the entire length of nerves suggesting that DDCs may receive signals from unmyelinated nociceptor axons and not just from nerve terminals. However, given the high density of peripheral nerves in the skin, it was difficult to judge whether the association with DDCs occurred merely by chance or reflected a biased distribution. To address this possibility, we compared DDC localization relative to two other dense anatomical structures: blood and lymph vessels. In resting tissues contacts of DDCs with these microvascular networks were only about half as frequent as with peripheral nerves (Fig. 4d).


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)

Dermal DCs (DDCs) are found in close apposition to NaV1.8+ nociceptors in skin, NaV-DTA mice express reduced levels of key nociceptor markers, yet nociceptor deletion does not grossly affect the peripheral neural network in skina, Representative confocal micrographs of CD11c-YFP mice stained for β3-tubulin, Lyve-1 (collecting lymphatics), and CD31 (blood and lymphatic endothelial cells). b, 3D quantification of DDC proximity to peripheral nerves in naïve and 6 hours post-IMQ treatment binned into contact (<0 um), proximal (0–7 um) and distal (>7 um) fractions as explained in the methods (n of DCs = 200). c, Total RNA from dorsal root ganglia (DRGs) (C1–C4) of littermate control and NaV1.8-DTA mice was isolated and levels of mRNA for trpv1 (TRPV1), scn10a (NaV1.8), tac1 (Substance P) and trpa1 (TRPA1) were determined relative to gapdh. This demonstrates the efficacy of the NaV1.8-DTA system and combined with the original reference characterizing the pain phenotype of these mice illustrates that a subset of peptidergic TRPV1+ nerve fibers is spared. d, Representative confocal micrograph of whole mount ear skin of Vehicle- and RTX-treated mice showing preserved nerve scaffold and e, representative confocal micrographs of whole mount ear skin of Control and NaV1.8-DTA mice showing preserved nerve scaffold. While DRGs showed a loss of the hallmark ion channels of these nerve subsets (Extended Data Fig. 1c and Extended Data Fig. 9c), surprisingly we still observed that RTX mice and NaV1.8-DTA mice maintain a meshwork of nerves in the skin.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 9: Dermal DCs (DDCs) are found in close apposition to NaV1.8+ nociceptors in skin, NaV-DTA mice express reduced levels of key nociceptor markers, yet nociceptor deletion does not grossly affect the peripheral neural network in skina, Representative confocal micrographs of CD11c-YFP mice stained for β3-tubulin, Lyve-1 (collecting lymphatics), and CD31 (blood and lymphatic endothelial cells). b, 3D quantification of DDC proximity to peripheral nerves in naïve and 6 hours post-IMQ treatment binned into contact (<0 um), proximal (0–7 um) and distal (>7 um) fractions as explained in the methods (n of DCs = 200). c, Total RNA from dorsal root ganglia (DRGs) (C1–C4) of littermate control and NaV1.8-DTA mice was isolated and levels of mRNA for trpv1 (TRPV1), scn10a (NaV1.8), tac1 (Substance P) and trpa1 (TRPA1) were determined relative to gapdh. This demonstrates the efficacy of the NaV1.8-DTA system and combined with the original reference characterizing the pain phenotype of these mice illustrates that a subset of peptidergic TRPV1+ nerve fibers is spared. d, Representative confocal micrograph of whole mount ear skin of Vehicle- and RTX-treated mice showing preserved nerve scaffold and e, representative confocal micrographs of whole mount ear skin of Control and NaV1.8-DTA mice showing preserved nerve scaffold. While DRGs showed a loss of the hallmark ion channels of these nerve subsets (Extended Data Fig. 1c and Extended Data Fig. 9c), surprisingly we still observed that RTX mice and NaV1.8-DTA mice maintain a meshwork of nerves in the skin.
Mentions: Having identified DDCs as the principal source of IMQ-induced IL-23, we sought to characterize the spatial relationship between DDCs and cutaneous nerves. Remarkably, confocal microscopy of skin whole mounts revealed that at steady state ~75% of DDCs were either in direct contact or in close proximity to sensory nerves (Fig. 4b–d; Extended Data Fig. 9a). Interactions were apparent along the entire length of nerves suggesting that DDCs may receive signals from unmyelinated nociceptor axons and not just from nerve terminals. However, given the high density of peripheral nerves in the skin, it was difficult to judge whether the association with DDCs occurred merely by chance or reflected a biased distribution. To address this possibility, we compared DDC localization relative to two other dense anatomical structures: blood and lymph vessels. In resting tissues contacts of DDCs with these microvascular networks were only about half as frequent as with peripheral nerves (Fig. 4d).

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