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  • In various models histamine has been shown to

    2021-09-06

    In various models, histamine has been shown to induce chemotaxis. This was first appreciated over 40 years’ ago in studies with eosinophils (Clark et al., 1977). At that time, only histamine H1 and histamine H2 receptors were recognized and studies with ligands to these receptors indicated that neither histamine H1 nor histamine H2 receptors were involved in causing chemotaxis in eosinophils. With the later discovery of the histamine H3 receptor and studies using ligands to this receptor, the indications were that the histamine H3 receptor was not involved in eosinophil chemotaxis (Raible et al., 1994). It was only after the histamine H4 receptor had been identified and probed pharmacologically that it was realized that the histamine H4 receptor was involved in initiating chemotaxis in eosinophils (Ling et al., 2004) and that the histamine H2 receptor might be involved in blunting chemotactic responses (Reher et al., 2012). In addition to eosinophils, histamine has also been shown to recruit other inflammatory YM201636 most notably mast cells. For example, aerosolized histamine in mice has been shown to increase mast cells in tracheal slices and also to induce migration of mast cells to sub-epithelial regions (Thurmond et al., 2004). This redistribution of mast cells by histamine was antagonized by the H4 antagonist, JNJ777120 (Thurmond et al., 2004). In the present study, histamine induced chemotaxis of human lung mast cells. This effect appeared to be mediated by histamine H4 receptors for two reasons. First, an H4-selective agonist, JNJ28610244, was also effective at inducing chemotaxis whereas an H1-selective agonist, 2-(2-pyridyl) ethylamine, was not. Second, migration of mast cells induced by the H4 agonist, JNJ28610244, was effectively prevented by the H4 antagonist, JNJ7777120. Collectively, these findings provide strong evidence that the histamine H4 receptor mediates chemotaxis of human lung mast cells. The extent to which these in vitro data might extrapolate to the in vivo situation is hard to equate. Quite high concentrations of agonists are needed to promote chemotaxis in the experimental system used in the present study. However, it is quite likely that, in an allergic disease context, quite high concentrations of histamine are generated locally. An additional consideration is whether an experimental chemotaxis chamber model using isolated cells can mimic closely the migration of cells in tissue. If the experimental system used herein is representative, then these data suggest that high, localized concentrations of histamine might mediate mast cell accumulation in the lung. As a corollary, these findings support ongoing initiatives to develop histamine H4 receptor antagonists for the treatment of asthma and related allergic diseases such as atopic dermatitis (Thurmond et al., 2008, Walter et al., 2011, Liu, 2014, Thurmond, 2015). In summary, we have shown that engagement of histamine receptors has no effect on mediator release from mast cells. By contrast, activation of histamine H4 receptors promotes migration of human lung mast cells. This mechanism may contribute to mast cell accumulation in the lung.
    Acknowledgements
    1. Introducion Histamine H4 receptor (H4R) is the last identified member of histamine receptors family. It is mainly distributed in the cells and tissues connected with inflammation, such as e.g. eosinophils, mast cells, monocytes, lymphocytes, and macrophages. The H4R shows high homology to human H3 receptor (∼35%), thus it is not a surprise that many histamine H3 receptor ligands (especially imidazole derivatives) show also affinity at H4R. However, to understand the function of this receptor, development of selective ligands was necessary. In 2003 Jablonowski et al. has described the first potent and selective H4R antagonist – JNJ7777120 (1; Fig. 1), which has become a standard H4R ligand and has been used in many in vitro and in vivo studies. In 2011, the situation has complicated as it was shown that JNJ7777120 could also behave as an agonist with respect to activation of Gi-proteins in some species (e.g. partial agonist at rat H4R.4, 5, or as partial agonist with respect to β-arrestin binding to the human H4R). However, most of data confirmed that JNJ7777120 acts as antagonist in vivo and in primary cells. During the years, since discovery of the H4R many scientists both from academia and industry have synthesized a lot of human H4R ligands (for review see7, 8, 9). Some of them have reached clinical studies, e.g. JNJ39758979 (2; Fig. 1), which was tested in therapy of histamine-induced itch, atopic dermatitis and asthma.8, 9 Recently, new compounds with novel scaffolds (e.g. 3 and 4; Fig. 1) were described.10, 11 Compound 3 was found by virtual screening of the Bioprojet chemical library, whereas compound 4 was found by homology model-guided optimization of a hit compound identified in virtual screening. Both compounds showed potent antagonism for hH4R in GTPγ [35S] binding assay with Ki of 5.2 nM for 3, and IC50 of 28 nM for 4. Moreover, 4 showed strong antipruritic and anti-inflammatory activity in several mice models of atopic dermatitis.