Associate editor: B. J. WhittleThe histamine H4 receptor: A novel modulator of inflammatory and immune disorders
Introduction
Histamine, a low molecular weight amine, is an important chemical mediator in physiological and pathological responses. The biological functions of histamine are mediated through 4 histamine receptors (H1R, H2R, H3R and H4R). Histamine receptors vary in expression, signaling, function and histamine binding ability, and therefore, have different potential therapeutic applications (Akdis and Simons, 2006, Jutel et al., 2006).
Of the 4 known histamine receptors, H1R, H2R and H4R have been shown to affect inflammation and other immune responses and have been used or have been proposed to be useful for treating immune and inflammatory disorders (Jutel et al., 2002, Akdis and Simons, 2006). The H1R was the first described histamine receptor and although ligands targeting this receptor were initially developed in the 1930s, the human receptor was not cloned until 1993 (Debacker et al., 1993).
The H1R has been identified as capable of causing smooth muscle contraction, vasodilation, and increasing vascular permeability. Its activation has also been associated with bronchoconstriction, increased pruritus and nociception (Raffa, 2001, Togias, 2003). For many years, the antiallergic and anti-inflammatory activities of H1R antagonists have been utilized to treat allergic disorders (Pearlman, 1976). The H2R is best known for its central role in gastric acid secretion but has also been reported to be involved in increasing vascular permeability and airway mucus production (White, 1990, Tamaoki et al., 1997). Antagonists of the H2R are widely used in treating peptic ulcers, gastroesophageal reflux disease and gastrointestinal bleeding (Carballo, 2005, Pettit, 2005). The H3R is primarily found in the central nervous system, where its activation is involved in the control of the release of multiple neurotransmitters, such as acetylcholine, dopamine, serotonin, and histamine (Arrang et al., 1983, Hill et al., 1997, Lovenberg et al., 1999). The H3R participates in the processes of cognition and memory. H3R antagonists potentially may be used for treating sleep and wakefulness disorders, attention disorders, metabolic disorders, obesity and Alzheimer's disease (Monti, 1993, Vohora, 2004, Celanire et al., 2005, Tokita et al., 2006). The subject of this review, the H4R, was characterized by several groups, concurrently (Oda et al., 2000, Liu et al., 2001a, Morse et al., 2001, Nguyen et al., 2001, Zhu et al., 2001). In contrast to the other histamine receptors, the H4R has a distinct expression profile on immune cells and has modulatory effects on the function of these cells, including mast cells, eosinophils, dendritic cells, and T cells. The H4R appears to play a role in multiple functions of these cells, such as, activation, migration, cytokine and chemokine production. The effect of the H4R in the immune system will be discussed further, herein.
All 4 histamine receptors are G protein-coupled receptors (GPCRs). Upon histamine or agonist binding, they activate distinct signaling pathways through G proteins. The H1R couples to the Gq family of G proteins and induces calcium mobilization. It can also mediate cyclic GMP (cGMP) production, phospholipases and NFkB activation (Richelson, 1978, Xu and Chuang, 1987, Tilly et al., 1990, Matsubara et al., 2005). The H2R couples to Gαs and increases cyclic AMP (cAMP) formation and calcium mobilization (Leurs et al., 1994, Smit et al., 1996, Alewijnse et al., 1998). The H3R mediates its function through Gαi/o proteins and signals by inhibiting cAMP formation, enhancing calcium mobilization (Krueger et al., 2005) and activating mitogen-activated protein (MAP) kinases (Oike et al., 1992, Clark et al., 1993, Laitinen and Jokinen, 1998, Drutel et al., 2001). H4R signaling is also mediated by coupling to Gαi/o G-proteins. It induces calcium mobilization, inhibits formation of cAMP, and stimulates phosphorylation of MAP kinases (Morse et al., 2001, Buckland et al., 2003, Hofstra et al., 2003).
Section snippets
H4R expression profile
In general, the H4R has low homology with other histamine receptors. The closest related member is the H3R, sharing ∼ 35–48% amino acid homology (Nakamura et al., 2000, Oda et al., 2000, Liu et al., 2001a, Morse et al., 2001, Nguyen et al., 2001, Zhu et al., 2001). The two also share similar genomic structures with 2 introns and 3 exons (Coge et al., 2001, Tardivel-Lacombe et al., 2001).
Despite some overlap and coexpression, the 4 histamine receptors are generally expressed on different cell
Mast cells
Mast cells, as a key component in allergic and other immune responses, are not only important producers of histamine but are also regulated by histamine. H4R activation induces calcium mobilization in mast cells and mediates mast cell migration towards histamine, but does not affect IgE crosslinking-induced degranulation (Hofstra et al., 2003). This was defined initially by histamine responses in murine, bone marrow derived mast cells after selective antagonism of the H4R or in H4R knockout
JNJ 7777120 and JNJ 10191584 pharmacology
As mentioned previously, H4R shares low sequence homology with other histamine receptors, especially H1R and H2R. Consistently, agonists or antagonists specific for H1R or H2R do not bind to H4R. The H4R has the highest homology with the H3R, and accordingly, is bound by some H3R ligands. The well-known imidazole-based H3R ligands thioperamide and (R)-α-methylhistamine serve as H4R ligands, with the inhibitory constants (Ki) of 27 and 146 nM, respectively (Jablonowski et al., 2003). Before the
TLR-mediated diseases and colitis
Given the ability of H4R to modulate the cellular function of eosinophils, mast cells, dendritic cells and T cells, it is natural to speculate that the H4R might be involved in various inflammatory diseases, and that H4R antagonists would have therapeutic potential (Jutel et al., 2006). Indeed, both in vitro and in vivo evidence has been provided for the utility of H4R antagonists as anti-inflammatory agents. TLR ligands are implicated in the pathology of numerous inflammatory conditions such
Conclusions
The H4R is the newest member of the histamine receptor family and has a distinctive expression profile on hematopoietic cells. So far, studies on the H4R on mast cells, eosinophils, T cells and dendritic cells have suggested its role in modulating a range of physiological functions of these cells including chemotaxis, cytokine and chemokine release, and adhesion molecule expression. These processes are integral to human immune disorders and to various animal immune disease models, such that
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2019, NeuroscienceCitation Excerpt :Histamine is the mediator of inflammation (Thurmond et al., 2008; Ahmad et al., 2015). Recent studies have revealed that the inflammatory effects of histamine may also involve the newly discovered histamine H4 receptor (H4R), which is predominantly expressed in immune cells (Zhang et al., 2007; Cricco et al., 2008; Suwa et al., 2011; Cowden et al., 2014). Indeed, several reports have demonstrated the anti-inflammatory effects induced by H4R antagonism in various animal models of inflammation (del Rio et al., 2012; Dib et al., 2014).
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2018, Neuroscience LettersCitation Excerpt :Hermann et al. reported that the injection of TNF-α into the brainstem, dorsal vagal complex, which has projections into multiple hypothalamic nuclei, inhibited gastric motility via the neural circuitry [28]. For these reasons, systemic circulating TNF-α secreted from peripheral tissue is considered to be the primary mediator of symptom development; however, although H4 receptors are mainly found in peripheral tissues, such as the bone marrow and white blood cells, spleen, liver, and intestinal tract [9], recent studies reported that H4 receptors are also distributed throughout the central nervous system [29]. It has been reported that JNJ7777120 passes the blood brain barrier [30].