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Fil: Speisky, Daniela. Hospital Británico. Departamento de Patología; Argentina Fil: Táquez Delgado, Mónica Alejandra. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas. Laboratorio de Biología Tumoral e Inflamación; Argentina Fil: Táquez Delgado, Mónica Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Iott, Alejandro. Hospital Británico. Departamento de Patología; Argentina Fil: Nicoud, Melisa Beatriz. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas. Laboratorio de Biología Tumoral e Inflamación; Argentina Fil: Nicoud, Melisa Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Ospital, Ignacio. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas. Laboratorio de Biología Tumoral e Inflamación; Argentina Fil: Ospital, Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Vigovich, Félix. Hospital Británico. Departamento de Patología; Argentina Fil: Dezanzo, Pablo. Hospital Británico. Departamento de Patología; Argentina Fil: Ernst, Glenda. Hospital Británico. Comité Científico; Argentina Fil: Uriburu, Juan Luis. Hospital Británico. Departamento de Mastología; Argentina Fil: Medina, Vanina A. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas. Laboratorio de Biología Tumoral e Inflamación; Argentina Fil: Medina, Vanina A. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Abstract: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype. There are neither universally accepted prognostic markers, nor molecular targets related to TNBC. The histamine H4 receptor (H4R) has been characterized in TNBC experimental models, demonstrating its critical role in tumor development and progression. In this study, H4R expression was compared in breast cancer subtypes and correlated with clinical features using The Cancer Genome Atlas data (TCGA, Pan-Cancer Atlas). The H4R status was further evaluated by immunohistochemistry in 30 TNBC human samples in relation to clinicopathological parameters. Results indicate that H4R was downregulated in basal-like/TNBC compared with luminal A and normal breastlike tumors. The higher expression of H4R was associated with improved progression free and overall survival outcomes in basal-like/TNBC. H4R immunoreactivity was detected in about 70% of tumors, and its expression was positively correlated with the levels in the histologically normal peritumoral tissue. High H4R expression in peritumoral tissue correlated with reduced number of lymph node involvement and unifocal TNBC while it was associated with increased patient survival. In conclusion, the H4R might represent a potential prognostic biomarker in TNBC. Further studies in large cohorts are needed to better understand the significance of H4R in breast cancer biology.

Adoptive T cell therapy (ACT) requires lymphodepletion preconditioning to eliminate immune-suppressive elements and enable efficient engraftment of adoptively transferred tumor-reactive T cells. As anti-CD4 monoclonal antibody depletes CD4+ immune-suppressive cells, the combination of anti-CD4 treatment and ACT has synergistic potential in cancer therapy. Here, we demonstrate a post-ACT conditioning regimen that involves transient anti-CD4 treatment (CD4post). Using murine melanoma, the combined effect of cyclophosphamide preconditioning (CTXpre), CD4post, and ex vivo primed tumor-reactive CD8+ T-cell infusion is presented. CTXpre/CD4post increases tumor suppression and host survival by accelerating the proliferation and differentiation of ex vivo primed CD8+ T cells and endogenous CD8+ T cells. Endogenous CD8+ T cells enhance effector profile and tumor-reactivity, indicating skewing of the TCR repertoire. Notably, enrichment of polyfunctional IL-18Rαhi CD8+ T cell subset is the key event in CTXpre/CD4post-induced tumor suppression. Mechanistically, the anti-tumor effect of IL-18Rαhi subset is mediated by IL-18 signaling and TCR–MHC I interaction. This study highlights the clinical relevance of CD4post in ACT and provides insights regarding the immunological nature of anti-CD4 treatment, which enhances anti-tumor response of CD8+ T cells., Lymphodepleting preconditioning is generally required prior to adoptive T cell therapy (ACT). Here the authors show in a preclinical melanoma model that anti-CD4 treatment as a post-conditioning regimen enhances the anti-tumor efficacy of ACT by promoting the expansion of IL-18Rαhi CD8+ T cells.

Atopic dermatitis (AD) is maintained by a variety of cells and inflammatory mediators, including eosinophils and histamine. We recently reported that eosinophils from AD patients highly express the H

Over the past decades, envenomation by caterpillars of

Chronic pruritus is a symptom that commonly observed in neurological diseases. It has been hypothesized that the chronic pruritus may result from sensitization of itch-signaling pathways but the mechanisms remain obscure. In this study, we established a mouse model of chronic compression of dorsal root ganglion (CCD) and injected various pruritogenic and algogenic agents intradermally to the calf skin ipsilateral to the compressed dorsal root ganglion (DRG). Compared to the naïve mice, a significant increase in itch-related behaviors was observed in the CCD mice after the injection of pruritogens including histamine and BAM8-22, but not after the injection of capsaicin, although all the above agents evoked enhanced pain-related behaviors toward the injected site. In addition, we investigated if pruritogen-evoked activities of DRG neurons are enhanced in this model. In vivo calcium imaging revealed that compressed DRG neurons exhibited significant enhanced responses to histamine and BAM8-22. Immunoflorescent staining also showed that the histamine receptor H1 and the capsaicin receptor TRPV1 were significantly upregulated in DRG neurons. Our findings indicated that in mice modeling the sensitization of primary pruriceptive neurons may underlie the enhanced itch sensation after chronic compression of DRG neurons, and may play a role in chronic pruritus in neurological diseases.

