Sensory nerves driving interleukin-23 in psoriasis
A study published in the June 05, 2014 issue of Nature magazine indicates that sensory nerves driving interleukin-23 (IL-23) production by dermal dendritic cells (DDCs) may contribute to psoriasis-like inflammation. These findings may represent a breakthrough in psoriasis research and the understanding of the pathogenesis of this skin disease.
The IL-23→IL-17 axis plays a major role in the development and progression of several inflammatory diseases, including psoriasis.
The skin is highly innervated by sensory and autonomic nerves loaded with a plethora of neuropeptides and neurotransmitters, which may be released upon central or peripheral stimulation.
Psoriasis is among a group of skin diseases long recognized to be influenced by neuronal and neurohormonal factors, and triggered by psychological stress.
In the Nature study Lorena Riol-Blanco and colleagues from the Department of Microbiology and Immunobiology, Harvard Medical School, USA and the Institute for Biomedical Research, University College London, UK, found that in the skin of mice approximately 75% of DDCs are in direct contact or in close proximity to sensory nerves.
When using pharmacological or genetic ablation of nociceptors, they observed that DDCs failed to produce IL-23 in an imiquimod model of psoriasiform skin inflammation.
The authors propose a model of skin neuroimmune-mediated inflammation, where a subset of sensory neurons expressing the ion channels TRPV1 (transient receptor potential vanilloid 1) and Nav1.8 may play a major role in triggering IL-23 production by nearby DDCs.
Thus, IL-23 in turn
may 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.
According to the authors these findings may suggest new strategies for the treatment of inflammatory diseases in the skin.
Source: Nature, 2014 Jun 5;510(7503):157-61. doi: 10.1038/nature13199. Epub 2014 Apr 23.
Read more: Nature
See also: Neuroendocrine Immunology in 2014 Overview
The ‘sensational IL-23 response’
In 2014, Yvonne Bordon, a Senior Editor at Nature Reviews Immunology, wrote a short Research Highlights article entitled “A sensational IL-23 response”.
She highlighted the important clinical feature in psoriaris, where patients frequently report symptoms of pain, itching and discomfort. Taking into account that pain sensations in the skin are transmitted by sensory fibres that express the cation channel TRPV1, Yvonne Bordon stressed the important experiments conducted by the authors of the Nature study, discussed above.
The authors, when performing a depletion of TRPV1+ sensory nerves, they found a markedly reduced both tissue swelling and inflammatory cell infiltration in response to imiquimod. The imiquimod-induced skin inflammation is now known to be IL-23-dependent. Thus, the authors proposed that “TRPV1+Nav1.8+ nociceptors can promote inflammatory responses in the skin by inducing IL-23 production by local DCs”.
In 2015, Sakeen Kashem and colleagues reported in Immunity journal new evidence that peripheral nerves sense infection and drive IL-23 production by skin dendritic cells. This indicates, as we discussed, that in the murine skin, IL-23, derived from CD301b+ DCs drives IL-17A production by γδ T cells, and this cytokine network is required to establish resistance to cutaneous candidiasis.
In 2020, Xuan Zhang and Yanling He discussed the emerging evidence that the neurogenic inflammation, induced by nociceptive neurons and Th17 responses, has a fundamental role in psoriasis. Nociceptive neurons, specific primary sensory nerves, have a multi-faceted role in detecting noxious stimuli, maintaining homeostasis, and regulating the immunity responses in the skin.
Numerous studies have reported increased innervation of primary sensory nerve fibers and elevated gene expression of TRP channels in psoriasis. Further research is needed to illuminate the role of TRPA1+ nociceptive neurons in psoriatic immune responses. But, the vicious circular pathway between nociceptive neurons and Th17 responses is responsible for pruritus, pain, and hyperalgesia experienced by patients with psoriasis (see Figure 1).
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.
Stress is a well-known triggering factor in the occurrence or exacerbation of psoriasis. Psoriasis is regarded as a Th1/Th17/Th22 cell subset autoimmune disease, and the IL-23/Th17 axis has a crucial role in psoriasis.
In the 2021 Journal of Leukocyte Biology study, Yan Wang et al. provide evidence suggesting that stress exacerbates and prolongs psoriasiform dermatitis in mice by up-regulating IL-1β and IL-23p40, which are related to local DCs activation stimulated by abnormal Substance P. These findings may also provide some mechanistic link between psychological stress and skin inflammation, and supports the integration of stress management into psoriasis treatment.
Cover Image: A collage with an inserted image from Figure 2, ‘Neuroimmune interactions in skin infection and psoriasis’ as of Neuronal Regulation of Immunity in the Skin and Lungs, Trends Neurosci, 2019;42(8):537-551. Public domain. Several pathogens, such as Candida albicans, Staphylococcus aureus, and Streptococcus pyogenes have been determined to interact with sensory nerves in the skin to drive neuro-immune modulation. Pathogenic activation of sensory nerves leads to release of neuropeptides that modulate immune cells during infection, affecting infection and disease outcome. a) The pathogenic yeast, C. albicans, activates sensory nerves during epicutaneous infection to release the neuropeptide CGRP, which augments the release of IL-23 from CD301b+ dermal dendritic cells (dDCs). IL-23 then drives IL-17 release from γδ T-cells, which mediates resistance against C. albicans due to induction of polymorphonuclear neutrophil (PMN) recruitment and expression of antimicrobial peptides (AMPs). In a mouse model of psoriasis, a similar neuroimmune interaction was found: sensory nerves mediate IL-23 release from dDCs which mediate IL-17 release by γδ T-cells that contribute to psoriatic inflammation and plaque formation.
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