The Histamine H4 Receptor Mediates Allergic Airway Inflammation by Regulating the Activation of CD4+ T Cells

Abstract

Histamine is an important inflammatory mediator that is released in airways during an asthmatic response. However, current antihistamine drugs are not effective in controlling the disease. The discovery of the histamine H4 receptor (H4R) prompted us to reinvestigate the role of histamine in pulmonary allergic responses. H4R-deficient mice and mice treated with H4R antagonists exhibited decreased allergic lung inflammation, with decreases in infiltrating lung eosinophils and lymphocytes and decreases in Th2 responses. Ex vivo restimulation of T cells showed decreases in IL-4, IL-5, IL-13, IL-6, and IL-17 levels, suggesting that T cell functions were disrupted. In vitro studies indicated that blockade of the H4R on dendritic cells leads to decreases in cytokine and chemokine production and limits their ability to induce Th2 responses in T cells. This work suggests that the H4R can modulate allergic responses via its influence on T cell activation. The study expands the known influences of histamine on the immune system and highlights the therapeutic potential of H4R antagonists in allergic conditions.

Cutting Edge: Histamine Receptor H4 Activation Positively Regulates In Vivo IL-4 and IFN-γ Production by Invariant NKT Cells

“…Our present data suggest an additional means for HA to enhance the severity of asthma by promoting optimal IL-4 production by iNKT cells. Consistent with this assumption, it has recently been reported that asthmatic mice treated with the JNJ7777120 antagonist used herein develop less airway inflammation than untreated controls (11).…”

Pleiotropic effect of histamine H4 receptor modulation in the central nervous system

“…The characterization of the H4 as the immune system histamine receptor directed growing attention toward its therapeutic exploitation in chronic inflammatory disorders, such as allergy, asthma (Dunford et al, 2006), chronic pruritus (Dunford et al, 2007;Dijkstra et al, 2007;Bäumer et al, 2008), inflammatory bowel disease (Varga et al, 2005;Dunford et al, 2007), and autoimmune diseases, such as rheumatoid arthritis (Ikawa et al, 2005) and multiple sclerosis (JadidiNiaragh and Mirshafiey, 2010).…”

Histamine H4 receptor–RGS fusion proteins expressed in Sf9 insect cells: A sensitive and reliable approach for the functional characterization of histamine H4 receptor ligands

“…In animal models, H 4 R antagonists were effective in the treatment of itch [10], colitis [11] or allergic airway inflammation [12]. Since pruritus, colitis or asthma still lack a curative or at least an optimized alleviating therapy, it is vitally important to investigate the potential of hH 4 R antagonists for the treatment of these widespread diseases.…”