Chronic pruritus, defined as an unpleasant sensation resulting in a need to scratch that lasts more than 6 weeks, is a prevalent and bothersome symptom associated with both cutaneous and systemic conditions. Due to complex pathogenesis and profuse contributing factors, chronic pruritus therapy remains challenging. Regardless of the well-established antipruritic properties of classic pharmacotherapy (topical therapy, phototherapy and systemic therapy), these methods often provide insufficient relief for affected individuals. Owing to the growing interest in the field of pruritic research, further experimental and clinical data have emerged, continuously supporting the possibility of instigating novel therapeutic measures. This review covers the most relevant current modalities remaining under investigation that possess promising perspectives of approval in the near future, especially opioidergic drugs (mu-opioid antagonists and kappa-opioid agonists), neurokinin-1 receptor antagonists, biologic drugs, Janus kinase inhibitors, ileal bile acid transporter inhibitors, aryl hydrocarbon receptor agonists and histamine H4 receptor antagonists.

Oral squamous cell carcinoma (OSCC), the most common oral malignancy, shows an increasing rate of incidence worldwide. In spite of the recent advances in cancer research, OSCC therapy continues to have unfavourable outcomes, and thus, patient’s prognosis remains relatively poor. Current research has been devoted to identifying novel therapeutic targets also in the tumour microenvironment (TME). Histamine and its G‐protein‐coupled receptors (H1R‐H4R) play vital roles in multiple cancer‐associated processes in TME, where histamine is mainly produced by mast cells. However, oral epithelial cells were recently shown to produce low concentrations of histamine in autocrine and paracrine modes. These findings, together with the discovery of the high‐affinity histamine H4 receptor, have led to a massive increase in our understanding of histamine functions. In this review, we aim to summarize the most recent findings regarding histamine and its receptors and their involvement in oral carcinogenesis—from oral potentially malignant disorders (OPMDs) to invasive OSCC. Importantly, histamine receptors are differentially expressed in OPMDs and OSCC. Furthermore, H1R and H4R are associated with clinicopathological characteristics of OSCC patients, suggesting a role in prognosis. Due to the enormous success of histamine‐based medications, histamine receptors may also represent promising and viable drug targets in oral cancer.

Fil: Clauzure, Mariángeles. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas. Laboratorio de Biología Tumoral e Inflamación; Argentina Fil: Clauzure, Mariángeles. Universidad Nacional de La Pampa. Facultad de Ciencias Veterinarias; Argentina Fil: Táquez Delgado, Mónica Alejandra. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas. Laboratorio de Biología Tumoral e Inflamación; Argentina Fil: Phillip, Jude M. Weill Cornell Medicine. Department of Medicine. Hematology and Oncology Division; Estados Unidos Fil: Revuelta, Maria V. Weill Cornell Medicine. Department of Medicine. Hematology and Oncology Division; Estados Unidos Fil: Cerchietti, Leandro. Weill Cornell Medicine. Department of Medicine. Hematology and Oncology Division; Estados Unidos Fil: Medina, Vanina A. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas. Laboratorio de Biología Tumoral e Inflamación; Argentina Fil: Medina, Vanina A. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Clauzure, Mariángeles. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Abstract: The discovery of the human histamine H4 receptor (H4R) has contributed to our understanding of the role of histamine in numerous physiological and pathological conditions, including tumor development and progression. The lymph nodes of patients with malignant lymphomas have shown to contain high levels of histamine, however, less is known regarding the expression and function of the H4R in T-cell lymphoma (TCL). In this work we demonstrate the expression of H4R isoforms (mRNA and protein) in three human aggressive TCL (OCI-Ly12, Karpas 299, and HuT78). Histamine and specific H4R agonists (VUF8430 and JNJ28610244) significantly reduced cell viability in a dose-dependent manner (p < 0.05). The combined treatment with the H4R antagonist (JNJ7777120, 10 µM) reversed the effects of the H4R ligands. Importantly, we screened a drug repurposing library of 433 FDA-approved compounds (1 µM) in combination with histamine (10 µM) in Hut78 cells. Histamine produced a favorable antitumor effect with 18 of these compounds, including the histone deacetylase inhibitor panobinostat. Apoptosis, proliferation, and oxidative stress studies confirmed the antitumoral effects of the combination. We conclude that the H4R is expressed in TCL, and it is involved in histamine-mediated responses.

