Neuroimmunology of Psoriasis: Possible Roles for Calcitonin Gene-Related Peptide in its Pathogenesis

Hou Y., Sun L., LaFleur M.W., Huang L., Lambden C., Thakore P.I., Geiger-Schuller K., Kimura K., Yan L., Zang Y., Tang R., Shi J., Barilla R., Deng L., Subramanian A., et. al.

The balance between T helper type 1 (TH1) cells and other TH cells is critical for antiviral and anti-tumour responses1–3, but how this balance is achieved remains poorly understood. Here we dissected the dynamic regulation of TH1 cell differentiation during in vitro polarization, and during in vivo differentiation after acute viral infection. We identified regulators modulating T helper cell differentiation using a unique TH1–TH2 cell dichotomous culture system and systematically validated their regulatory functions through multiple in vitro and in vivo CRISPR screens. We found that RAMP3, a component of the receptor for the neuropeptide CGRP (calcitonin gene-related peptide), has a cell-intrinsic role in TH1 cell fate determination. Extracellular CGRP signalling through the receptor RAMP3–CALCRL restricted the differentiation of TH2 cells, but promoted TH1 cell differentiation through the activation of downstream cAMP response element-binding protein (CREB) and activating transcription factor 3 (ATF3). ATF3 promoted TH1 cell differentiation by inducing the expression of Stat1, a key regulator of TH1 cell differentiation. After viral infection, an interaction between CGRP produced by neurons and RAMP3 expressed on T cells enhanced the anti-viral IFNγ-producing TH1 and CD8+ T cell response, and timely control of acute viral infection. Our research identifies a neuroimmune circuit in which neurons participate in T cell fate determination by producing the neuropeptide CGRP during acute viral infection, which acts on RAMP3-expressing T cells to induce an effective anti-viral TH1 cell response. RAMP3, a component of the receptor for the neuropeptide CGRP, has a cell-intrinsic role in T helper type 1 cell fate determination.

Huang C., Sun P., Jiang Y., Liu Y., Liu Z., Han S., Wang B., Huang Y., Ren A., Lu J., Jiang Q., Li Y., Zhu M.X., Yao Z., Tian Y., et. al.

AbstractPsoriasis is an immune-mediated skin disease associated with neurogenic inflammation, but the underlying molecular mechanism remains unclear. We demonstrate here that acid-sensing ion channel 3 (ASIC3) exacerbates psoriatic inflammation through a sensory neurogenic pathway. Global or nociceptor-specific Asic3 knockout (KO) in female mice alleviates imiquimod-induced psoriatic acanthosis and type 17 inflammation to the same extent as nociceptor ablation. However, ASIC3 is dispensable for IL-23-induced psoriatic inflammation that bypasses the need for nociceptors. Mechanistically, ASIC3 activation induces the activity-dependent release of calcitonin gene-related peptide (CGRP) from sensory neurons to promote neurogenic inflammation. Botulinum neurotoxin A and CGRP antagonists prevent sensory neuron-mediated exacerbation of psoriatic inflammation to similar extents as Asic3 KO. In contrast, replenishing CGRP in the skin of Asic3 KO mice restores the inflammatory response. These findings establish sensory ASIC3 as a critical constituent in psoriatic inflammation, and a promising target for neurogenic inflammation management.

Wienholtz N.K., Christensen C.E., Do T.P., Frifelt L.E., Snellman J., Lopez-Lopez C.L., Egeberg A., Thyssen J.P., Ashina M.

