Calcitonin gene-related peptide upregulates IL-17A and IL-22 in γδ-T cells through the paracrine effect of langerhans cells on LC/γδ-T co-culture model

Mercurio L., Morelli M., Scarponi C., Scaglione G.L., Pallotta S., Albanesi C., Madonna S.

The phosphatidylinositol 3-kinase (PI3K)-dependent signaling pathway is aberrantly activated in psoriatic lesions and contributes to disease pathogenesis. Among PI3Ks enzymes, PI3Kα, β, and δ isoforms are known to bind the p85 regulatory subunit and mediate activation of AKT and other downstream effectors. In this study, we deepened our understanding of the expression and function of PI3Kδ in skin lesions of patients affected by psoriasis. For the first time, we found that PI3Kδ is overexpressed in psoriatic plaques, and its expression is not only confined to infiltrating immune cells but also accumulates in proliferating keratinocytes of the epidermal basal layer. We investigated the function of PI3Kδ in psoriatic skin by evaluating the impact of seletalisib, a newly developed selective PI3Kδ inhibitor, in both in vitro and in vivo experimental models of psoriasis. Of note, we found that PI3Kδ sustains keratinocyte hyperproliferation and impaired terminal differentiation induced by IL-22, as well as induces epithelial inflammation and resistance to apoptosis mediated by TNF-α in human keratinocytes. Mechanistically, PI3Kδ promotes PDK1 phosphorylation and signals through AKT-dependent or -independent pathways. It is worth mentioning that PI3Kδ inhibition by seletalisib attenuates the severity of psoriasiform phenotype induced in the Imiquimod-induced mouse model of psoriasis by restoring the physiological proliferation and differentiation programs in epidermal keratinocytes and contrasting the cutaneous inflammatory responses. Therefore, we suggest PI3Kδ as a potential topically druggable target in psoriasis and skin diseases characterized by epidermal hyperproliferation and skin inflammation.

Qin B., Sun C., Chen L., Wang S., Yang J., Xie Z., Shen Z.

Background The involvement of the nerve in psoriasis development was suggested by sporadic case reports. Objectives To provide multiple evidence for the nerve in psoriasis development with a retrospective case review, a literature review and a mouse-based experimental experiment. Methods Psoriatic patients who had concomitant nerve injuries and such cases from literatures were reviewed. And, on wild-type mouse level, unilateral denervation surgery was performed on the dorsal skin before and after the induction of psoriasiform dermatitis, respectively. Lesion visual scores were calculated, and biopsies were taken for hematoxylin-eosin (HE) staining, immunofluorescence analysis, and RNA sequencing & bioinformatics analysis before denervation surgery and the 2nd, 4th, 6th, 8th day after the surgery. Results All clinical cases (20/20) showed that local lesions under the control of injured nerves relieved spontaneously or even cleared/spared, and only about 1/3 experienced partial recurrence. Next, mouse psoriasiform experiments demonstrated that unilateral denervation prior to imiquimod application attenuated the enhancement of inflammatory reactions (e.g. adaptive immune response and Th17 cell differentiation pathway) and the induction of ipsilateral psoriasiform dermatitis. On the other hand, unilateral denervation after psoriasiform dermatitis induction promoted the regression of inflammatory reactions (e.g. T cell activation, TNF signaling, and Th17 cell differentiation pathway) and ipsilateral dermatitis recovery. Conclusion Our study based on both retrospective clinical case review and wild-type mouse experiments provides multiple evidence for the involvement of the nerve in psoriasis development. Regulation of immune events, including TNF signaling and Th17 cell differentiation, may be the mechanisms of the nerve in psoriasis.

Yamanaka K., Yamamoto O., Honda T.