Multiple sclerosis is an autoimmune disease with a strong neuroinflammatory component that contributes to severe demyelination, neurodegeneration and lesions formation in white and grey matter of the spinal cord and brain. Increasing attention is being paid to the signaling of the biogenic amine histamine in the context of several pathological conditions. In multiple sclerosis, histamine regulates the differentiation of oligodendrocyte precursors, reduces demyelination, and improves the remyelination process. However, the concomitant activation of histamine H1–H4 receptors can sustain either damaging or favorable effects, depending on the specifically activated receptor subtype/s, the timing of receptor engagement, and the central versus peripheral target district. Conventional drug development has failed so far to identify curative drugs for multiple sclerosis, thus causing a severe delay in therapeutic options available to patients. In this perspective, drug repurposing offers an exciting and complementary alternative for rapidly approving some medicines already approved for other indications. In the present work, we have adopted a new network-medicine-based algorithm for drug repurposing called SAveRUNNER, for quantifying the interplay between multiple sclerosis-associated genes and drug targets in the human interactome. We have identified new histamine drug-disease associations and predicted off-label novel use of the histaminergic drugs amodiaquine, rupatadine, and diphenhydramine among others, for multiple sclerosis. Our work suggests that selected histamine-related molecules might get to the root causes of multiple sclerosis and emerge as new potential therapeutic strategies for the disease.

Nitrogen-containing bisphosphonates (NBPs, anti-bone-resorptive agents) have inflammatory side-effects. Alendronate (Ale, an NBP) intradermally injected into mouse ear-pinnae together with LPS (bacterial cell-wall component) induces augmented ear-swelling that depends on IL-1 and neutrophils. Using this model, we examined histamine's involvement in Ale + LPS-induced inflammation.Ale increased histamine in ear-pinnae by inducing histidine decarboxylase (HDC). This induction was augmented by LPS. In HDC-deficient mice, such augmented ear-swelling was not induced. At peak-swelling, 74.5% of HDC-expressing cells were neutrophils and only 0.2% were mast cells (MCs). The augmented swelling was markedly reduced by a histamine H4-receptor (H4R) antagonist, but not by an H1R antagonist. In MC-deficient mice, unexpectedly, Ale + LPS induced prolonged ear-swelling that was augmented and more persistent than in normal mice. MCs highly expressed H4Rs and produced MCP-1(inflammatory cytokine that recruits macrophages) and IL-10 (anti-inflammatory cytokine) in response to an H4R agonist.Histamine produced by HDC-induction mainly in infiltrated neutrophils stimulates H4Rs, leading to augmented Ale + LPS-induced ear-swelling via MCP-1 production by MCs. Since MCP-1 is produced by other cells, too, the contribution of MCs and their H4Rs to augmented ear-swelling is partial. In the later phase of the swelling, MCs may be anti-inflammatory via IL-10 production.

Military personnel deployed in combat operations are highly prone to develop Parkinson's disease (PD) in later lives. PD largely involves dopaminergic pathways with hallmarks of increased alpha synuclein (ASNC), and phosphorylated tau (p-tau) in the cerebrospinal fluid (CSF) precipitating brain pathology. However, increased histaminergic nerve fibers in substantia nigra pars Compacta (SNpc), striatum (STr) and caudate putamen (CP) associated with upregulation of Histamine H3 receptors and downregulation of H4 receptors in human cases of PD is observed in postmortem cases. These findings indicate that modulation of histamine H3 and H4 receptors and/or histaminergic transmission may induce neuroprotection in PD induced brain pathology. In this review effects of a potent histaminergic H3 receptor inverse agonist BF-2549 or clobenpropit (CLBPT) partial histamine H4 agonist with H3 receptor antagonist, in association with monoclonal anti-histamine antibodies (AHmAb) in PD brain pathology is discussed based on our own observations. Our investigation shows that chronic administration of conventional or TiO

Histone variants are different from their canonical counterparts in structure and are encoded by solitary genes with unique regulation to fulfill tissue or differentiation specific functions. A single H4 variant gene (His4r or H4r) that is located outside of the histone cluster and gives rise to a polyA tailed messenger RNA via replication-independent expression is preserved in Drosophila strains despite that its protein product is identical with canonical H4. In order to reveal information on the possible role of this alternative H4 we epitope tagged endogenous H4r and studied its spatial and temporal expression, and revealed its genome-wide localization to chromatin at the nucleosomal level. RNA and immunohistochemistry analysis of H4r expressed under its cognate regulation indicate expression of the gene throughout zygotic and larval development and presence of the protein product is evident already in the pronuclei of fertilized eggs. In the developing nervous system a slight disequibrium in H4r distribution is observable, cholinergic neurons are the most abundant among H4r-expressing cells. ChIP-seq experiments revealed H4r association with regulatory regions of genes involved in cellular stress response. The data presented here indicate that H4r has a variant histone function.

Previous studies implicated the histamine H4 receptor in renal pathophysiology. The aim here is to elucidate the role of this receptor on renal function using H4 receptor knockout mice (H4R−/−). Healthy and diabetic H4R−/− mice compared to their C57BL/6J wild-type counterpart for renal function and the expression of crucial tubular proteins. H4R−/− and wild-type mice, matched for ages, showed comparable weight gain curves reaching similar median weight at the end of the study. However, H4R−/− mice displayed a higher basal glycemia. H4R−/− mice showed a lower urine 24 h outflow, and albumin-to-creatinine ratio (ACR) compared to wild-type mice. Consistently, H4R−/− mice presented a higher expression of megalin and a lower basal expression of the sodium-hydrogen exchanger (NHE)3 and aquaporin (AQP)2. According to these basal differences, diabetic H4R−/− mice developed more severe hyperglycemia and a higher 24 h urine volume, but a lower increase in ACR and decrease in urine pH were observed. These events were paralleled by a reduced NHE3 over-expression and megalin loss in diabetic H4R−/− mice. The AQP1 and AQP7 patterns were also different between H4R−/− and wild-type diabetic mice. The collected results highlight the role of the histamine H4 receptor in the control of renal reabsorption processes, particularly albumin uptake.

