In addition to H1R, H4R is considered as a novel drug target for the treatment of allergy and inflammation. Recently, the H4R antagonists such as JNJ and JNJ have been extensively used as a tools to understand the pathophysiological involvement of H4R and have been studied extensively in both cell culture and in vivo animal models , Furthermore, H4R antagonists have been used to explore the role of H4R in allergic inflammatory disorders, such as allergic asthma, allergic rhinitis, and chronic pruritus Mast cells play an active role in various allergic diseases such as acute pruritus, atopic dermatitis, allergic asthma, allergic rhinitis, and pulmonary fibrosis , H 1 -antihistamines, such as azatadine, cetirizine, and mizolastine are used for the treatment mast cell activated diseases Cimetidine, ranitidine, famotidine, and nizatidine are H2R selective antihistamines that reduce gastric acid secretion H3R antihistamines include thioperamide, clobenpropit, BF2.
JNJ is a selective H4R antihistamine that is widely used in inflammation and pruritus H 1 -antihistamines are a standard treatment for mast cell-mediated allergic diseases.
There is increasing evidence that histamine binding to H4 receptors exacerbates allergy and inflammation. Indeed, mast cells themselves have H4 receptors which when stimulated increased degranulation and cytokine production.
Therefore, antihistamines targeting both the H1 and H4 receptor could be an effective treatment for mast cell-mediated allergic diseases Pharmacological properties of H4R have been exhibited by various H4R transfected cells 87 , 89 , 99 , , However, some H3R ligands such as imetit, clobenpropit, thioperamide, and R -methylhistamine are also able to bind to the H4R with different affinities.
Currently, a number of H4R antagonists have been developed but only a few are undergoing clinical trials. JNJ , a potent and selective H4R antagonist, has shown impressive results in different allergic inflammatory diseases such as dermatitis, asthma, pruritus, and arthritis , Interestingly, the combination therapy of this H4R antagonist and the H1R antihistamine, cetirizine, showed a more beneficial effect in the treatment of pruritus as compared with H1R alone — Furthermore, a study was carried out by using JNJ to treat persistent asthma NCT , but no results have yet been reported.
However, a study in rheumatoid arthritis NCT was terminated due to issues related to efficacy. The recent developments in research on histamine pathway underscore the importance of histamine in allergic inflammation through its effects on the H1R and H4R.
Although, drugs targeting H1R are being explored for the treatment of various mast cell-associated allergic disorders, they are not always clinically effective. Several H4R antagonists have entered the later stages of clinical trials for a different range of allergic and inflammatory diseases. However, their clinical efficacy reports are not yet published.
Furthermore, there appears to be some overlap in function between H1R and H4R, opening up the possibility for using synergistic strategies for therapeutic approaches. As such, we suggest the combination therapies by using both H4R together with H1R antagonists may provide a potential benefit in the treatment of various allergic and inflammatory diseases.
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Inflammatory conditions e. Recent evidence strongly suggests that H4R ligands might be exploited as potential therapeutics in allergy, inflammation, autoimmune disorders, and possibly cancer. Overall, exploiting the impact of histamine on innate and adaptive immune responses may be helpful for understanding receptor signaling and trends during inflammation or regulation. Histamine shows a dichotomous nature, whereby it is able to promote inflammatory and regulatory responses that contribute to pathological processes, such as allergy induction, as well as homeostatic functions, such as intestinal regulation.
In this review, we summarize recent findings about the regulation of the immune response by histamine. A general overview of the immune cascades triggered by histamine receptor activation is provided. Histamine 2-[3H-imidazolyl]ethanamine is an important chemical mediator that causes vasodilation and increased vascular permeability and may even contribute to anaphylactic reactions [ 1 ].
It also acts on several physiological functions, such as cell differentiation, proliferation, haematopoiesis, and cell regeneration. Synthesis of histamine occurs through decarboxylation of the amino acid histidine by the enzyme L-histidine decarboxylase HDC , which is expressed in neurons, parietal cells, gastric mucosal cells, mast cells, and basophils; degradation of histamine is mediated by the enzyme diamine oxidase DAO and histamine N-methyltransferase HNMT , which catalyses histamine deamination [ 2 , 3 ].