ImportanceTreatment of erythema and flushing in rosacea is challenging. Calcitonin gene-related peptide (CGRP) has been associated with the pathogenesis of rosacea, raising the possibility that inhibition of the CGRP pathway might improve certain features of the disease.ObjectiveTo examine the effectiveness, tolerability, and safety of erenumab, an anti–CGRP-receptor monoclonal antibody, for the treatment of rosacea-associated erythema and flushing.Design, Setting, and ParticipantsThis single-center, open-label, single-group, nonrandomized controlled trial was conducted between June 9, 2020, and May 11, 2021. Eligible participants included adults with rosacea with at least 15 days of either moderate to severe erythema and/or moderate to extreme flushing. No concomitant rosacea treatment was allowed throughout the study period. Visits took place at the Danish Headache Center, Copenhagen University Hospital, Rigshospitalet in Copenhagen, Denmark. Participants received 140 mg of erenumab subcutaneously every 4 weeks for 12 weeks. A safety follow-up visit was performed at week 20. Data analysis occurred from January 2023 to January 2024.Intervention140 mg of erenumab every 4 weeks for 12 weeks.Main Outcomes and MeasuresThe primary outcome was mean change in the number of days with moderate to extreme flushing during weeks 9 through 12, compared with the 4-week run-in period (baseline). The mean change in number of days with moderate to severe erythema was a secondary outcome. Adverse events were recorded for participants who received at least 1 dose of erenumab. Differences in means were calculated with a paired t test.ResultsA total of 30 participants (mean [SD] age, 38.8 [13.1] years; 23 female [77%]; 7 male [23%]) were included, of whom 27 completed the 12-week study. The mean (SD) number of days with moderate to extreme flushing was reduced by −6.9 days (95% CI, −10.4 to −3.4 days; P < .001) from 23.6 (5.8) days at baseline. The mean (SD) number of days with moderate to severe erythema was reduced by −8.1 days (95% CI, −12.5 to −3.7 days; P < .001) from 15.2 (9.1) days at baseline. Adverse events included transient mild to moderate constipation (10 participants [33%]), transient worsening of flushing (4 participants [13%]), bloating (3 participants [10%]), and upper respiratory tract infections (3 participants [10%]), consistent with previous data. One participant discontinued the study due to a serious adverse event (hospital admission due to gallstones deemed unrelated to the study), and 2 participants withdrew consent due to lack of time.Conclusions and RelevanceThese findings suggest that erenumab might be effective in reducing rosacea-associated flushing and chronic erythema (participants generally tolerated the treatment well, which was consistent with previous data), and that CGRP-receptor inhibition holds potential in the treatment of erythema and flushing associated with rosacea. Larger randomized clinical trials are needed to confirm this finding.Trial RegistrationClinicalTrials.gov Identifier: NCT04419259

Russo A.F., Hay D.L.

Calcitonin gene-related peptide (CGRP) is a neuropeptide with diverse physiological functions. Its two isoforms (α and β) are widely expressed throughout the body in sensory neurons, as well as in other cell types, such as motor neurons and neuroendocrine cells. CGRP acts via at least two G protein-coupled receptors that form unusual complexes with receptor activity-modifying proteins. These are the CGRP receptor and the AMY1 receptor; in rodents, additional receptors come into play. Although CGRP is known to produce many effects, the precise molecular identity of the receptor(s) that mediate CGRP effects is seldom clear. Despite the many enigmas still in CGRP biology, therapeutics that target the CGRP axis to treat or prevent migraine are a bench to bedside success story. This review provides a contextual background on the regulation and sites of CGRP expression and CGRP receptor pharmacology. The physiological actions of CGRP in the nervous system are discussed, along with updates on CGRP actions in the cardiovascular, pulmonary, gastrointestinal, immune, hematopoietic, and reproductive systems, and metabolic effects of CGRP in muscle and adipose tissues. We cover how CGRP in these systems is associated with disease states, most notably migraine. In this context, we discuss how CGRP actions in both the peripheral and central nervous systems provide a basis for therapeutic targeting of CGRP in migraine. Finally, we highlight potentially fertile ground for the development of additional therapeutics and combinatorial strategies that could be designed to modulate CGRP signaling for migraine and other diseases.

Zhou Y., Xu F., Chen X., Yan B., Wang Z., Chen S., Zheng M., Man X.