G protein-coupled receptors (GPCRs) are targets of extracellular stimuli and hence occupy a key position in drug discovery. By specific and not yet fully elucidated coupling profiles with α subunits of distinct G protein families, they regulate cellular responses. The histamine H2 and H4 receptors (H2R and H4R) are prominent members of Gs- and Gi-coupled GPCRs. Nevertheless, promiscuous G protein and selective Gi signaling have been reported for the H2R and H4R, respectively, the molecular mechanism of which remained unclear. Using a combination of cellular experimental assays and Gaussian accelerated molecular dynamics (GaMD) simulations, we investigated the coupling profiles of the H2R and H4R to engineered mini-G proteins (mG). We obtained coupling profiles of the mGs, mGsi, or mGsq proteins to the H2R and H4R from the mini-G protein recruitment assays using HEK293T cells. Compared to H2R–mGs expressing cells, histamine responses were weaker (pEC50, Emax) for H2R–mGsi and –mGsq. By contrast, the H4R selectively bound to mGsi. Similarly, in all-atom GaMD simulations, we observed a preferential binding of H2R to mGs and H4R to mGsi revealed by the structural flexibility and free energy landscapes of the complexes. Although the mG α5 helices were consistently located within the HR binding cavity, alternative binding orientations were detected in the complexes. Due to the specific residue interactions, all mG α5 helices of the H2R complexes adopted the Gs-like orientation toward the receptor transmembrane (TM) 6 domain, whereas in H4R complexes, only mGsi was in the Gi-like orientation toward TM2, which was in agreement with Gs- and Gi-coupled GPCRs structures resolved by X-ray/cryo-EM. These cellular and molecular insights support (patho)physiological profiles of the histamine receptors, especially the hitherto little studied H2R function in the brain, as well as of the pharmacological potential of H4R selective drugs.

High levels of histamine and histamine receptors (HRs), including H1R~H4R, are found in many different types of tumor cells and cells in the tumor microenvironment, suggesting their involvement in tumor progression. This review summarizes the latest evidence demonstrating the pathophysiological roles of histamine and its cognate receptors in cancer biology. We also discuss the novel therapeutic approaches of selective HR ligands and their potential prognostic values in cancer treatment. Briefly, histamine is highly implicated in cancer development, growth, and metastasis through interactions with distinct HRs. It also regulates the infiltration of immune cells into the tumor sites, exerting an immunomodulatory function. Moreover, the effects of various HR ligands, including H1R antagonists, H2R antagonists, and H4R agonists, on tumor progression in many different cancer types are described. Interestingly, the expression levels of HR subtypes may serve as prognostic biomarkers in several cancers. Taken together, HRs are promising targets for cancer treatment, and HR ligands may offer novel therapeutic potential, alone or in combination with conventional therapy. However, due to the complexity of the pathophysiological roles of histamine and HRs in cancer biology, further studies are warranted before HR ligands can be introduced into clinical settings.

A3 adenosine receptor (A3AR) agonists have emerged as potent relievers of neuropathic pain by a T cell-mediated production of IL-10. The H4 histamine receptor (H4R), also implicated in pain modulation, is expressed on T cells playing a preeminent role in its activation and release of IL-10. To improve the therapeutic opportunities, this study aimed to verify the hypothesis of a possible cross-talk between A3AR and H4R in the resolution of neuropathic pain. In the mouse model of Chronic Constriction Injury (CCI), the acute intraperitoneal co-administration of the A3AR agonist IB-MECA (0.5 mg/kg) and the H4R agonist VUF 8430 (10 mg/kg), were additive in counteracting mechano-allodynia increasing IL-10 plasma levels. In H4R−/− mice, IB-MECA activity was reduced, lower pain relief and lower modulation of plasma IL-1β, TNF-α, IL-6 and IL-10 were shown. The complete anti-allodynia effect of IB-MECA in H4R−/− mice was restored after intravenous administration of CD4+ T cells obtained from naïve wild type mice. In conclusion, a role of the histaminergic system in the mechanism of A3AR-mediated neuropathic pain relief was suggested highlighting the driving force evoked by CD4+ T cells throughout IL-10 up-regulation.