Psoriasis is a complex chronic inflammatory skin disease caused by the dynamic interplay between multiple genetic risk foci, environmental risk factors, and excessive immunological abnormalities. Psoriasis affects approximately 2% of the population worldwide, and dramatic advances have been achieved in the understanding and treatment options for psoriasis. Recent progress in biological therapies has revealed the fundamental roles of tumor necrosis factor-α, interleukin (IL)-23p19, and the IL-17A axis together with skin-resident immune cells and major signal transduction pathways in the pathogenesis of psoriasis. In addition to IL-17-producing T helper17 cells, innate lymphoid cell (ILC)3 induces psoriasis rashes directly without T-cell/antigen interaction in response to the released antimicrobial peptides from activated keratinocytes and inflammatory cytokines. ILC3 typically expresses retinoic acid receptor-related orphan receptor gamma t in the nucleus, matures in the presence of IL-7 and IL-23, and produces IL-17 and IL-22. The number of ILC3s is increased in the blood, psoriasis rash, and even in nonrash areas of psoriatic skin. Psoriasis is significantly associated with cardiovascular disease, metabolic syndrome, and inflammatory disorders, particularly the severe type. The similarity of enterobacteria in the psoriasis gut to that in diabetic patients may be related to its pathogenesis. In the current review, we focus on the pathophysiology of psoriasis in the accelerated immunological inflammatory loop, danger signal from keratinocytes, and cytokines, particularly IL-17 and IL-23p19. In addition, pathophysiological speculation with regard to morphology has been supplemented. Finally, the differences and similarities between psoriasis and atopic dermatitis are discussed.

Qi C., Wang Y., Li P., Zhao J.

γδT cells are an unconventional population of T lymphocytes that play an indispensable role in host defense, immune surveillance, and homeostasis of the immune system. They display unique developmental, distributional, and functional patterns and rapidly respond to various insults and contribute to diverse diseases. Although γδT cells make up only a small portion of the total T cell pool, emerging evidence suggest that aberrantly activated γδT cells may play a role in the pathogenesis of psoriasis. Dermal γδT cells are the major IL-17-producing cells in the skin that respond to IL-23 stimulation. Furthermore, γδT cells exhibit memory-cell-like characteristics that mediate repeated episodes of psoriatic inflammation. This review discusses the differentiation, development, distribution, and biological function of γδT cells and the mechanisms by which they contribute to psoriasis. Potential therapeutic approaches targeting these cells in psoriasis have also been detailed.

Zhang X., He Y.

Psoriasis is a chronic inflammatory skin disease. Emerging evidence shows that neurogenic inflammation, induced by nociceptive neurons and T helper 17 cells (Th17) responses, has a is fundamental in the role in maintenmaintainingance the of changes in the immune system due to psoriasis. immune alterations. NThe nociceptive neurons, specific primary sensory nerves, have a multi-faceted roles in detecting noxious stimuli, maintaining homeostasis, and regulating the immunity responses in the skin. Therefore, it is critical to understand the connections and interplay between the nociceptive neurons and the immune system in psoriasis. Here, we review works on the altered innervation that occurs in psoriasis. We examine how these distinct sensory neurons and their signal transducers participate in regulating inflammation. Numerous clinical studies reported the dysfunction of nociceptive neurons in psoriasis., Wwe discuss the mechanism under behind the unfaithful inconsistent activation ofn nociceptive neurons. Moreover, we review how neuropeptides, involved in regulating Th17 responses and the role of nociceptive neurons, regulate immunity in psoriasis. Understanding how nociceptive neurons regulate the immuneity responses enhances our knowledge of the neuroimmunitye involved in the pathogenesis of psoriasis and may form the basis for new approaches to treat psoriasisit.

Choi J.E., Di Nardo A.