Psoriasis is a common chronic inflammatory skin disease. The diversity and heterogeneity of immune cells in human skin have been studied in recent years, but the spatial distribution of immune cells at the single-cell level in the human psoriatic epidermis and dermis remains unclear. In this study, we mapped psoriatic skin immune cells from paired lesional, perilesional, and nonlesional skin samples using mass cytometry. Phenotypic dendritic cells (DCs) were found in the psoriatic epidermis and dermis. Psoriatic dermal CD1c+CD11b+ cDC2s migrated to the epidermis in the perilesional skin during the preinitiation stage. CD1c+CD11b+ cDC2s rapidly replaced EpCAM+CD11clow LC cells and initiated inflammation. Simultaneously, CD207+CD11chi LC and CD5+ T cells accumulated in the psoriatic epidermis and orchestrated epidermal inflammation in psoriasis. The immune cell pool in the psoriatic dermis primarily included APCs and T cells. However, unlike that in the dermis, the epidermal immune environment was more significant and coincided with the inflammation occurring during psoriasis. The epidermal immune microenvironment plays a dominant role in psoriasis. Langerhans cells, epidermis-resident memory T cells and macrophages together contribute to healthy epidermal immune homeostasis. However, psoriatic CD1c+CD11b+ epidermal cDC2s are positioned in the perilesional area, replacing EpCAM+CD11clow LCs rapidly and initiating inflammation. Epidermal CD141+ cDC1s, CD1c+ cDC2s, CD14+ moDCs, and BDCA2+ pDCs orchestrate psoriatic inflammation. Meanwhile, CD11chi LCs and CD5+ T cells accumulate in the psoriatic epidermis

Yin Q., Sun L., Cai X., Lou F., Sun Y., Wang B., Jiang B., Bao L., Li X., Song N., Tang S., Bai J., Wang Z., Wu Y., Zhou H., et. al.

Psoriasis is a chronic immune-mediated skin disorder with the nervous system contributing to its pathology. The neurogenic mediators of psoriasis are elusive, and whether the intervention of the cutaneous nervous system can treat psoriasis remains to be determined. In this study, we conducted a pilot study using an epidural injection of lidocaine to treat patients with psoriasis. Lidocaine treatment markedly reduced patients' clinical scores and improved an imiquimod-induced rat model of psoriasis as competent as systemic delivery of a TNF-α antibody. Imiquimod application elicited aberrant cutaneous nerve outgrowth and excessive generation of neuropeptide calcitonin gene-related peptide from dorsal root ganglion neurons, both of which were inhibited by epidural lidocaine treatment. Single-cell RNA sequencing unveiled the overrepresentation of calcitonin gene-related peptide receptors in dermal dendritic cell populations of patients with psoriasis. Through disturbing calcitonin gene-related peptide signaling, lidocaine inhibited IL-23 production by dendritic cells cocultured with dorsal root ganglion neurons. Thus, epidural nerve block with lidocaine demonstrates an effective therapy for psoriasis, which suppresses both inordinate sensory nerve growth in the inflamed skin and calcitonin gene-related peptide–mediated IL-23 production from psoriatic dendritic cells.

Chen S., Chen X., Cui Y., Yan B., Zhou Y., Wang Z., Xu F., Huang Y., Zheng Y., Man X.

Recent studies have illustrated that psoriatic lesions are innervated by dense sensory nerve fibers. Psoriatic plaques appeared to improve after central or peripheral nerve injury. Therefore, the nervous system may play a vital role in psoriasis. We aimed to clarify the expression of nerve fibers in psoriasis and their relationship with immune cells and keratinocytes, and to explore the effect of skin nerve impairment. Our results illustrated that nerve fibers in psoriatic lesions increased and were closely innervated around immune cells and keratinocytes. RNA-seq analysis showed that peripheral sensory nerve-related genes were disrupted in psoriasis. In spinal cord hemi-section mice, sensory impairment improved psoriasiform dermatitis and inhibited the abnormal proliferation of keratinocytes. Botulinum toxin A alleviated psoriasiform dermatitis by inhibiting the secretion of calcitonin gene-related peptide. Collectively, cutaneous nerve fibers participate in the progression of psoriasis by linking epidermal keratinocytes and immunocytes. Neurological intervention may be a new treatment strategy for psoriasis.

