Lidocaine and psoriasis
A study by Qianqian Yin et al., published in the Journal of Investigative Dermatology found that lidocaine acting on sensory neurons is able to down-regulate disordered neurite growth and pro-inflammatory calcitonin gene-related peptide (CGRP) release. As a consequence, the restricted CGRP+ nerve density contributes to reduced interleukin-23 (IL-23) production from dendritic cells (DCs), which express excessive CGRP receptors.
A 2014 study, published in Nature magazine, provided a breakthrough in psoriasis research indicating that sensory nerves driving IL-23 production by dermal dendritic cells (DDCs) may contribute to psoriasis-like inflammation. This study showed that in the skin of mice approximately 75% of DDCs are in direct contact or in close proximity to sensory nerves.
In the model of skin neuroimmune-mediated inflammation – proposed by the authors of this study – a subset of sensory neurons expressing the ion channels TRPV1 (transient receptor potential vanilloid 1) and Nav1.8 play a major role in triggering IL-23 production by nearby DDCs. In this model, IL-23, in turn act on skin-resident T cells to induce IL-17 and IL-22, and precipitating the recruitment of neutrophils and monocytes that drive psoriasiform skin inflammation.
By 2020, it became clear that the neurogenic inflammation, induced by nociceptive neurons and Th17 responses, has a fundamental role in psoriasis. In addition, the number of peptide-containing nerve fibers in psoriatic epidermal tissue is elevated as compared to non-psoriatic nerve tissue. This includes particularly SP+ nerve fibers and CGRP+ nerve fibers. The increased NGF is responsible for these elevations. Thus, the content of CGRP and SP in psoriatic lesions in psoriasis is elevated, accompanied by an increased expression of their receptors.
Figure 1. The vicious circular pathway between nociceptive neurons and Th17 immune responses in psoriatic lesions. Neuropeptides (CGRP, SP, VIP) prompt the release of IL-6 and IL-23 and bias antigen presentation for Th17 cell responses. Neuropeptides also prompt Th cells to release IL-17, IL-31, and IL-33. Increased cytokines can sensitize TRPV1 and TRPA1 channels through GPCRs via secondary messenger-signaling pathways, the cAMP/PKA and PLC/PKC pathways, following Ca2+ elevation.
An elevated Ca2+ concentrate prompts the release of neuropeptides, which forms a vicious circle pathway between nociceptive neurons and the local immune system. Sensitized TRPV1 and TRPA1 channels result in pruritus, pain, and hyperalgesia experienced by patients with psoriasis. From ‘The Role of Nociceptive Neurons in the Pathogenesis of Psoriasis’ by Xuan Zhang and Yanling He, Front. Immunol., 29 September 2020. Public Domain.
Lidocaine is a non-selective blocker to voltage-gated sodium channels, which are specifically expressed on primary sensory nerves. Among them, Nav1.8 and Nav1.9 are concordantly expressed along with CGRP.
Also, according to Honglin Wang, PhD, Lead Investigator, Shanghai Institute of Immunology:
“Case studies have shown that psoriasis patients have experienced significant symptom relief after receiving epidural anesthesia during surgery, suggesting a pivotal role of the nervous system in psoriasis pathogenesis. Additionally, there is increasing evidence linking the neuroimmune connection to psoriasis and other skin diseases. These factors inspired us to explore the possibility of directly targeting the nervous system for psoriasis treatment and the detailed mechanism of neuroimmune crosstalk in psoriasis.”
The sensory nervous system has been reported to participate in psoriasis-like skin inflammation, but directly targeting sensory nerves for clinical therapy is rarely accessible. Given the safety of epidural nerve block, the authors of the Journal of Investigative Dermatology study determined the clinic-translational validity of lidocaine in treating psoriasis.
For clinical treatment, epidural catheterization was conducted between T12 and L1 segments of the patients’ spinal cord. For one single injection, 5 ml of 1% lidocaine was injected within 3 minutes at a constant speed by manual push.
Qianqian Yin et al., reported that lidocaine treatment markedly reduced patients’ clinical scores. In fact, patients achieved remarkable and equably improvements in almost all lesion dermatomes, and skin improvements were maintained for at least 24 weeks after the endpoint of lidocaine treatment.
Lidocaine also improved an imiquimod (IMQ)-induced rat model of psoriasis. The IMQ rats treated with lidocaine achieved competent improvement in epidermal acanthosis. It is known that as a local anesthetic, when epidurally delivered, lidocaine mainly blocks the sympathetic and sensory nerve activities. To address whether sympathetic nerves contributed to psoriasis pathology, the authors conducted chemical sympathectomy by 6-hydroxydopamine on the IMQ model. The investigators found no significant difference in epidermal acanthosis from that of sham controls.
Importantly, in this study, the IMQ-treated rat skin contained higher CGRP protein levels than the skin of wild-type controls, and lidocaine treatment abrogated such increase. The investigators found increased IL-23A+ cells in IMQ-treated mice, and in IMQ-treated mice skin, RAMP1+ DCs showed a significantly higher proportion of IL-23A expression.
Of note, single-cell RNA sequencing unveiled the overrepresentation of calcitonin gene-related peptide receptors in dermal dendritic cell populations of patients with psoriasis. To determine the effect of lidocaine on sensory neuron‒DC interaction, the authors co-cultured bone marrow‒derived DCs with primary sensory neurons. Notably, through disturbing calcitonin gene-related peptide signaling, lidocaine inhibited IL-23 production by dendritic cells co-cultured with the dorsal root ganglion neurons.
Discussion and Implications
“Epidural lidocaine therapy provides a novel choice for patients who respond poorly to the current treatment modalities for psoriasis,” commented the lead author Qianqian Yin, PhD, Shanghai Institute of Immunology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
“Although these findings are promising, this was a small pilot study that lacks a placebo-controlled arm and controls to prevent interference by environmental changes. We next need to conduct large-scale clinical studies,” commented co-investigator Libo Sun, PhD, Shanghai Institute of Immunology, Shanghai, China.
In conclusion, this study draws a special attention to the potential for epidural lidocaine injection as an effective and safe therapeutic strategy for psoriasis treatment. Thus, it further expands our understanding of the role of the peripheral nerve system in psoriasis.
The study may also suggest that modulating the neuro-immune cross-talk is apparently a new approach to control neurogenic inflammation and downstream key inflammatory cytokine production. This may provide novel therapeutic tools for sensory neuron‒orchestrated inflammatory skin diseases.