Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation.
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.
1] Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA [2].
Lorena
L
Riol-Blanco
1] Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA [2].
Jose
J
Ordovas-Montanes
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Mario
M
Perro
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Elena
E
Naval
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Aude
A
Thiriot
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
David
D
Alvarez
1] Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.
Silke
S
Paust
Institute for Biomedical Research, University College London, London WC1E 6BT, UK.
John N
JN
Wood
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Ulrich H
UH
von Andrian
D000634:Aminoquinolines; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D000077271:Imiquimod; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D020381:Interleukin-17 / Q000096:biosynthesis / Q000276:immunology; D053759:Interleukin-23 / Q000096:biosynthesis / Q000276:immunology*; D007378:Interleukins / Q000096:biosynthesis / Q000276:immunology; D007801:Langerhans Cells / Q000276:immunology / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000378:metabolism; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism*; D011565:Psoriasis / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology*; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism*; D012867:Skin / Q000166:cytology / Q000276:immunology / Q000294:innervation* / Q000473:pathology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D050916:TRPV Cation Channels / Q000378:metabolism; D000097043:Interleukin-22
D000634:Aminoquinolines; D000077271:Imiquimod; D020381:Interleukin-17; D053759:Interleukin-23; D007378:Interleukins; D062559:NAV1.8 Voltage-Gated Sodium Channel; D050916:TRPV Cation Channels; D000097043:Interleukin-22; C568318:Scn10a protein, mouse; C493921:TRPV1 protein, mouse