Cohen E., Mariotton J., Rozenberg F., Sams A., van Kuppevelt T.H., Barry Delongchamps N., Zerbib M., Bomsel M., Ganor Y.

Herpes simplex virus (HSV) is widespread globally, with both HSV-1 and HSV-2 responsible for genital herpes. During sexual transmission, HSV targets epithelial cells, sensory peripheral pain neurons secreting the mucosal neuropeptide calcitonin gene-related peptide (CGRP), and mucosal immune cells including Langerhans cells (LCs). We previously described a neuro-immune crosstalk, whereby CGRP inhibits LCs-mediated human immunodeficiency virus type 1 (HIV-1) transmission. Herein, to further explore CGRP-mediated anti-viral function, we investigated whether CGRP affects LCs infection with HSV. We found that both HSV-1 and HSV-2 primary isolates productively infect monocyte-derived LCs (MDLCs) and inner foreskin LCs. Moreover, CGRP significantly inhibits infection with both HSV subtypes of MDLCs and langerinhigh, but not langerinlow, inner foreskin LCs. For HSV-1, infection is mediated via the HSV-1-specific entry receptor 3-O sulfated heparan sulfate (3-OS HS) in a pH-depended manner, and CGRP down-regulates 3-OS HS surface expression, as well as abrogates pH dependency. For HSV-2, infection involves langerin-mediated endocytosis in a pH-independent manner, and CGRP up-regulates surface expression of atypical langerin double-trimer oligomers. Our results show that CGRP inhibits mucosal HSV infection by differentially modulating subtype-specific entry receptors and mechanisms in human LCs. CGRP could turn out useful for prevention of LCs-mediated HSV infection and HSV/HIV-1 co-infection.

Peng F., Zhao S., Zhang X., Long S., He Y.

AbstractIntense mental stimulation and stress often directly induce or exacerbate psoriasis. On the contrary, patients with nerve injury and nervous system dysfunction have psoriasis remission. The nervous system plays an important role in the inflammatory process of psoriasis, and neuropeptides are considered as local mediators of disease maintenance. To examine the molecular mechanism involved in this, first we analyzed calcitonin gene-related peptide (CGRP)-treated langerhans Cells and γδ-T cells separately. CGRP induced IL-23 mRNA and protein expression via PDK1-Rsk signaling pathway. However, CGRP had no effect on secretion of IL-17A and IL-22 in γδ-T cells. Then we treated LCs/γδ-T cells Co-culture Model with CGRP. CGRP upregulated IL-17A and IL-22 expression in co-culture model through the paracrine effect of LCs. IL-17A and IL-22 are key cytokines of psoriasis. These findings provide a potential mechanism by which nerve factors affect the development of psoriasis.

Davidson L., van den Reek J.M., Bruno M., van Hunsel F., Herings R.M., Matzaraki V., Boahen C.K., Kumar V., Groenewoud H.M., van de Veerdonk F.L., Netea M.G., de Jong E.M., Kullberg B.J.

Biologics directed against the T-helper (Th)-17 pathway have been approved for several inflammatory diseases. Interleukin (IL)-17 is involved in anti- Candida host defense, and clinical trials suggested increased candidiasis incidence during IL-17 inhibitor therapy. We describe the worldwide epidemiology of candidiasis during Th17 inhibitor therapy, and immunological mechanisms involved in candidiasis susceptibility.A comprehensive analysis of multiple independent sources reporting Candida adverse events during biologics inhibiting the Th17 pathway was performed. Association between Th17 inhibitors and candidiasis was assessed using safety reports of (1) WHO and (2) EMA, (3) a population-based prescriptions registry, and (4) a psoriasis cohort. In a cohort of psoriasis patients experiencing candidiasis during Th17 inhibitors, Candida killing by immune cells and serum inflammatory proteome were analyzed.A strong association between IL-17 inhibitors and candidiasis (ROR 10·20) was found in the WHO database, particularly for cutaneous (ROR 12·28), oropharyngeal (ROR 19·18), and esophageal candidiasis (ROR 21·20). Risk was higher relative to TNF-α inhibitors (4-10-fold, depending on candidiasis type), confirmed by EMA reports (16-33-fold), prescriptions registry (2-42-fold), and a psoriasis cohort (3-25-fold). After start of IL-17 inhibitors, patients' risk of candidiasis requiring antifungals increased 2-16 fold. In the psoriasis cohort, 58% of IL-17 treatment episodes were associated with candidiasis. In Th17 inhibitor recipients, proteins involved in anti- Candida immunity and Candida killing by mononuclear leukocytes were impaired.IL-17 inhibitors are associated with an increased risk of oropharyngeal, esophageal, and cutaneous candidiasis, posing a significant disease burden for IL-17 inhibitor recipients.RadboudUMC.