HNMT is expressed in the central nervous system, where it may play a critical regulatory role because its deficiency is related to aggressive behaviour and abnormal sleep-wake cycles in mice [ 4 ].
The active and inactive conformations of these receptors coexist in equilibrium. Agonists of these receptors stabilize the active conformation, whereas antagonists stabilize the inactive conformation. Curiously, the ageing process impairs expression or activity of HRs, and the enzymes HDC and DAO may contribute to the progression of allergic reactions and various neurodegenerative disorders [ 5 ].
Chronic itch in the elderly is a common problem that is often multifactorial due to physiological changes in ageing skin, including impaired skin barrier function, and changes in immunological, neurological, and psychological systems associated with age. H1R is expressed in various cell types, such as neurons, endothelial cells, adrenal medulla, muscle cells, hepatocytes, chondrocytes, monocytes, neutrophils, eosinophils, DCs, T cells, and B cells.
H1R signaling results in the following: synthesis of prostacyclins; activation of platelet factor; synthesis of nitric oxide, arachidonic acid and its metabolites, and thromboxane; and contraction of smooth muscle cells. In addition, H1R activation leads to increased chemotaxis of eosinophils and neutrophils at the site of inflammation, higher functional capacity of antigen-presenting cells APCs , activation of Th1 lymphocytes, and decreased humoral immunity but the promotion of IgE production [ 6 ].
As expected for such biological actions, H1R antagonists, including pyrilamine, fexofenadine, diphenhydramine, and promethazine, are commonly used for the treatment of allergic symptoms.
In addition, H1R was demonstrated in an experimental allergy model to play a critical role together with histamine in orchestrating recruitment of Th2 cells to the site of allergic lung inflammation [ 9 ].
H2R is expressed by parietal cells of the gastric mucosa, muscle, epithelial, endothelial, neuronal, hepatocyte, and immune cells. H2R antagonizes some of the effects mediated by H1R and leads to the relaxation of smooth muscle cells, causing vasodilation.
H2R activation regulates several of the functions mediated by histamine, including cardiac contraction, gastric acid secretion, cell proliferation, and differentiation [ 10 ]. It also acts as a suppressor molecule in DCs, increasing IL production [ 11 ]. One recent study demonstrated that histamine acts on H2R and induces inhibition of leukotriene synthesis in human neutrophils through cAMP-dependent protein kinase PKA signaling [ 12 ].
In a murine lung inflammation model, H2R loss has an effect on invariant natural killer T iNKT cells, aggravating local inflammation [ 13 ]. While the activation H1R and H2R mainly accounts for mast cell- and basophil-mediated allergic disorders [ 15 ], H3R functions were identified in the central nervous system and peripheral and presynaptic receptors to control the release of histamine and other neurotransmitters. H3R knockout mice exhibit an obese phenotype, suggesting that H3R regulates insulin resistance and leptin release, as well as a decrease in homeostatic energy, the cellular process for coordinating homeostatic regulation of food intake energy inflow and energy expenditure energy outflow , as associated with the UCP1 and UCP3 genes [ 17 ].
H3R expression may be associated with bronchoconstriction, pruritus without involvement of mast cells , increased proinflammatory activity, and antigen-presentation capacity [ 18 ]. Neuromodulation and the waking state are related to histaminergic neurons. The waking state is maintained by continual activation of aminergics such as histamine, dopamine, noradrenaline, and acetylcholine. Three subtypes of HRs are widely distributed in the brain, not only on neurons but also on astrocytes and blood vessels.
Targeting the histamine and noradrenergic systems may aid in the design of more precise sedatives and, at the same time, may reveal more about the natural sleep-wake circuitry [ 19 ]. This finding may be useful for the development of new therapeutic approaches to treat neurodegenerative disorders [ 20 ].
H4R is preferentially expressed in the intestine, spleen, thymus, bone marrow, peripheral haematopoietic cells, and cells of the innate and adaptive immune systems. Activation of this receptor causes chemotaxis in mast cells and eosinophils, leading to an accumulation of inflammatory cells and control of cytokine secretion by DC and T cells. H4R is also involved in increased secretion of IL by Th2 cells [ 21 ].
