A study published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS) indicates that substance P (SP) stimulates human mast cells to secrete vascular endothelial growth factor (VEGF) and that this action is augmented by interleukin (IL)-33.
Substance P-positive nerve ﬁbers are denser in psoriatic lesions and have an increased number of mast cell contacts as compared with normal skin.
In correlation, SP-positive nerve ﬁbers and mast cell contacts are also increased by acute stress in mice, and psoriasis is known to worsen with acute stress. Psoriatic plaques also contain increased levels of VEGF compared with normal skin, and VEGF is a major proangiogenic factor involved in many inﬂammatory diseases.
In the PNAS study Theoharides et al. report that IL-33, the newest inﬂammatory member of the IL-1 cytokine family, augments the SP-induced VEGF mRNA expression and VEGF protein secretion in both leukemic and normal human mast cells, but cannot induce VEGF secretion without SP presence.
The authors conclude that the interactions among SP, IL-33, and mast cells may be important in inﬂammatory diseases where there is excessive angiogenesis, such as psoriasis. In this respect, they also discuss that the ability of IL-33 to augment the effect of SP on inducing mast cell release of VEGF is of particular interest, as angiogenesis is at the core of psoriasis pathogenesis.
Thus, SP, IL-33 and mast cells may also represent novel therapeutic targets in this condition.
A 2020 review by Xuan Zhang and Yanling He published in Front. Immunol., summarizes recent evidence showing that neurogenic inflammation, induced by nociceptive neurons and T helper 17 cell (Th17) responses, plays a crucial, fundamental role in psoriasis.
Thus, 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 calcitonin gene-related peptide (CGRP)+ nerve fibers. The increased NGF is responsible for these elevations. Importantly, recent data confirmed that 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, Front. Immunol., 29 September 2020
Also recent evidence confirmed that, compared to healthy controls and non-itchy or non-pain lesions, pruritic psoriatic skin contains elevated gene transcription levels of IL-17, IL-23, and IL-31 and hyperalgesia psoriatic skin has higher expression levels of IL-33.
As per these authors, the vicious circular pathway between nociceptive neurons and Th17 responses is responsible for pruritus, pain, and hyperalgesia experienced by patients with psoriasis. The effective targeting of this pathway is the reason anti-IL-17 therapy proved most effective in reducing pruritus, while traditional immune system suppressants (methotrexate and retinoids) failed. This review also provides a theoretical basis for the formulation of promising nerve-targeting treatments for psoriasis in the future.
A2021 study by Fanfan Zeng et al.published in the Journal of Investigative Dermatology demonstrates that IL-33 is predominantly expressed by keratinocytes (KCs), and that IL-33 is actively released by KCs.
The authors of this study identified that the expression of IL-33 was increased in the lesional skin of patients with psoriasis and in an imiquimod (IMQ)-induced psoriasis-like dermatitis in mice. STAT3, NF-κB, and STAT1 are known to be activated in psoriasis, and in this study, the in vitro assay showed that in addition to NF-κB, IL-33 also induced Jak2/STAT3 axis activation in KCs.
Of note, IL-33 promoted the psoriatic inflammation associated genes transcription probably through both MAPK and Jak2 signaling pathway. Moreover, recombinant IL-33 alone injection induced psoriasis-like dermatitis in this study, and IL-33‒injected skin was infiltrated with a large number of neutrophils. Importantly, IL-33‒specific deficiency in KCs ameliorated imiquimod-induced psoriatic dermatitis. In IMQ-induced psoriasis-like dermatitis, IL-33 was able to recruit IL-17A+ cells in the lesional skin, whereas in IL-33 intradermal injection‒induced psoriasis-like dermatitis, the roles of IL-33 are independent of IL-17A.
The authors concluded that intradermal injection of recombinant IL-33 alone induced psoriasis-like dermatitis, which is attributed to the transcriptional upregulation of genes enriched in IL-17, TNF, and chemokine signaling pathway in KCs on recombinant IL-33 stimulation.
A 2022 review by XuYue Zhou et al., published in Front. Immunol., discusses the putative interactions of mast cells with T cells, Tregs, keratinocytes, adipocytes, and sensory neurons and their role in the pathogenesis of psoriasis.
Figure 2. Overview of mast cell involvement in psoriasis. Overview of mast cell involvement in psoriasis. When exposed to external stresses, stimulated keratinocytes can promote angiogenesis and amplify inflammation by releasing alarmins to trigger ST2-positive MCs secreting TNF and VEGF, etc. The skin microbiota induces keratinocytes to produce more SCF, which bind to the c-kit and are involved in the recruitment and regulation of dermal MCs. MCs can activate T lymphocytes and strengthen Th17 and Th22 responses by interaction with TCR, secretion of extracellular vesicles, and formation of MCETs. MCs also regulate Treg function through the OX40/OX40L axis. Activated MCs were found to increase the sensitivity of TRPV1 in peripheral neurons by releasing nociceptive and pruritogenic mediators. While the stimulated nerve fibers release CRH and neuropeptides, which induce the activation of MCs via CRH-R1 and MRGPRX2 on the MC surface in a feedback manner. In addition, nerve fibers release norepinephrine into adipose tissue to regulate the secretion of leptin, resistin, and lipocalin in adipocytes, which promote the conversion of MCs to a proinflammatory phenotype, thus constituting a neuroendocrine-immune loop that is involved in the development of psoriasis. From: Mast cells as important regulators in the development of psoriasis, by XuYue Zhou et al., Front. Immunol. 03 November 2022.
Mast cells are highlighted as the bridge between innate and adaptive immunity, involved in the regulation of inflammation and immune homeostasis in psoriasis by interacting with a variety of cells, including T cells, Tregs, neutrophils, DCs, keratinocytes, adipocytes, and sensory nerve cells, forming a complex cellular network (see Figure 2).