Ding W., Stohl L.L., Saab J., Azizi S., Zhou X.K., Mehta D., Granstein R.D.

Abstract Calcitonin gene–related peptide (CGRP) can bias the outcome of Ag presentation to responsive T cells in vitro away from Th1-type immunity and toward the Th2 and Th17 poles through actions on endothelial cells (ECs). To test the in vivo significance of this observation, we engineered a mouse lacking functional CGRP receptors on ECs (EC receptor activity modifying protein 1 [RAMP1] knockout mice). On percutaneous immunization to 1-fluoro-2,4-dinitrobenzene, stimulated CD4+ T cells from draining lymph nodes showed significantly reduced IL-17A expression with significantly increased IFN-γ, IL-4, and IL-22 expression at the protein and mRNA levels compared with control mice. Retinoic acid receptor-related orphan receptor γ t mRNA was significantly reduced, while mRNAs for T-box expressed in T cells and GATA binding protein 3 were significantly increased. In addition, EC RAMP1 knockout mice had significantly reduced contact hypersensitivity responses, and systemic administration of a CGRP receptor antagonist similarly inhibited contact hypersensitivity in wild-type mice. These observations provide compelling evidence that CGRP is a key regulator of cutaneous immunity through effects on ECs and suggest a novel pathway for potential therapeutic manipulation.

Kim Y.J., Granstein R.D.

Skin immunity is regulated by many mediator molecules. One is the neuropeptide calcitonin gene-related peptide (CGRP). CGRP has roles in regulating the function of components of the immune system including T cells, B cells, dendritic cells (DCs), endothelial cells (ECs), and mast cells (MCs). Herein we discuss actions of CGRP in mediating inflammatory and vascular effects in various cutaneous models and disorders.

Liu X., Zhu R., Luo Y., Wang S., Zhao Y., Qiu Z., Zhang Y., Liu X., Yao X., Li X., Li W.

Langerhans cells (LCs) play a pivotal role in skin homeostasis, and the heterogeneity of LCs has long been considered. In this study, we have identified two steady-state (LC1 and LC2) and two activated LC subsets in the epidermis of human skin and in LCs derived from CD34+ hemopoietic stem cells (HSC-LCs) by utilizing single-cell RNA sequencing and mass cytometry. Analysis of HSC-LCs at multiple time-points during differentiation revealed that EGR1 and Notch signaling were among the top pathways regulating the bifurcation of LC1 and LC2. LC1 were characterized as classical LCs, mainly related to innate immunity and antigen processing. LC2 were similar to monocytes or myeloid dendritic cells, involving in immune responses and leukocyte activation. LC1 remained stable under inflammatory microenvironment, whereas LC2 were prone to being activated and demonstrated elevated expression of immuno-suppressive molecules. We revealed distinct human LC subsets that require different developmental regulation and orchestrate reciprocal functions.

Armstrong A.W., Mehta M.D., Schupp C.W., Gondo G.C., Bell S.J., Griffiths C.E.

