Ulcerative colitis (UC) patients exhibit elevated histamine, but how histamine exacerbates disease is unclear since targeting histamine 1 receptor (H1R) or H2R is clinically ineffective. We hypothesized that histamine functioned instead through the other colon-expressed histamine receptor, H4R. In humans, UC patient biopsies exhibited increased H4R RNA and protein expression over control tissue, and immunohistochemistry showed that H4R was in proximity to immunopathogenic myeloperoxidase-positive neutrophils. To characterize this association further, we employed both the oxazolone (Ox)- and dextran sulfate sodium (DSS)-induced experimental colitis mouse models and also found upregulated H4R expression. Mast cell (MC)-derived histamine and H4R drove experimental colitis, as H4R−/− mice had lower symptom scores, neutrophil-recruitment mediators (colonic IL-6, CXCL1, CXCL2), and mucosal neutrophil infiltration than wild-type (WT) mice, as did MC-deficient KitW-sh/W-sh mice reconstituted with histidine decarboxylase–deficient (HDC−/−) bone marrow–derived MCs compared to WT-reconstituted mice; adaptive responses remained intact. Furthermore, Rag2−/−×H4R−/− mice had reduced survival, exacerbated colitis, and increased bacterial translocation than Rag2−/− mice, revealing an innate protective anti-bacterial role for H4R. Taken together, colonic MC-derived histamine initiates granulocyte infiltration into the colonic mucosa through H4R, suggesting alternative therapeutic targets beyond adaptive immunity for UC.

Recent studies have described novel mast cell-derived molecules, both secreted and membrane-bound, that facilitate cross-talk with a variety of immune effector cells to mediate type 2 inflammatory responses. Mast cells are complex and dynamic cells that are persistent in allergy and are capable of providing signals that lead to the initiation and persistence of allergic mechanisms.

The rise in incidence of asthma and allergic diseases over the past half century has led to the development of the hygiene hypothesis, which posits that lack of exposure to environmental microbes during childhood leads to inappropriate immune responses to innocuous antigens. Evidence for the hygiene hypothesis is particularly compelling in studies of rural farm children, where infants that live on farms had reduced prevalence of asthma at school age, as compared to their non-farming counterparts. In particular, the presence of exopolysaccharide (EPS) in farm dust independently predicted lower rates of asthma diagnosis. The purpose of this study is to investigate the protective effects of EPS from a common farm microorganism, the hay bacillus B. subtilis, in limiting TH2-type inflammation in a mouse model of asthma. Treatment of house dust mite (HDM)-sensitized mice with EPS was sufficient to block eosinophilia and TH2 accumulation in the lungs, without affecting accumulation of other TH subsets. These effects were dependent on TLR4, the putative receptor for EPS, as EPS no longer protected against eosinophilia and TH2 infiltration in Tlr4−\− mice. Additionally, lung-derived dendritic cells exposed to EPS and HDM in vivo were phenotypically distinct from dendritic cells recovered from mice treated with HDM alone. These data support a protective role for EPS in the inhibition of allergic asthma, potentially by affecting TLR4-dependent dendritic cell priming of TH2 responses.

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