Previous studies implicated the histamine H4 receptor in renal pathophysiology. The aim here is to elucidate the role of this receptor on renal function using H4 receptor knockout mice (H4R−/−). Healthy and diabetic H4R−/− mice compared to their C57BL/6J wild-type counterpart for renal function and the expression of crucial tubular proteins. H4R−/− and wild-type mice, matched for ages, showed comparable weight gain curves reaching similar median weight at the end of the study. However, H4R−/− mice displayed a higher basal glycemia. H4R−/− mice showed a lower urine 24 h outflow, and albumin-to-creatinine ratio (ACR) compared to wild-type mice. Consistently, H4R−/− mice presented a higher expression of megalin and a lower basal expression of the sodium-hydrogen exchanger (NHE)3 and aquaporin (AQP)2. According to these basal differences, diabetic H4R−/− mice developed more severe hyperglycemia and a higher 24 h urine volume, but a lower increase in ACR and decrease in urine pH were observed. These events were paralleled by a reduced NHE3 over-expression and megalin loss in diabetic H4R−/− mice. The AQP1 and AQP7 patterns were also different between H4R−/− and wild-type diabetic mice. The collected results highlight the role of the histamine H4 receptor in the control of renal reabsorption processes, particularly albumin uptake.

Histamine is a pleiotropic mediator involved in a broad spectrum of (patho)-physiological processes, one of which is the regulation of inflammation. Compounds acting on three out of the four known histamine receptors are approved for clinical use. These approved compounds comprise histamine H1-receptor (H1R) antagonists, which are used to control allergic inflammation, antagonists at H2R, which therapeutically decrease gastric acid release, and an antagonist at H3R, which is indicated to treat narcolepsy. Ligands at H4R are still being tested pre-clinically and in clinical trials of inflammatory diseases, including rheumatoid arthritis, asthma, dermatitis, and psoriasis. These trials, however, documented only moderate beneficial effects of H4R ligands so far. Nevertheless, pre-clinically, H4R still is subject of ongoing research, analyzing various inflammatory, allergic, and autoimmune diseases. During inflammatory reactions in gut tissues, histamine concentrations rise in affected areas, indicating its possible biological effect. Indeed, in histamine-deficient mice experimentally induced inflammation of the gut is reduced in comparison to that in histamine-competent mice. However, antagonists at H1R, H2R, and H3R do not provide an effect on inflammation, supporting the idea that H4R is responsible for the histamine effects. In the present review, we discuss the involvement of histamine and H4R in inflammatory and inflammation-associated diseases of the gut.

Histamine H4 receptor (H4R) orthologues are G‐protein‐coupled receptors (GPCRs) that exhibit species‐dependent basal activity. In contrast to the basally inactive mouse H4R (mH4R), human H4R (hH4R) shows a high degree of basal activity. We have performed long‐timescale molecular dynamics simulations and rigidity analyses on wild‐type hH4R, the experimentally characterized hH4R variants S179M, F169V, F169V+S179M, F168A, and on mH4R to investigate the molecular nature of the differential basal activity. H4R variant‐dependent differences between essential motifs of GPCR activation and structural stabilities correlate with experimentally determined basal activities and provide a molecular explanation for the differences in basal activation. Strikingly, during the MD simulations, F16945.55 dips into the orthosteric binding pocket only in the case of hH4R, thus adopting the role of an agonist and contributing to the stabilization of the active state. The results shed new light on the molecular mechanism of basal H4R activation that are of importance for other GPCRs., How does it work? In addition to ligand‐dependent G‐protein‐coupled receptor (GPCR) activation, which has been studied intensively, GPCRs can also be activated spontaneously in the absence of a ligand. This study highlights the mechanisms behind such basal GPCR activation by using the example of the H4R, a GPCR with extraordinarily high basal activity.

Vertigo is associated with a wide range of vestibular pathologies. It increasingly affects the elderly, with a high cost to society. Solutions include vestibular suppressants and vestibular rehabilitation, which form the mainstay of therapy. Antihistamines represent the largest class of agents used to combat vestibular vertigo symptoms. Agents targeting the H(1) and H(3) receptors have been in clinical use for several decades as single agents. Nonetheless, effective management of vertigo proves elusive as many treatments largely address only associated symptoms, and with questionable efficacy. Additionally, the primary and limiting side effect of sedation is counterproductive to normal functioning and the natural recovery process occurring via central compensation. To address these issues, the timing of administration of betahistine, the mainstay H(3) antihistamine, can be fine‐tuned, while bioavailability is also being improved. Other approaches include antihistamine combination studies, devices, physical therapy and behavioural interventions. Recently demonstrated expression of H(4) receptors in the peripheral vestibular system represents a new potential drug target for treating vestibular disorders. A number of novel selective H(4) antagonists are active in vestibular models in vivo. The preclinical potential of SENS‐111 (Seliforant), an oral first‐in‐class selective H(4) antagonist is the only such molecule to date to be translated into the clinical setting. With an excellent safety profile and notable absence of sedation, encouraging outcomes in an induced vertigo model in healthy volunteers have led to ongoing clinical studies in acute unilateral vestibulopathy, with the hope that H(4) antagonists will offer new effective therapeutic options to patients suffering from vertigo.