The epidermis closely interacts with nerve endings, and both epidermis and nerves produce substances for mutual sustenance. Neuropeptides, like substance P (SP) and calcitonin gene-related protein (CGRP), are produced by sensory nerves in the dermis; they induce mast cells to release vasoactive amines that facilitate infiltration of neutrophils and T cells. Some receptors are more important than others in the generation of itch. The Mas-related G protein-coupled receptors (Mrgpr) family as well as transient receptor potential ankyrin 1 (TRPA1) and protease activated receptor 2(Par2) have important roles in itch and inflammation. The activation of MrgprX1 degranulates mast cells to communicate with sensory nerve and cutaneous cells for developing neurogenic inflammation. Mrgprs and transient receptor potential vanilloid 4 (TRPV4) are crucial for the generation of skin diseases like rosacea, while SP, CGRP, somatostatin, β-endorphin, vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating polypeptide (PACAP) can modulate the immune system during psoriasis development. The increased level of SP, in atopic dermatitis, induces the release of interferon (IFN)-γ, interleukin (IL)-4, tumor necrosis factor (TNF)-α, and IL-10 from the peripheral blood mononuclear leukocytes. We are finally starting to understand the intricate connections between the skin neurons and resident skin cells and how their interaction can be key to controlling inflammation and from there the pathogenesis of diseases like atopic dermatitis, psoriasis, and rosacea.

Stewart T.J., Tong W., Whitfeld M.J.

Psoriasis is estimated to affect around 2-3% of the general population. More than one-third of Australians report having a significant level of distress in their daily lives. Psychological stress has long been shown to play an important role in the natural history of psoriasis, but the details of this relationship remain to be clearly defined. We performed a systematic review of the literature with the aim of determining whether there is a temporal association between psychological stress as the predictor and onset and/or exacerbation of psoriasis as the outcome measure. Our secondary aim was to establish whether there is a relationship between the degree of psychological stress and clinical severity of psoriasis. Our systematic review demonstrates a probable temporal association between different measures of psychological stress and onset, recurrence, and severity of psoriasis. In the light of this, we suggest clinicians include "stress" as a trigger factor in their psoriasis assessment and consider psychological interventions as adjuncts, particularly in those who identify as "stress-responders".

Snast I., Reiter O., Atzmony L., Leshem Y.A., Hodak E., Mimouni D., Pavlovsky L.

Psychological stress has long been linked with the exacerbation/onset of psoriasis.To determine if antecedent psychological stress is associated with the exacerbation/onset of psoriasis.A search of the PubMed, PsycINFO, Cochrane library and ClinicalTrials.gov databases was performed. Surveys evaluating beliefs about stress reactivity were analysed separately. Suitable studies were meta-analysed.Thirty-nine studies (32 537 patients) were included: 19 surveys, seven cross-sectional studies, 12 case-control studies and one cohort study. Forty-six per cent of patients believed their disease was stress reactive and 54% recalled preceding stressful events. Case-control studies evaluating stressful events rates prior to the exacerbation (n = 6) or onset (n = 6) of psoriasis varied in time lag to recollection (≤ 9 months to ≥ 5 years). Pooling five studies evaluating stressful events preceding onset of psoriasis gave an odds ratio (OR) of 3·4 [95% confidence interval (CI) 1·8-6·4; I2 = 87%]; the only study evaluating a documented stress disorder diagnosis reported similar rates between patients and controls (OR 1·2, 95% CI 0·8-1·8). Four studies evaluating stressful events prior to psoriasis exacerbation reported comparable rates with controls, whereas two found more frequent/severe preceding events among patients with psoriasis. A small prospective cohort study reported a modest association between stress levels and exacerbation of psoriasis (r = 0·28, P < 0·05).The association between preceding stress and exacerbation/onset of psoriasis is based primarily on retrospective studies with many limitations. No convincing evidence exists that preceding stress is strongly associated with exacerbation/onset of psoriasis.

Dainichi T., Hayden M., Park S., Oh H., Seeley J., Grinberg-Bleyer Y., Beck K., Miyachi Y., Kabashima K., Hashimoto T., Ghosh S.

