Psoriasis is a chronic skin inflammation. Immunological mechanisms play a pivotal role in its pathogenesis, and recent clinical practices have demonstrated the effectiveness of biological antibodies targeting dysregulated cytokines in psoriasis, especially interleukin-17A.22 On the other hand, as the largest organ of our body, the skin contains abundant nerve fibers, which are densely distributed in various layers of the skin. They communicate with various skin cell groups by releasing neuropeptides, and almost all of the skin cells express receptors for neuropeptides. Meanwhile, the stimulated skin cells also can produce neuropeptides, which in turn act on the nerves. It is such bidirectional communication creates feedback loops in chronic inflammatory skin diseases.23
There are increasing observations supporting the direct or indirect participation of the nerve in psoriasis development. (1) The stimulation of the nerves (e.g. herpes zoster) can induce or aggravate psoriasis, most likely through Koebner phenomenon.24 We add here a representative case of thigh psoriasis aggravated by herpes zoster at the same site (more details in supplementary material #4). (2) A series of early histological studies indicated that the nerve fibers, Schwann cells and other nerve supporting cells in psoriatic lesions were remarkably elevated than the normal skin.25 Moreover, results have confirmed the significant increase of nerve fibers in both imiquimod-induced psoriasiform dermatitis (Fig. 2A and C) and the severe combined immunodeficient mouse-human skin model.26 (3) Reduced large fiber functioning and altered small fiber functioning in psoriasis have been demonstrated, and there is up-regulation of neuropeptides released by sensory nerve cells that innervate psoriatic lesions.23,27,28 (4) Trigger factors of psoriasis can upregulate and activate some receptors and ion channels on sensory nerves, leading to neurogenic inflammation and pruritus in psoriasis.23,29 (5) Several tentative therapies, including dermatiome-shaving, capsaicin cream, resiniferatoxin, onabotulinumtoxinA, and K252a (a high-affinity nerve growth factor receptor blocker), can improve psoriasis or psoriasiform dermatitis, through reducing lesional nerve fibers or sensory denervation.30–36 And nerve blockade based on locoregional anaesthesia has been proposed in psoriasis treatment.37,38 (6) Sporadic case reports of psoriasis spared or alleviated in the site of nerve injured (e.g. poliomyelitis, trauma) provide direct evidences for the roles of the nerve in psoriasis development.12,14,15
In this study, we further analyzed case collections of psoriatic patients who complicated with nerve injury in two hospitals and such cases from published literatures. We found that 100% local lesions under the control of the injured nerves spontaneously relieved or even cleared/spared. For patients whose nerve injuries happened after their psoriasis, the nerve injuries relieved (33%) or cleared (67%) their local psoriatic lesions. And for psoriatic patients with early poliomyelitis, poliomyelitis spared their psoriasis on the affected limb (80%), or alleviate it (20%). Only about one third patients experienced partial recurrence of psoriatic lesions, probably with the regaining of their nerve functions. This analysis further support the involvement of the nerve in psoriasis.
With these clinical cases alone, the conclusion that the nerve is involved in psoriasis cannot be fully drawn. Therefore, on the basis of these clinical observations, we further solidified the conclusion with mouse psoriasiform models. Based on the levels of lesion scores and histopathological changes, we demonstrated that the unilateral denervation surgery prior to the application of imiquimod interfered the enhancement of inflammatory reactions (e.g. adaptive immune response and Th17 cell differentiation pathway) and the induction of ipsilateral psoriasiform dermatitis. Moreover, the unilateral denervation after the induction of psoriasiform dermatitis could promote the regression of inflammatory reactions (e.g. T cell activation, TNF signaling, and Th17 cell differentiation pathway) and the recovery of ipsilateral dermatitis. Thus we solid the contribution of the nerve in the development of psoriasiform dermatitis from two aspects, unilateral denervation before and after the induced dermatitis respectively. This research design is based on clinical observations (e.g. peripheral nerve trauma, poliomyelitis), and there are no such studies based on both two aspects in previous literatures. Moreover, our results from wild-type mice, not transgenic mice, can better imitate clinical practice. We also performed the above experiments on wild-type BABL/C mice in order to avoid the possible influence of strain differences, and we obtained consistent results (data not shown).
The involvement of the nerve in psoriasis development have long been explored. Firstly, the upregulated neuropeptides released by sensory nerve in psoriatic lesions, such as substance P (SP), calcitonin gene related protein (CGRP), nerve growth factor (NGF), vasoactive intestinal peptide (VIP), can interact with various types of skin cells, including keratinocytes, endothelial cells, and mast cells.39 For example, SP, NGF and VIP can induce the degranulation of mast cells, and promote keratinocyte and endothelial cell hyperproliferation;40–42 CGRP cooperates with SP to induce the vasodilation and various pruritus/pain states.43 More importantly, the use of neuropeptide receptor antagonist improved the psoriasiform dermatitis in the transgenic KC-Tie2 mouse model, and SP and CGRP receptor agonist administration into denervated mouse skin resumed keratinocyte hyperproliferation in a neuropeptide specific manner.6 Secondly, the dynamic neuronal-immune system cross-talk has been implicated in various chronic inflammations.44,45 Upon infections and chronic inflammations, the nerve can control immune molecular cascades from dendritic cells, T cells, mast cells or keratinocytes, leading to activation of innate and adaptive immune system. On the other hand, immune chemokines and cytokines (e.g. Th2 type IL-4, IL-5, and IL-13) can trigger the activation of sensory fibers to coordinate host-protective behavioral responses.23,29,44 It has been demonstrated that, based on transgenic KC-Tie2 mouse model of psoriasiform dermatitis, nervous interventions of surgical denervation, neuropeptide blocker, and botulinum neurotoxin A injection can significantly decrease IL-23, CD4 + T cells, especially CD11 + dendritic cells, along with the improvement of psoriatic acanthosis.6,46 With wild-type mice, here we demonstrated here that unilateral denervation surgery remarkably decreased Th17 cell differentiation, TNF signaling, Toll-like receptor signaling, Th1 and Th2 cell differentiation, and JAK-STAT signaling pathways on ipsilateral side. Together, relationship between the nervous and immune systems in psoriasis have been recognized, however the precise underlying mechanisms are just starting to be elucidated.
It is noteworthy that psoriasiform lesions on the denervated side of mouse were not extremely relieved as expected. Similar phenomena also can be observed in clinical cases in Fig. 1C and 1D. Moreover, very few mice in this study were found to delay the recovery of psoriasiform dermatitis by denervation surgery (Supplementary material #5). These observations suggest that the nerve may not work alone in psoriasis development. Alternatively there may be dysregulated compensatory repair mechanisms of the nerves (e.g. over-repair), or repair divergence of different types of nerves (sensory, autonomic and motor) that may play distinct functions in the balance of skin neuroimmune47,48. These observations suggest the complexity of neuroimmune regulation in psoriasis.
Limitations of this study are (1) The collateral reinnervation of the nerves in the dorsal skin of mice limits the longer-period investigation; (2) Hair re-growth (approximately 10th day after the depilation) on the back also limits longer-period observation; (3) Imiquimod-induced dermatitis has been the most widely used animal model of psoriasis, however it is different in terms of psoriatic pathogenesis to some extent.