The use of this synthetic H4R antagonist in a murine encephalomyelitis model resulted in an increase in the clinical and pathological signs of the disease, suggesting a modulatory role [ 23 ]. HRs are present on tumour cells, making them sensitive to variations in histamine. High levels of histamine are associated with bivalent behaviour in the regulation of several tumours i. The presence of H3R and H4R in human mammary tissue suggests that H3R may be involved in regulating breast cancer growth and progression [ 25 ], emphasizing the possible use of antihistamines as adjuvants in cancer chemotherapy.
Asthma is prevalent in males during childhood but is more frequent in females during adolescence and adulthood. Furthermore, allergic diseases are common in women of childbearing age. Both asthma and atopic conditions may worsen, improve, or remain the same during pregnancy.
Female hormones, such as estrogen, can modulate the inflammatory response, and histamine receptors can differ between males and females, which might explain the different incidence of allergy between the sexes [ 31 ]. For example, H2R and H3R are highly expressed in female compared to male rats and are downregulated in ovariectomized females, whereas H1R is equally expressed in both sexes [ 32 ]. The cascades and effects of different histamine receptors are summarized in Figure 1 and Table 1.
Inflammatory mediators are molecules produced by activated cells that intensify and prolong the inflammatory response. Histamine is a potent inflammatory mediator, commonly associated with allergic reactions, promoting vascular and tissue changes and possessing high chemoattractant activity.
The binding of histamine to eosinophil H4R induces increased expression of macrophage-1 antigen Mac1 and ICAM-1 adhesion molecules, in addition to promoting actin filament rearrangement [ 33 , 34 ]. These events favour the migration of eosinophils from the bloodstream to the site of inflammation.
In mast cells, the binding of histamine to this same receptor promotes the intracellular release of calcium and recruitment of mast cells into tissues [ 35 ]. Mast cells from H4R-knockout mice lose the ability to migrate against a histamine gradient [ 35 ]. Recruitment of these cells to sites of inflammation amplifies the inflammatory reactions mediated by histamine and may favour the establishment of a chronic inflammatory response. In experimental models, histamine drives colitis via HR4 by promoting granulocyte infiltration into the colonic mucosa [ 36 ].
Together, these events suggest that histamine may contribute to the maintenance of inflammatory conditions in the airways. In an animal model of allergic airway inflammation, H4R-knockout mice present lower inflammation, reduced pulmonary infiltrate of eosinophils and lymphocytes and an attenuated Th2 response [ 41 ].
The contribution of histamine to the induction of airway inflammation is also due to its effect on nonimmune cells. In nasal fibroblasts, there is a dose-dependent increase in IL-6 production in response to histamine stimulation [ 42 ]. Histamine also activates pulmonary epithelial cells. In addition to inducing iNOS expression and NO production, histamine promotes the loss of mitochondrial membrane potential and the production of ROS in microglia by binding to these same receptors [ 46 , 47 ].
Overall, the accumulation of these cytokines and proinflammatory molecules can be deleterious, leading to nerve damage. Histamine also modulates the response of DCs. In a food allergy model, simultaneous blockage of H1R and H4R inhibited the development of intestinal inflammation and diarrhoea when the animals were exposed to the allergen by suppressing histamine-mediated DC antigen presentation and chemotaxis [ 48 ].
In contrast, Th1 and Th2 responses are inhibited by histamine stimulation via H2R. Histamine also alters the response of other subpopulations of lymphocytes. In addition, histamine stimuli induces IL production in human Th17 cells, suggesting the contribution of this inflammatory mediator to the activation of lymphocytes present in skin lesions in atopic dermatitis and psoriasis [ 51 ]. Other evidence, indicates that histamine plays an important role in inflammatory skin diseases.
As H4R knockout mice display a lower influx of inflammatory cells and less cell proliferation at the lesion sites, H4R is associated with the inflammatory response in atopic dermatitis [ 53 ].
