Neuroimmunology

RESEARCH HIGHLIGHTS

Nature Reviews Immunology | AOP, published online 16 May 2014; doi:10.1038/nri3691

imiquimod application. However, mice in which nociceptors had been depleted developed a psoriasis-like inflammation following intradermal injection of IL‑23. Thus, TRPV1+ nociceptors seem to promote skin inflammation by stimulating the

Ethan Vasquez/Alamy production of IL‑23. The authors found that neutro- phils and inflammatory monocytes were not required for IL‑12p40 production in response to imiquimod. By contrast, depletion of dermal dendritic cells (DCs) led to reduced Il23a expression in the skin of imiquimod-treated mice. Confocal NEUROIMMUNOLOGY microscopy imaging of the steady- state skin showed that approximately 75% of dermal DCs are in direct contact with, or in close proximity A sensational IL‑23 response to, sensory nerves. Furthermore, real-time imaging of Nav1.8‑reporter Patients with psoriasis develop prom- reduced ear swelling in this model mice that had been reconstituted inent skin lesions and frequently but had no marked effect on skin with fluorescently labelled bone report associated symptoms of pain, inflammation. By contrast, depletion marrow cells indicated that dermal itching and discomfort. There is evi- of TRPV1+ sensory nerves markedly DCs interact with local nociceptors dence that local anaesthetics or surgi- reduced both tissue swelling and in diverse ways — some dermal cal denervation can not only alleviate inflammatory cell infiltration in DCs were imaged attaching to nerve these pain sensations but can also response to imiquimod. Further fibres and extending protrusions decrease inflammation in psoriatic experiments showed that these effects into the surrounding tissue, whereas skin. This suggests that the peripheral are independent of T cell responses other DCs seemed to be using the nervous system may contribute to the in the draining lymph nodes, which nerve fibres as a scaffold for their development of skin inflammation in suggests that sensory TRPV1+ noci migration through the tissue. this disease. In support of this idea, ceptors promote local immune The authors propose that Riol-Blanco, Ordovas-Montanes et al. responses directly in the skin. TRPV1+Nav1.8+ nociceptors can pro- now report that a subset of sensory As imiquimod-induced skin mote inflammatory responses in the neurons in the skin is essential for inflammation is known to be skin by inducing IL‑23 production interleukin‑23 (IL‑23) production IL‑23‑dependent, the authors by local DCs. This IL‑23 can then and local inflammation in a mouse examined how TRPV1+ nociceptor stimulate other local immune cells to model of psoriasis. ablation affects the production of produce cytokines — such as IL‑17 Pain sensations in the skin are this cytokine. Following imiquimod and IL‑22 — that drive psoriasiform transmitted by sensory fibres that treatment, the skin of control mice skin inflammation. The molecular express the cation channel TRPV1 showed an upregulation of mRNA basis of the nociceptor–DC inter and most of these nociceptors also sensory nerves encoding IL‑23p19 (Il23a) but not of action that is involved here remains express the sodium channel Nav1.8 mRNA encoding IL‑12p35 (Il12a). to be determined, but the study (also known as SCN10A). The interpret In addition, both mRNA and protein suggests that sensory nerves interpret authors treated mice with different environmental levels of the IL‑12p40 subunit — environmental signals in order to neurotoxins to deplete either signals in which is shared by IL‑12 and IL‑23 shape local immune responses. + TRPV1 nociceptors or sympathetic order to shape — were increased in these mice. Yvonne Bordon neurons and then induced psoriasis- Notably, upregulation of Il23a mRNA ORIGINAL RESEARCH PAPER Riol-Blanco, L. et al. like inflammation by applying local immune and of the p40 protein was almost Nociceptive sensory neurons drive interleukin‑23‑ imiquimod to the ear skin. They responses completely abolished if TRPV1+ mediated psoriasiform skin inflammation. Nature http://dx.doi.org/10.1038/nature13199 (2014) found that sympathetic denervation nociceptors were depleted before

NATURE REVIEWS | IMMUNOLOGY VOLUME 14 | JUNE 2014