Antagonism of histamine H₄ receptors exacerbates clinical and pathological signs of experimental autoimmune encephalomyelitis

Abstract

BACKGROUND AND PURPOSEThe histamine H4 receptor has a primary role in inflammatory functions, making it an attractive target for the treatment of asthma and refractory inflammation. These observations suggested a facilitating action on autoimmune diseases. Here we have assessed the role of H4 receptors in experimental autoimmune encephalomyelitis (EAE) a model of multiple sclerosis (MS). EXPERIMENTAL APPROACHWe induced EAE with myelin oligodendrocyte glycoprotein (MOG35-55) in C57BL/6 female mice as a model of MS. The histamine H4 receptor antagonist 5-chloro-2-[(4-methylpiperazin-1-yl)carbonyl]-1H-indole (JNJ7777120) was injected i.p. daily starting at day 10 post-immunization (D10 p.i.). Disease severity was monitored by clinical and histopathological evaluation of inflammatory cells infiltrating into the spinal cord, anti-MOG35-55 antibody production, assay of T-cell proliferation by [ 3 H]-thymidine incorporation, mononucleate cell phenotype by flow cytometry, cytokine production by ELISA assay and transcription factor quantification of mRNA expression. KEY RESULTSTreatment with JNJ7777120 exacerbated EAE, increased inflammation and demyelination in the spinal cord of EAE mice and increased IFN-γ expression in lymph nodes, whereas it suppressed IL-4 and IL-10, and augmented expression of the transcription factors Tbet, FOXP3 and IL-17 mRNA in lymphocytes. JNJ7777120 did not affect proliferation of anti-MOG35-55 T-cells, anti-MOG35-55 antibody production or mononucleate cell phenotype.

The histamine H4-receptor and the central and peripheral nervous system: A critical analysis of the literature

“…Unfortunately, the effect of JNJ 7777120 on H 4 R-deficient mice was not analyzed in this report. Taken together, these results indicate that blockade of H 4 R is detrimental in the EAE model, which is a potential problem, when H 4 R antagonists are used as anti-inflammatory compounds (Ballerini et al, 2013). The publications about the role of H 4 R in the EAE model are summarized in Table 4.…”

“…Interestingly, the course of EAE disease was ameliorated in H 1 R/H 2 R double-deficient mice as compared to wild-type animals, while H 3 R/H 4 R double-knockout mice exhibited a more severe disease phenotype . The effect of H 4 R-deficiency was mimicked in mice by the H 4 R antagonist JNJ 7777120, which increased EAE severity as well as the expression of the inflammatory cytokine IL-17 (Ballerini et al, 2013). When T cells were re-stimulated in vitro, JNJ 7777120 increased the production of the pro-inflammatory cytokine IFN-g (interferon-g), but reduced secretion of the anti-inflammatory cytokines IL-4 and IL-10 ( Ballerini et al, 2013).…”

“…The effect of H 4 R-deficiency was mimicked in mice by the H 4 R antagonist JNJ 7777120, which increased EAE severity as well as the expression of the inflammatory cytokine IL-17 (Ballerini et al, 2013). When T cells were re-stimulated in vitro, JNJ 7777120 increased the production of the pro-inflammatory cytokine IFN-g (interferon-g), but reduced secretion of the anti-inflammatory cytokines IL-4 and IL-10 ( Ballerini et al, 2013). Unfortunately, the effect of JNJ 7777120 on H 4 R-deficient mice was not analyzed in this report.…”

Analysis of Histamine Receptor Knockout Mice in Models of Inflammation

“…These results would render H 4 R antagonists as promising drugs to treat asthma or dermatitis (Dunford et al, 2007;Cowden et al, 2010a,b;Beermann et al, 2012a;Coruzzi et al, 2012). However, as expected from the knockout data, in the model of experimental autoimmune encephalomyelitis, the H 4 R antagonist JNJ 7777120 exacerbates the disease (Ballerini et al, 2013), indicating a considerable harmful potential of antagonism at the H 4 R. Whether this is specific for the compound JNJ 7777120 or a general effect of antagonism at the H 4 R has to be examined.…”

Clinical and Preclinical Characterization of the Histamine H4 Receptor Antagonist JNJ-39758979

“…Mice deficient in the H 4 R are protected in the asthma, dermatitis, and arthritis models, further boosting the conclusion that inhibiting the receptor would yield anti-inflammatory effects in humans (Dunford et al, 2006;Cowden et al, 2010bCowden et al, , 2014. However, the H 4 R may not play the same role in all diseases, as it appears that neuronal inflammation in experimental autoimmune encephalomyelitis models is exacerbated in H 4 R-deficient mice or with treatment with an H 4 R antagonist (del Rio et al, 2012;Ballerini et al, 2013). In addition to a role in inflammation, the receptor also appears to control pruritus in numerous preclinical models of itch (Dunford et al, 2007;Yamaura et al, 2009;Rossbach et al, 2011;Ohsawa and Hirasawa, 2012;Shin et al, 2012).…”