Determining psoriasis prevalence is fundamental to understanding the burden of the disease, the populations most affected, and health policies to address the disease.(1) To determine the prevalence of psoriasis among adults in the US and (2) to evaluate the change in psoriasis prevalence over time since the 2003-2004 National Health and Nutrition Examination Survey (NHANES) data.This population-based cross-sectional study used 2011-2014 NHANES data (collected from January 1, 2011, to December 31, 2014) with sampling from a general, noninstitutionalized US civilian population. Participants were 20 years or older and were selected via a multistage probability sampling design to ensure that surveys were nationally representative. Eligible participants had an in-person interview followed by a medical examination by medical professionals. Data were analyzed from July 15, 2019, to December 23, 2020.None.Psoriasis prevalence in the US, as measured by the percentage of people in the representative sample with psoriasis, and trend statistics comparing prevalence estimates from the 2003-2004, 2009-2010, and 2011-2014 NHANES cycles.A total of 12 625 participants (mean [SD] age, 32.8 [24.1] years; 6492 women [51.4%]; and 4828 non-Hispanic White participants [38.2%]) answered the question of whether they were given the diagnosis of psoriasis by a physician or another health care professional. Psoriasis prevalence among US adults 20 years or older was 3.0% (95% CI, 2.6%-3.4%). Based on the 2020 US census data, this outcome translates to an estimated 7.55 million US adults with psoriasis. Psoriasis prevalence was similar between women and men, with 3.2% (95% CI, 2.6%-3.8%) in women and 2.8% (95% CI, 2.4%-3.3%) in men. Psoriasis prevalence was highest in White individuals at 3.6% (95% CI, 2.9%-4.2%), followed by other racial/ethnic groups (non-Hispanic, including multiracial) at 3.1% (95% CI, 1.2%-5.1%), Asian individuals at 2.5% (95% CI, 1.6%-3.3%), Hispanic individuals (including Mexican American and other Hispanic individuals) at 1.9% (95% CI, 1.3%-2.5%), and Black individuals at 1.5% (95% CI, 1.0%-2.0%). Psoriasis prevalence was not different based on patients' marital status, education, income, or medical insurance status. The prevalence of psoriasis among US adults did not differ significantly since 2003.The results of this cross-sectional study suggest that psoriasis remains a common, immune-mediated disease that affects 3.0% of the US adult population, or more than 7.5 million adults. Its prevalence has not differed since evaluation in 2003. These prevalence data are foundational to determining the burden of psoriasis and for supporting efforts in research, education, and health policy.

Ailani J., Burch R.C., Robbins M.S.

To incorporate recent research findings, expert consensus, and patient perspectives into updated guidance on the use of new acute and preventive treatments for migraine in adults.The American Headache Society previously published a Consensus Statement on the use of newly introduced treatments for adults with migraine. This update, which is based on the expanded evidence base and emerging expert consensus concerning postapproval usage, provides practical recommendations in the absence of a formal guideline.This update involved four steps: (1) review of data about the efficacy, safety, and clinical use of migraine treatments introduced since the previous Statement was published; (2) incorporation of these data into a proposed update; (3) review and commentary by the Board of Directors of the American Headache Society and patients and advocates associated with the American Migraine Foundation; (4) consideration of these collective insights and integration into an updated Consensus Statement.Since the last Consensus Statement, no evidence has emerged to alter the established principles of either acute or preventive treatment. Newly introduced acute treatments include two small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists (ubrogepant, rimegepant); a serotonin (5-HT1F ) agonist (lasmiditan); a nonsteroidal anti-inflammatory drug (celecoxib oral solution); and a neuromodulatory device (remote electrical neuromodulation). New preventive treatments include an intravenous anti-CGRP ligand monoclonal antibody (eptinezumab). Several modalities, including neuromodulation (electrical trigeminal nerve stimulation, noninvasive vagus nerve stimulation, single-pulse transcranial magnetic stimulation) and biobehavioral therapy (cognitive behavioral therapy, biofeedback, relaxation therapies, mindfulness-based therapies, acceptance and commitment therapy) may be appropriate for either acute and/or preventive treatment; a neuromodulation device may be appropriate for acute migraine treatment only (remote electrical neuromodulation).The integration of new treatments into clinical practice should be informed by the potential for benefit relative to established therapies, as well as by the characteristics and preferences of individual patients.