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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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TRPV1+ nociceptors regulate the expression of il12b and il23a upon IMQ challenge, the inflammatory response to DNFB application, and IL-23 injection can bypass their contribution to activate γδ T cellsa–c, After 3 days of IMQ challenge, ears were harvested and processed for total RNA isolation and (a)il12b(b)il23a and (c)il12a mRNA levels were analyzed by qPCR (n=5). d, DNFB (0.5% in acetone) was applied topically to DMSO and RTX mice. Time course of change in ear thickness of IMQ treated ear relative to the contralateral ear is represented (n=10). Two-way ANOVA was run to compare ear swelling under DMSO and RTX conditions over time (****, P < 0.0001). e, Representative FACS plots from ears harvested after 24h of DNFB application. f, IL-23R−/− mice were treated with RTX and then compared to WT and IL-23RGFP/GFP littermate controls during IMQ treatment. Ear thickness was calculated relative to the contralateral ear (n=5). g, After two IL-23 injections into the ear skin of WT and IL-23RGFP/GFP mice, the frequency of IL-17F+ cells within dermal γδ T cells was determined by flow cytometry (n=5). h, IL-23 was injected twice into the ear skin of Vehicle- and RTX-treated mice and the total numbers of IL17A+ or IL-17F+ dermal γδ T cells per ear were determined by flow cytometry (n=5).
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Figure 7: TRPV1+ nociceptors regulate the expression of il12b and il23a upon IMQ challenge, the inflammatory response to DNFB application, and IL-23 injection can bypass their contribution to activate γδ T cellsa–c, After 3 days of IMQ challenge, ears were harvested and processed for total RNA isolation and (a)il12b(b)il23a and (c)il12a mRNA levels were analyzed by qPCR (n=5). d, DNFB (0.5% in acetone) was applied topically to DMSO and RTX mice. Time course of change in ear thickness of IMQ treated ear relative to the contralateral ear is represented (n=10). Two-way ANOVA was run to compare ear swelling under DMSO and RTX conditions over time (****, P < 0.0001). e, Representative FACS plots from ears harvested after 24h of DNFB application. f, IL-23R−/− mice were treated with RTX and then compared to WT and IL-23RGFP/GFP littermate controls during IMQ treatment. Ear thickness was calculated relative to the contralateral ear (n=5). g, After two IL-23 injections into the ear skin of WT and IL-23RGFP/GFP mice, the frequency of IL-17F+ cells within dermal γδ T cells was determined by flow cytometry (n=5). h, IL-23 was injected twice into the ear skin of Vehicle- and RTX-treated mice and the total numbers of IL17A+ or IL-17F+ dermal γδ T cells per ear were determined by flow cytometry (n=5).

Mentions: In light of the preferential expression of IL-23R on dermal γδT17 cells, the known role of IL-23 as a driver of IL-17 and IL-22 generation in psoriasiform inflammation13 and our finding that RTX pretreatment profoundly diminished IMQ-induced cytokine production by γδT17 cells, we hypothesized that TRPV1+ nociceptors might control dermal IL-23 production. Topical IMQ treatment of control mice dramatically increased p40 protein levels, as well as mRNA levels of il12b (IL-12/23p40) and il23a (IL-23p19), but not il12a (IL-12p35). These effects were nearly abolished after RTX treatment (Fig. 3a; Extended Data Fig. 7a–c), suggesting that TRPV1+ nociceptors are essential for cutaneous IL-23 production. It seems unlikely that IL-12 had a major impact in the IMQ model, because IMQ-induced inflammatory parameters were markedly reduced in IL-23RGFP/GFP mice, which respond to IL-12 but not IL-23, (Fig. 3b–f). However, IL-12-dependent skin inflammation induced using a chemical irritant, DNFB26, was profoundly reduced in RTX-treated mice, suggesting that RTX-sensitive fibers also play a role in IL-12-driven dermatitis (Extended Data Fig. 7d&e).