Summary Asymmetric cell division (ACD) in a perpendicular orientation promotes cell differentiation and organizes the stratified epithelium. However, the upstream cues regulating ACD have not been identified. Here, we report that phosphoinositide-dependent kinase 1 (PDK1) plays a critical role in establishing ACD in the epithelium. Production of phosphatidyl inositol triphosphate (PIP 3 ) is localized to the apical side of basal cells. Asymmetric recruitment of atypical protein kinase C (aPKC) and partitioning defective (PAR) 3 is impaired in PDK1 conditional knockout (CKO) epidermis. PDK1 CKO keratinocytes do not undergo calcium-induced activation of aPKC or IGF1-induced activation of AKT and fail to differentiate. PDK1 CKO epidermis shows decreased expression of Notch, a downstream effector of ACD, and restoration of Notch rescues defective expression of differentiation-induced Notch targets in vitro. We therefore propose that PDK1 signaling regulates the basal-to-suprabasal switch in developing epidermis by acting as both an activator and organizer of ACD and the Notch-dependent differentiation program.

Zhu T.H., Nakamura M., Farahnik B., Abrouk M., Lee K., Singh R., Gevorgyan A., Koo J., Bhutani T.

As most efforts in the last decade have focused on the immunologic basis of inflammatory skin disease, there has been less emphasis on the role of the nervous system in the disease process of psoriasis. Evidence in support of the neurocutaneous pathway has come from observations of patients experiencing unilateral improvement and even complete remission following nerve damage in the affected dermatomal region. The aim of this review was to investigate the role of neuropeptides in the intricate pathophysiology of psoriasis. The PubMed database was searched for individual case reports or case series that reported clearance or significant improvement in psoriatic disease in patients following documented nerve injury. A total of 11 cases were found that reported improvement of psoriatic lesions in areas afflicted by central or peripheral nerve injury. The most common causes of denervation were inadvertent surgical interruption, cerebrovascular accident, and poliomyelitis. In four cases the patients eventually regained neurologic function, which was associated with a recurrence of skin lesions. In cases of permanent nerve damage, there was remission of psoriasis. The cases reported in the literature to date provide clinical evidence that absence of neural input leads to psoriasis improvement, suggesting a crucial role of the nervous system in the pathophysiology of psoriatic disease. In fact, neuropeptides such as nerve growth factor, substance P, calcitonin gene-related peptide, and vasoactive intestinal peptide may be important contributors of psoriatic disease and potential targets for future therapies.

Ding W., Stohl L.L., Xu L., Zhou X.K., Manni M., Wagner J.A., Granstein R.D.

Abstract Calcitonin gene–related peptide (CGRP) is a neuropeptide with well-established immunomodulatory functions. CGRP-containing nerves innervate dermal blood vessels and lymph nodes. We examined whether CGRP regulates the outcome of Ag presentation by Langerhans cells (LCs) to T cells through actions on microvascular endothelial cells (ECs). Exposure of primary murine dermal microvascular ECs (pDMECs) to CGRP followed by coculture with LCs, responsive CD4+ T cells and Ag resulted in increased production of IL-6 and IL-17A accompanied by inhibition of IFN-γ, IL-4, and IL-22 compared with wells containing pDMECs treated with medium alone. Physical contact between ECs and LCs or T cells was not required for this effect and, except for IL-4, we demonstrated that IL-6 production by CGRP-treated pDMECs was involved in these effects. CD4+ cells expressing cytoplasmic IL-17A were increased, whereas cells expressing cytoplasmic IFN-γ or IL-4 were decreased by the presence of CGRP-treated pDMECs. In addition, the level of retinoic acid receptor–related orphan receptor γt mRNA was significantly increased, whereas T-bet and GATA3 expression was inhibited. Immunization at the site of intradermally administered CGRP led to a similar bias in CD4+ T cells from draining lymph node cells toward IL-17A and away from IFN-γ. Actions of nerve-derived CGRP on ECs may have important regulatory effects on the outcome of Ag presentation with consequences for the expression of inflammatory skin disorders involving Th17 cells.

Fehres C.M., Duinkerken S., Bruijns S.C., Kalay H., van Vliet S.J., Ambrosini M., de Gruijl T.D., Unger W.W., Garcia-Vallejo J.J., van Kooyk Y.

