The histamine H₄ receptor mediates inflammation and Th17 responses in preclinical models of arthritis

Abstract

ObjectiveThe histamine H4 receptor (H4R) has been shown to drive inflammatory responses in models of asthma, colitis and dermatitis, and in these models it appears to affect both innate and adaptive immune responses. In this study, we used both H4R-deficient mice and a specific H4R antagonist, JNJ 28307474, to investigate the involvement of the H4R in mouse arthritis models.MethodsH4R-deficient mice and wild-type mice administered the H4R antagonist were studied in models of collagen antibody-induced arthritis (CAIA) and collagen-induced arthritis (CIA). The impact on Th17 cells was assessed by restimulation of inguinal lymphocytes in the disease or immunisation models and with in vitro stimulation of whole blood.ResultsBoth H4R-deficient mice and mice treated with the H4R antagonist exhibited reduced arthritis disease severity in both CAIA and CIA models. This was evident from the reduction in disease score and in joint histology. In the CIA model, treatment with the H4R antagonist reduced the number of interleukin (IL)-17 positive cells in the lymph node and the total production of IL-17. Th17 cell development in vivo was reduced in H4R-deficient mice or in mice treated with an H4R antagonist. Finally, treatment of both mouse and human blood with an H4R antagonist reduced the production of IL-17 when cells were stimulated in vitro.ConclusionsThese results implicate the H4R in disease progression in arthritis and in the production of IL-17 from Th17 cells. This work supports future clinical exploration of H4R antagonists for the treatment of rheumatoid arthritis.

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

“…Furthermore, it was shown that Th17 cell development in vivo was inhibited in H 4 R-deficient mice or mice treated with an H 4 receptor antagonist . Finally, a reduction in IL-17 levels via H 4 receptor blockade has been noted in mouse models of asthma, dermatitis, and arthritis (Dunford et al, 2006;Cowden et al, 2010bCowden et al, , 2014. Basophils have been implicated in enhancing Th17 responses in humans, and this effect appears to be mediated by H 2 receptor and H 4 receptor (Wakahara et al, 2012).…”

“…Expression coupled with function defined by pharmacological methods has been shown on mast cells; eosinophils; neutrophils; dendritic cells; Langerhans cells; natural killer cells; monocytes; T cells, including gdT cells, T helper 1, 2, and 17 cells; keratinocytes; inflammatory dendritic epidermal cells; and fibroblasts (Gantner et al, 2002;Hofstra et al, 2003;Ling et al, 2004;Lippert et al, 2004;Gutzmer et al, 2005Gutzmer et al, , 2009Sander et al, 2006;Damaj et al, 2007;Dijkstra et al, 2007Dijkstra et al, , 2008Godot et al, 2007;Bäumer et al, 2008;Ikawa et al, 2008;Yamaura et al, 2009;Gschwandtner et al, 2010Gschwandtner et al, , 2011Gschwandtner et al, , 2012Gschwandtner et al, , 2013Truta-Feles et al, 2010;Mommert et al, 2012;Glatzer et al, 2013;Mirzahosseini et al, 2013;Cowden et al, 2014;Czerner et al, 2014;Dib et al, 2014;Jemima et al, 2014). In addition, expression data, but as to date no functional data, have been reported in epithelial cells and basophils (Hofstra et al, 2003;Sander et al, 2006).…”

“…A link between TLR signaling and the H 4 receptor may be a general effect as TNF production upon in vivo administration of LPS has been shown to be reduced in H 4 R-deficient mice or upon treatment with H 4 receptor antagonists (Cowden et al, 2013). The role of the H 4 receptor in both innate and adaptive immune responses may explain the protective effect of H 4 receptor antagonists or genetic deficiency in the receptor in mouse models of arthritis (Nent et al, 2013;Cowden et al, 2014).…”

Evaluating the Anti-nociceptive and Anti-inflammatory Effects of Ketotifen and Fexofenadine in Rats

“…their efforts to search for safer drugs representing the same effect or even less potencies but with less adverse effects. Histaminic receptors especially H1 3,20 and H4 [21][22][23] receptors have been shown to interfere with pain and inflammation. Therefore it can be deducted that their antagonists could possibly inhibit pain and inflammation.…”

Pain and Inflammation. Part 2. The Analgesic Potential of Anti-Inflammatory Drugs

“…Пока остались на уровне лабораторных разработок перспективный ингибитор фактора активации тромбоци-тов исрапафант [76] и серия антигистаминных препара-тов нового поколения, способных блокировать Н4-ре-цепторы [77,78]. Продолжаются клинические испытания синтетических препаратов, способных блокировать ре-цептор кальцитонин-ген-связанного пептида (КГСП) -телкагепанта и олсегепанта, а также мАТ против молеку-лы КГСП и его мембранного рецептора.…”