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)

TRPV1+ nociceptors regulate the expression of il12b and il23a upon IMQ challenge, the inflammatory response to DNFB application, and IL-23 injection can bypass their contribution to activate γδ T cellsa–c, After 3 days of IMQ challenge, ears were harvested and processed for total RNA isolation and (a)il12b(b)il23a and (c)il12a mRNA levels were analyzed by qPCR (n=5). d, DNFB (0.5% in acetone) was applied topically to DMSO and RTX mice. Time course of change in ear thickness of IMQ treated ear relative to the contralateral ear is represented (n=10). Two-way ANOVA was run to compare ear swelling under DMSO and RTX conditions over time (****, P < 0.0001). e, Representative FACS plots from ears harvested after 24h of DNFB application. f, IL-23R−/− mice were treated with RTX and then compared to WT and IL-23RGFP/GFP littermate controls during IMQ treatment. Ear thickness was calculated relative to the contralateral ear (n=5). g, After two IL-23 injections into the ear skin of WT and IL-23RGFP/GFP mice, the frequency of IL-17F+ cells within dermal γδ T cells was determined by flow cytometry (n=5). h, IL-23 was injected twice into the ear skin of Vehicle- and RTX-treated mice and the total numbers of IL17A+ or IL-17F+ dermal γδ T cells per ear were determined by flow cytometry (n=5).
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Figure 7: TRPV1+ nociceptors regulate the expression of il12b and il23a upon IMQ challenge, the inflammatory response to DNFB application, and IL-23 injection can bypass their contribution to activate γδ T cellsa–c, After 3 days of IMQ challenge, ears were harvested and processed for total RNA isolation and (a)il12b(b)il23a and (c)il12a mRNA levels were analyzed by qPCR (n=5). d, DNFB (0.5% in acetone) was applied topically to DMSO and RTX mice. Time course of change in ear thickness of IMQ treated ear relative to the contralateral ear is represented (n=10). Two-way ANOVA was run to compare ear swelling under DMSO and RTX conditions over time (****, P < 0.0001). e, Representative FACS plots from ears harvested after 24h of DNFB application. f, IL-23R−/− mice were treated with RTX and then compared to WT and IL-23RGFP/GFP littermate controls during IMQ treatment. Ear thickness was calculated relative to the contralateral ear (n=5). g, After two IL-23 injections into the ear skin of WT and IL-23RGFP/GFP mice, the frequency of IL-17F+ cells within dermal γδ T cells was determined by flow cytometry (n=5). h, IL-23 was injected twice into the ear skin of Vehicle- and RTX-treated mice and the total numbers of IL17A+ or IL-17F+ dermal γδ T cells per ear were determined by flow cytometry (n=5).
Mentions: In light of the preferential expression of IL-23R on dermal γδT17 cells, the known role of IL-23 as a driver of IL-17 and IL-22 generation in psoriasiform inflammation13 and our finding that RTX pretreatment profoundly diminished IMQ-induced cytokine production by γδT17 cells, we hypothesized that TRPV1+ nociceptors might control dermal IL-23 production. Topical IMQ treatment of control mice dramatically increased p40 protein levels, as well as mRNA levels of il12b (IL-12/23p40) and il23a (IL-23p19), but not il12a (IL-12p35). These effects were nearly abolished after RTX treatment (Fig. 3a; Extended Data Fig. 7a–c), suggesting that TRPV1+ nociceptors are essential for cutaneous IL-23 production. It seems unlikely that IL-12 had a major impact in the IMQ model, because IMQ-induced inflammatory parameters were markedly reduced in IL-23RGFP/GFP mice, which respond to IL-12 but not IL-23, (Fig. 3b–f). However, IL-12-dependent skin inflammation induced using a chemical irritant, DNFB26, was profoundly reduced in RTX-treated mice, suggesting that RTX-sensitive fibers also play a role in IL-12-driven dermatitis (Extended Data Fig. 7d&e).

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