The potential of the skin immune system to generate immune responses is well established, and the skin is actively exploited as a vaccination site. Human skin contains several antigen-presenting cell subsets with specialized functions. In particular, the capacity to cross-present exogenous antigens to CD8+ T cells is of interest for the design of effective immunotherapies against viruses or cancer. Here, we show that primary human Langerhans cells (LCs) were able to cross-present a synthetic long peptide (SLP) to CD8+ T cells. In addition, modification of this SLP using antibodies against the receptor langerin, but not dectin-1, further enhanced the cross-presenting capacity of LCs through routing of internalized antigens to less proteolytic early endosome antigen 1+ early endosomes. The potency of LCs to enhance CD8+ T-cell responses could be further increased through activation of LCs with the toll-like receptor 3 ligand polyinosinic:polycytidylic acid (pI:C). Altogether, the data provide evidence that human LCs are able to cross-present antigens after langerin-mediated internalization. Furthermore, the potential for antigen modification to target LCs specifically provides a rationale for generating effective anti-tumor or anti-viral cytotoxic T lymphocyte responses.

Zaru R., Matthews S.P., Edgar A.J., Prescott A.R., Gomez-Nicola D., Hanauer A., Watts C.

Abstract Langerhans cells (LC), the dendritic cells of the epidermis, are distributed in a distinctive regularly spaced array. In the mouse, the LC array is established in the first few days of life from proliferating local precursors, but the regulating signaling pathways are not fully understood. We found that mice lacking the kinase phosphoinositide-dependent kinase 1 selectively lack LC. Deletion of the phosphoinositide-dependent kinase 1 target kinases, ribosomal S6 kinase 1 (Rsk1) and Rsk2, produced a striking perturbation in the LC network: LC density was reduced 2-fold, but LC size was increased by the same magnitude. Reduced LC numbers in Rsk1/2−/− mice was not due to accelerated emigration from the skin but rather to reduced proliferation at least in adults. Rsk1/2 were required for normal LC patterning in neonates, but not when LC were ablated in adults and replaced by bone marrow–derived cells. Increased LC size was an intrinsic response to reduced LC numbers, reversible on LC emigration, and could be observed in wild type epidermis where LC size also correlated inversely with LC density. Our results identify a key signaling pathway needed to establish a normal LC network and suggest that LC might maintain epidermal surveillance by increasing their “footprint” when their numbers are limited.

Kopp T., Riedl E., Bangert C., Bowman E.P., Greisenegger E., Horowitz A., Kittler H., Blumenschein W.M., McClanahan T.K., Marbury T., Zachariae C., Xu D., Hou X.S., Mehta A., Zandvliet A.S., et. al.

A proof-of-concept phase I clinical trial demonstrates that targeting interleukin (IL)-23 with an antibody that binds to the p19 subunit leads to clinical improvement of disease in patients with moderate to severe psoriasis. Sauzanne Khalilieh and colleagues report a proof-of-concept phase I clinical trial which demonstrates that targeting the pro-inflammatory cytokine interleukin-23 (IL-23) with tildrakizumab, an antibody that binds to the p19 subunit of IL-23, leads to symptomatic improvement of disease in patients with moderate to severe psoriasis. The antibody is well tolerated, suggesting that selective targeting of IL-23 merits further study. Psoriasis is a chronic inflammatory skin disorder that affects approximately 2–3% of the population worldwide and has severe effects on patients’ physical and psychological well-being1,2,3. The discovery that psoriasis is an immune-mediated disease has led to more targeted, effective therapies; recent advances have focused on the interleukin (IL)-12/23p40 subunit shared by IL-12 and IL-23. Evidence suggests that specific inhibition of IL-23 would result in improvement in psoriasis. Here we evaluate tildrakizumab, a monoclonal antibody that targets the IL-23p19 subunit, in a three-part, randomized, placebo-controlled, sequential, rising multiple-dose phase I study in patients with moderate-to-severe psoriasis to provide clinical proof that specific targeting of IL-23p19 results in symptomatic improvement of disease severity in human subjects. A 75% reduction in the psoriasis area and severity index (PASI) score (PASI75) was achieved by all subjects in parts 1 and 3 (pooled) in the 3 and 10 mg kg−1 groups by day 196. In part 2, 10 out of 15 subjects in the 3 mg kg−1 group and 13 out of 14 subjects in the 10 mg kg−1 group achieved a PASI75 by day 112. Tildrakizumab demonstrated important clinical improvement in moderate-to-severe psoriasis patients as demonstrated by improvements in PASI scores and histological samples.