Background The immune system is likely involved in the pathophysiology of Meniere’s disease (MD). However, its role of patients with MD has not been well studied. Given that histamine H4 receptors are highly expressed in immune system, we tested the hypothesis that histamine H4 receptor gene polymorphisms are a potential contributor to the risk of MD. Methods A group of patients was enrolled with a diagnosis of definite MD based on the American Academy of Otolaryngology-Head and Neck Surgery Committee on Hearing and Equilibrium guidelines and a control group of patients without any vestibular disease. We selected one SNP, rs77485247 in HRH4 and conducted an exploratory investigation of its correlations with the symptoms of vertigo and proinflammatory cytokines levels in MD patients. Results HRH4 rs77485247 polymorphism may be associated with the risk of MD. Furthermore, basal levels of proinflammatory cytokines, such as IL-1β and TNF-α, in PBMCs are increased in patients with MD compared to control patients. This increased basal level of proinflammatory cytokines is prominent in MD patients with the A allele. Conclusions These suggested that HRH4 rs77485247 polymorphism may be an important mediator in regulating proinflammatory cytokines, which are involved in the pathogenesis of MD.

BACKGROUND AND PURPOSE: Th9 cells represent a recently defined subset of CD4(+) T‐helper cells, characterized by a high production of IL‐9. They are found at increased frequency in lesions of atopic dermatitis, where IL‐9 is also elevated. As histamine is up‐regulated in lesions of inflammatory skin diseases, we investigated the expression profile of histamine receptors and their functional role on Th9 cells. EXPERIMENTAL APPROACH: Naïve CD4(+) T‐cells were purified from human peripheral blood mononuclear cells, using magnetic beads and further differentiated into Th9 cells. During differentiation, cells were additionally stimulated with histamine receptor agonists or left untreated. Histamine receptor expression as well as IL‐9 production was measured. KEY RESULTS: As proof of a successful differentiation, IL‐9 production was measured at mRNA and protein level. Expression of mRNA for histamine H(1), H(2) and H(4) receptors were up‐regulated in differentiated Th9 cells compared to Th0 cells, while no mRNA for the H(3) receptor was detectable. Stimulation of Th9 cells with histamine significantly up‐regulated expression of mRNA and protein for IL‐9 . Experiments with specific histamine receptor agonists and antagonists revealed that this up‐regulation was mediated by H(4) receptors. CONCLUSIONS AND IMPLICATIONS: In summary, our study demonstrates a functional role for histamine H(4) receptors on Th9 cells, which might amplify the pro‐inflammatory potency of these cells. Together with earlier studies on Th2 and Th17 cells, this study underlines the promising approach for the use of H(4) receptor antagonists in inflammatory and allergic diseases such as atopic dermatitis. LINKED ARTICLES: This article is part of a themed section on New Uses for 21st Century. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.3/issuetoc

Background: The histamine H4 receptor (H4R) is preferentially expressed in immune cells and is a potential therapeutic target for inflammatory and autoimmune diseases. This study aimed at further exploring the role of H4R in the immunobiology of breast cancer. Methods: We used wild type (WT) and H4R deficient mice (KO) to evaluate whether H4R genotypes show a different distribution of T cell subsets in spleens, tumours and tumour draining lymph nodes (TDLN) in a syngeneic ErbB2-positive breast cancer model developed orthotopically with LM3 cells and its impact on tumour growth. Results: The presence of tumours had a differential impact on the distribution of T cells in TDLN from KO mice compared to WT ones. At day 21 post-inoculation (p.i.) of cells, despite no significant changes in the tumour weight, TDLN from KO mice showed a significantly increased proportion of CD8+ T cells compared to WT mice. At day 38 p.i. of cells a reduced tumour weight was evident in KO mice. This was accompanied by a decreased proportion of CD4+CD25+FoxP3+ regulatory T cells in TDLN of KO compared to WT mice. Tumour-bearing KO mice showed a better survival compared to WT mice. Conclusions: H4R-mediated mechanisms may modulate the immune tumour microenvironment, promoting an immunosuppressive milieu. Results suggest that H4R could be explored as an immunotherapeutic target with potential benefit in combination with immunotherapy. Further preclinical and clinical studies are necessary to confirm this hypothesis. Fil: Nicoud, Melisa Beatriz. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina Fil: Táquez Delgado, Mónica Alejandra. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina Fil: Sarasola, María de la Paz. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina Fil: Vidal, Maria Agustina. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina Fil: Speisky, Daniela Lorena. Hospital Británico de Buenos Aires; Argentina Fil: Cremaschi, Graciela Alicia. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina Fil: Sterle, Helena Andrea. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina Fil: Medina, Vanina Araceli. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina

A3 adenosine receptor (A3AR) agonists have emerged as potent relievers of neuropathic pain by a T cell-mediated production of IL-10. The H4 histamine receptor (H4R), also implicated in pain modulation, is expressed on T cells playing a preeminent role in its activation and release of IL-10. To improve the therapeutic opportunities, this study aimed to verify the hypothesis of a possible cross-talk between A3AR and H4R in the resolution of neuropathic pain. In the mouse model of Chronic Constriction Injury (CCI), the acute intraperitoneal co-administration of the A3AR agonist IB-MECA (0.5 mg/kg) and the H4R agonist VUF 8430 (10 mg/kg), were additive in counteracting mechano-allodynia increasing IL-10 plasma levels. In H4R−/− mice, IB-MECA activity was reduced, lower pain relief and lower modulation of plasma IL-1β, TNF-α, IL-6 and IL-10 were shown. The complete anti-allodynia effect of IB-MECA in H4R−/− mice was restored after intravenous administration of CD4+ T cells obtained from naïve wild type mice. In conclusion, a role of the histaminergic system in the mechanism of A3AR-mediated neuropathic pain relief was suggested highlighting the driving force evoked by CD4+ T cells throughout IL-10 up-regulation.