H4R is also involved in NK cell recruitment and induction of CCL17 production by DCs at lesion sites in murine models of atopic dermatitis, contributing to increased local inflammation [ 54 ]. In an experimental model of pruriginous dermatitis, H4R blockage decreases itching because the activation of this receptor is involved in increased IL secretion by Th2 cells [ 21 , 55 ]. Moreover, blocking H4R improves skin lesions and reduces the number of mast cells at lesion sites [ 55 ].
Within the context of vascular inflammatory diseases, histamine produced by the tunica intima stimulates the monocytes present in atherosclerotic plaques to express CCL2 and its receptor CCR2, via activation of H2R [ 56 ]. Furthermore, higher production of IL-6 and adhesion molecules, such as ICAM-1 and VCAM-1, occurs in endothelial cells stimulated by histamine, thereby favouring progression of the disease [ 56 , 57 ]. In an experimental model, the absence of H1R reduced the development of atherosclerosis, whereas the absence of H2R exerted the opposite effect [ 58 ].
As discussed above, the pleiotropic effects of histamine are a consequence of the existence of four different receptors that belong to the same family of G-coupled proteins and trigger different signaling cascades; these receptors are differentially distributed across tissues and cells [ 59 ].
Therefore, in addition to its classical roles in the inflammatory process, histamine is recognized as a key player in immune regulation. In a murine psoriasis-like model induced by imiquimod administration, Kim et al. These findings suggest that histamine targeting has pharmacological potential. The contribution of histamine to inflammatory neurological diseases, such as multiple sclerosis, is controversial: although H1R and H2R appear to favour the inflammatory response in brain lesions [ 64 ], H3R dampens neuroinflammation, mainly by modulating the production of chemokines and maintaining the integrity of the blood-brain barrier [ 65 ] in a murine model of multiple sclerosis, experimental autoimmune encephalomyelitis EAE.
Pharmacological blockage of H4R exacerbates EAE, as observed by increased recruitment of inflammatory mediators, larger lesion areas, and enhanced activation of T cells, indicating that H4R also plays a regulatory role in a neurological context [ 23 ]. The findings suggest deregulation of the histaminergic pathway in ALS patients [ 66 ].
Regardless, the role of histamine in gut homeostasis maintenance is clearly essential, as exemplified in a murine model of HDC deficiency. Yang et al. Most HDC expression in these tissues was found in immature myeloid cells IMCs , rather than in resident mast cells; curiously, histamine administration, acting through H1R and H2R, was required to promote terminal differentiation of IMCs into monocytes and neutrophils [ 67 ].
Expression levels of HDC and H2R are positively associated with increased survival in colorectal cancer patients [ 68 ], and some epidemiological studies support the association of atopy with the reduced incidence of some cancers [ 69 , 70 ], reinforcing a possible role of histamine in blocking tumour development.
In addition to tumour biology, histamine has a regulatory function in gut inflammatory diseases, such as in a murine trinitrobenzene sulfonic acid- TNBS- induced model of colonic inflammation, which promotes a delayed hypersensitivity reaction that resembles the phenotype [ 71 ].
By employing H4R-deficient mice, Wunschel et al. Strikingly, Schirmer et al. Differences between the models, such as the chemical stimulation used and the route of administration, may account for the opposite results. Overall, the response that prevails in humans requires further investigation. Recently, the microbiota was revealed to be very important for gut pathophysiology.
Indeed, the microbial community in the intestine shapes the health status of the host and its susceptibility to a broad range of local and systemic diseases [ 74 ].
The microbiota supplies the host with a number of metabolites, such as short-chain fatty acids, tryptophan metabolites and histamine [ 75 , 76 ], and a recent work highlights the key role of microbe-derived histamine in the host response. For example, histamine-secreting bacteria Escherichia coli , Lactobacillus vaginalis , and Morganella morganii are found at higher frequency in faecal samples from asthmatic patients, with a possible contribution to their atopic phenotype [ 76 , 77 ], as microbial-derived histamine is indistinguishable from the human-produced form.