Granstein R.D., Wagner J.A., Stohl L.L., Ding W.

Calcitonin gene-related peptide (CGRP) has been viewed as a neuropeptide and vasodilator. However, CGRP is more appropriately thought of as a pleiotropic signalling molecule. Indeed, CGRP has key regulatory functions on immune and inflammatory processes within the skin. CGRP-containing nerves are intimately associated with epidermal Langerhans cells (LCs), and CGRP has profound regulatory effects on Langerhans cell antigen-presenting capability. When LCs are exposed to CGRP in vitro, their ability to present antigen for in vivo priming of naïve mice or elicitation of delayed-type hypersensitivity is inhibited in at least some situations. Administration of CGRP intradermally inhibits acquisition of immunity to Th1-dominant haptens applied to the injected site while augmenting immunity to Th2-dominant haptens, although the cellular targets of activity in these experiments remain unclear. Although CGRP can be a pro-inflammatory agent, several studies have demonstrated that administration of CGRP can inhibit the elicitation of inflammation by inflammatory stimuli in vivo. In this regard, CGRP inhibits the release of certain chemokines by stimulated endothelial cells. This is likely to be physiologically relevant as cutaneous blood vessels are innervated by sensory nerves. Exciting new studies suggest a significant role for CGRP in the pathogenesis of psoriasis and, most strikingly, that CGRP inhibits the ability of LCs to transmit the human immunodeficiency virus 1 to T lymphocytes. A more complete understanding of the role of CGRP in the skin immune system may lead to new and novel approaches for the therapy of immune-mediated skin disorders.

Kotlyar J., Granstein R.D.

Keenan E.L., Granstein R.D.

AbstractPsoriasis vulgaris has established associations with psychiatric conditions such as depression, anxiety, and chronic stress. This review aims to evaluate current theories and evidence regarding the role of proinflammatory cytokines and neuropeptides in connecting systemic inflammation, psychological stress, and inflammatory skin diseases, namely psoriasis. A literature review was conducted to analyze studies that explore the connections between psoriasis, psychiatric conditions, and biological mediators, including inflammatory cytokines [interferon (IFN)‐γ, interleukin (IL)‐1, IL‐2, IL‐6, IL‐12, tumor necrosis factor (TNF)‐α, IL‐22, IL‐17], neuropeptides [calcitonin gene‐related peptide (CGRP), substance P (SP), and vasoactive intestinal peptide (VIP)], as well as the hypothalamic–pituitary–adrenal (HPA) axis. Existing literature indicates that psychiatric state can influence cutaneous conditions through immune, neural, and endocrine mediators. The elevated rates of anxiety and depression observed in psoriasis patients are likely due to both the inflammatory process itself and the chronic stress associated with disease management, highlighting the importance of managing stress, and addressing mental health to improve clinical outcomes. While the literature suggests proinflammatory cytokines and neuropeptides may be key links between systemic inflammation, psoriasis, and psychiatric comorbidities, further research is necessary to continue to elucidate physiological mechanisms and explore the potential for new treatment modalities.

Peng F., Xia T.

Bailey M.T.

Body surfaces are colonized by an enormous array of microbes collectively referred to as the microbiota. In the past decade, there has been an increase in research activity directed toward understanding the importance of microbiota for human health and disease. This research activity has clearly established that the commensal microbiota play an essential role in the development and maintenance of physiological processes, including neuroendocrine and immune responses, throughout life. Although our understanding of exactly how these microbes exert their effects on the host is still in its infancy, multiple pathways have been identified in recent years. These pathways are described here, along with a description of some of the tools needed for their study.

Zhang J., Zhao S., Xing X., Shang L., Cao J., He Y.