Growing evidence indicates that microglia activation and a neuroinflammatory trigger contribute to dopaminergic cell loss in Parkinson's disease (PD). Furthermore, increased density of histaminergic fibers and enhanced histamine levels have been observed in the substantia nigra of PD-postmortem brains. Histamine-induced microglial activation is mediated by the histamine-4 receptor (H4R). In the current study, gene set enrichment and pathway analyses of a PD basal ganglia RNA-sequencing dataset revealed that upregulation of H4R was in the top functional category for PD treatment targets. Interestingly, the H4R antagonist JNJ7777120 normalized the number of nigrostriatal dopaminergic fibers and striatal dopamine levels in a rotenone-induced PD rat model. These improvements were accompanied by a reduction of α-synuclein-positive inclusions in the striatum. In addition, intracerebroventricular infusion of JNJ7777120 alleviated the morphological changes in Iba-1-positive microglia and resulted in a lower tumor necrosis factor-α release from this brain region, as well as in ameliorated apomorphine-induced rotation behaviour. Finally, JNJ7777120 also restored basal ganglia function by decreasing the levels of γ-aminobutyric acid (GABA) and the 5-hydroxyindoleactic acid to serotonin (5-HIAA/5-HT) concentration ratios in the striatum of the PD model. Our results highlight H4R inhibition in microglia as a promising and specific therapeutic target to reduce or prevent neuroinflammation, and as such the development of PD pathology.

Histamine is an important chemical transmitter involved in inflammatory processes, including asthma and other chronic inflammatory diseases. Its inflammatory effects involve mainly the histamine HWe carried out a more focused evaluation of the modulatory effects of LINS01005 and LINS01007 in a murine asthma model. The compounds were given i.p. (1-7 mg/kg) to ovalbumin sensitized BALB/c male mice (12 weeks old) 30 min before the antigen challenging, and after 24 h the cell analysis from the bronchoalveolar lavage fluid (BALF) was performed. The lung tissue was used for evaluation by western blot (COX-2, 5-LO, NF-κB and STAT3 expressions) and histological analysis.Treatment with the more potent HThese results show important down regulatory effect of novel H

Histamine acts through four different receptors (H

Histamine is a pleiotropic biogenic amine, having affinity towards four distinct histamine receptors. The existing pharmacological studies suggest the usefulness of histamine H

Comprehensively characterized fluorescent probes for the histamine H

Context: Allergic asthma is a multifactorial airway disease characterised by chronic lung inflammation and airway remodelling. The histamine H4 receptor involved in the chemotaxis of leukocytes and...

The present review will give an update of recently published clinical studies on novel systemic treatment approaches in atopic dermatitis.Until 2017 immunosuppressive drugs such as cyclosporine had to be used in atopic dermatitis when the disease could not sufficiently be treated with topical drugs. Several new substances specifically targeting inflammation in atopic dermatitis are currently studied. In 2017, dupilumab was approved in the United States and in Europe for first-line biologic treatment of moderate to severe atopic dermatitis in adults. The antibody blocks a subunit of the interleukin (IL)-4 and IL-13 receptor, thus inhibiting effects of two key cytokines in type 2 polarized inflammation. In addition to the studies on dupilumab recent clinical investigations on the effects on anti-IL-13 (lebrikizumab, tralokinumab), anti-IL-31 receptor (nemolizumab), anti-IL-22 (fezakinumab), and on small molecules targeting the histamine-4-receptor (ZPL389) and the Janus kinase inhibitor baricitinib have been published as full papers in the last 2 years.A couple of promising novel therapeutical targets have recently been investigated and published in clinical trials on atopic dermatitis.

We hypothesized that, in mice, histamine via the histamine receptor subtype 4 (H

To evaluate the treatment revolution atopic dermatitis, the most common inflammatory skin disease, has been going through in recent years, thanks to breakthroughs in disease understanding, delineating the immune fingerprint of atopic dermatitis.The treatment for moderate-to-severe atopic dermatitis patients has been largely unchanged for decades and relied on broad-acting immunosuppressants. A huge unmet need existed for effective, well tolerated and narrow-targeted therapeutics. Multiple therapies, targeting various aspects of the complex immune activation of atopic dermatitis, are now assessed in clinical trials, and hold promise for a new era in the treatment of atopic dermatitis, comparable with the treatment shift seen for psoriasis in the last decade. The first effective monoclonal antibody licensed for the treatment of atopic dermatitis, dupilumab, not only offers a much-needed systemic agent for moderate-to-severe patients but also provides strong evidence for the potential role of other monoclonal antibodies in disease management.In this rapidly changing field, new atopic dermatitis-targeted monoclonal antibodies will be reviewed in light of the recently discovered pathomechanisms of the disease.