Lactobacillus reuteri is a member of the gut microbiota that belongs to the Firmicutes family; HDC gene expression by this commensal bacterium confers the ability to produce histamine from histidine [ 78 ]. Interestingly, histamine modulates the response of myeloid and plasmacytoid DCs to LPS, favouring IL production over the secretion of inflammatory cytokines [ 14 ] and enhancing their ability to phagocytose soluble antigens and upregulate expression of the costimulatory molecules CD86 and inducible costimulator ligand ICOS-L [ 81 ].
In addition to H2R agonism, L. Thus, L. Importantly, L. This highlights the critical interplay between the host immune response, the microbiota, and environmental dietary influences on biological outcomes.
In addition to L. Another lactobacilli, Lactobacillus rhamnosus , is a source of histamine that promotes a regulatory Foxp3-T cell response profile in intestinal Peyer patches while dampening Th1 polarization in an H2R-dependent fashion [ 14 ].
The lung is a classical mucosal site under histamine control. Although histamine is associated with deleterious inflammation in asthmatic patients, triggering airway hyperresponsiveness and remodelling [ 84 , 85 ], recent evidence suggests that the contribution of histamine to pulmonary homeostasis is not straightforward and depends on the receptor and cell type involved.
Although the regulatory properties of histamine reveal a promising therapeutic potential, histamine may also exert deleterious effects in some clinical conditions. For example, histamine immunomodulation might contribute to higher susceptibility to sepsis in diabetic mice. Mast cell-derived histamine is increased in diabetic settings and reduces neutrophil recruitment due to repression of CXCR2 [ 87 ].
In addition, histamine may impair the oxidative burst of neutrophils [ 88 ]. Because neutrophils produce histamine once stimulated [ 89 ], a negative feedback loop is established, attenuating the microbicidal mechanism against invading bacteria. Histamine research is an attractive perspective for the potential therapeutic exploitation of new drug targets. The main actions of histamine in controlling the immune response are summarized in Figure 2.
The pleiotropic actions of histamine due to the different natures of its receptors allow this simple molecule to exert broad and oppose effects on the immune system, highlighting the importance of a fine-tune control that promotes a homeostatic environment in the body, balancing important inflammatory reactions to host protection as well as immunomodulation. The findings about the role of histamine in carcinogenesis, allergic regulation, and even behavioural regulation underscore histamine as a remarkable therapeutic target.
New insight about the role of histamine in different body sites and cell types may result in more targeted therapies. Overall, recent findings about the microbial contribution to histamine homeostasis add a new layer of complexity to the picture.
Ideal histaminergic therapy should be composed of a mixture of agonists and antagonists that would avoid deleterious side effects. Future studies may improve our understanding of the histamine network in organisms and its paradoxical nature.
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Special Issues. Received 23 Feb Revised 15 Jun Accepted 04 Jul Published 27 Aug Abstract Inflammatory mediators, including cytokines, histamine, bradykinin, prostaglandins, and leukotrienes, impact the immune system, usually as proinflammatory factors. Introduction Histamine and its receptors represent a complex system of immunoregulation with distinct effects mediated by four GPCRs G protein-coupled receptors HRs 1—4 and their differential expression, which changes according to the stage of cell differentiation and microenvironmental influences.
Histamine and Histamine Receptors Histamine 2-[3H-imidazolyl]ethanamine is an important chemical mediator that causes vasodilation and increased vascular permeability and may even contribute to anaphylactic reactions [ 1 ].
Figure 1. Intracellular activation cascades triggered by histamine receptors HRs. Table 1. Immunological functions mediated by histamine receptors signaling. Figure 2. Inflammatory and regulatory functions of histamine on different body sites. Histamine plays dual functions according to the cell type and the receptor. As an inducer of inflammation, histamine can contribute to pulmonary fibrosis, cardiovascular diseases and atherosclerosis, atopic dermatitis, central nervous system damage, and colitis in some experimental models, besides favoring the polarization of the immune response to a Th1 profile.
On the other hand, histamine can regulate inflammation in models of experimental autoimmune encephalomyelitis EAE and colitis, favor wound healing in skin lesions, and inhibit tumour development. Also, microbiota-derived histamine can regulate the inflammatory picture of asthma.
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