Mast cell (MC) activation through H4R releases various inflammatory mediators which are associated with allergic asthma.To investigate the siRNA-mediated gene silencing effect of H4R on human mast cells (HMCs) functions and the activation of stress-activated protein kinases (SAPK)/jun amino-terminal kinases (JNK) signaling pathways for the release of ineterleukin-1β (IL-1β) in HMCs.H4R expression was analyzed by RT-PCR and western blotting in human mast cell line-1 (HMC-1) cells and H4RsiRNA transfected cells. The effect of H4RsiRNA and H4R-antagonist on H4R mediated MC functions such as intracellular CaWe found that the HMC-1 cells expressed H4R and H4RsiRNA treatment down regulated the H4R expression in HMC-1 cells. Both His and 4-MH induced the intracellular CaTaken together, the silencing of H4R inhibited the H4R mediated MC functions and SAPK/JNK phosphorylation. Furthermore, the H4R activation utilized SAPK/JNK signaling pathway for IL-1β release in HMC-1 cells.

Ulcerative colitis (UC) patients exhibit elevated histamine, but how histamine exacerbates disease is unclear as targeting histamine 1 receptor (H1R) or H2R is clinically ineffective. We hypothesized that histamine functioned instead through the other colon-expressed histamine receptor, H4R. In humans, UC patient biopsies exhibited increased H4R RNA and protein expression over control tissue, and immunohistochemistry showed that H4R was in proximity to immunopathogenic myeloperoxidase-positive neutrophils. To characterize this association further, we employed both the oxazolone (Ox)- and dextran sulfate sodium (DSS)-induced experimental colitis mouse models and also found upregulated H4R expression. Mast cell (MC)-derived histamine and H4R drove experimental colitis, as H4R-/- mice had lower symptom scores, neutrophil-recruitment mediators (colonic interleukin-6 (IL-6), CXCL1, CXCL2), and mucosal neutrophil infiltration than wild-type (WT) mice, as did MC-deficient KitW-sh/W-sh mice reconstituted with histidine decarboxylase-deficient (HDC-/-) bone marrow-derived MCs compared with WT-reconstituted mice; adaptive responses remained intact. Furthermore, Rag2-/- × H4R-/- mice had reduced survival, exacerbated colitis, and increased bacterial translocation than Rag2-/- mice, revealing an innate protective antibacterial role for H4R. Taken together, colonic MC-derived histamine initiates granulocyte infiltration into the colonic mucosa through H4R, suggesting alternative therapeutic targets beyond adaptive immunity for UC.

Histamine is an important mediator of biological functions and present in high amounts in inflammatory skin lesions which are characterised by a marked infiltration of myeloid derived cell populations. The aim of the study was to investigate the expression and function of histamine receptors, with a focus on the histamine H4 receptor (H4R) in detail during the differentiation process from monocytes to macrophages and on fully differentiated M1 macrophages. Quantitative PCR, ELISA technique, and flow cytometry were applied to analyze expression levels of histamine receptors, of CXCL10, CCL4, CCL3, or IL-23 and of the macrophage differentiation marker CD68, respectively. We demonstrated that monocytes and fully differentiated M1 macrophages express H1R-, H2R-, and H4R mRNA which were differentially regulated during the differentiation process and in IFN-Ƴ and LPS classically activated M1 macrophages. The H3R mRNA was not expressed. During in vitro differentiation from monocytes to macrophages, the H4R agonist ST-1006 modified the M1 phenotype by up-regulating the macrophage differentiation marker CD68, by down-regulating the production of CXCL10, and by changing the morphology. In fully differentiated M1 macrophages, histamine or ST-1006 decreased the IFN-Ƴ- and LPS-induced CCL4 mRNA expression and protein production, whereas CCL3 or IL-23 production was not regulated via H4R. We describe novel immunomodulatory functions of the H4R during the differentiation process of human monocyte-derived macrophages and in fully differentiated M1 macrophages. The down-regulation of Th1-related chemokines during the differentiation process or in classically activated macrophages via H4R may contribute to decreased migration of immune cells to the site of inflammation. This may have implications for the treatment of allergic diseases with H4R ligands regulating the dysbalance of Th2/Th1 polarizations in these disorders.

The histamine H4 receptor (H4R), a member of the G-protein coupled receptor family, has been considered as a potential therapeutic target for treating atopic dermatitis (AD). A large number of H4R antagonists have been disclosed, but no efficient agents controlling both pruritus and inflammation in AD have been developed yet. Here, we have discovered a novel class of orally available H4R antagonists showing strong anti-itching and anti-inflammation activity as well as excellent selectivity against off-targets. A pharmacophore-based virtual screening system constructed in-house successfully identified initial hit compound 9, and the subsequent homology model-guided optimization efficiently led us to discover pyrido[2,3- e]tetrazolo[1,5- a]pyrazine analogue 48 as a novel chemotype of a potent and highly selective H4R antagonist. Importantly, orally administered compound 48 exhibits remarkable efficacy on antipruritus and anti-inflammation with a favorable pharmacokinetic (PK) profile in several mouse models of AD. Thus, these data strongly suggest that our compound 48 is a promising clinical candidate for treatment of AD.