Ulcerative colitis (UC) patients exhibit elevated histamine, but how histamine exacerbates disease is unclear as 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 interleukin-6 (IL-6), CXCL1, CXCL2), and mucosal neutrophil infiltration than wild-type (WT) mice, as did MC-deficient Kit^W-sh/W-sh mice reconstituted with histidine decarboxylase-deficient (HDC^-/-) bone marrow-derived MCs compared with 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 antibacterial 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.

中文翻译：

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在小鼠实验性结肠炎中，组胺通过组胺 4 受体驱动先天性炎症的严重程度。

溃疡性结肠炎 (UC) 患者表现出组胺升高，但组胺如何加重疾病尚不清楚，因为靶向组胺 1 受体 (H1R) 或 H2R 在临床上无效。我们假设组胺通过另一种结肠表达的组胺受体 H4R 发挥作用。在人类中，UC 患者活检显示 H4R RNA 和蛋白质表达高于对照组织，免疫组织化学显示 H4R 接近免疫致病性髓过氧化物酶阳性中性粒细胞。为了进一步表征这种关联，我们采用了恶唑酮 (Ox) 和葡聚糖硫酸钠 (DSS) 诱导的实验性结肠炎小鼠模型，并且还发现了上调的 H4R 表达。肥大细胞 (MC) 衍生的组胺和 H4R 驱动实验性结肠炎，因为 H4R ^-/-小鼠的症状评分、中性粒细胞募集介质（结肠白介素 6 (IL-6)、CXCL1、CXCL2）和粘膜中性粒细胞浸润均低于野生型 (WT) 小鼠，MC 缺陷型试剂盒^{W-sh/W也是如此-sh}小鼠与 WT 重组小鼠相比，用组氨酸脱羧酶缺陷 (HDC ^-/- ) 骨髓来源的 MC 重组；适应性反应保持不变。此外，与 Rag2 -/- 相比，Rag2 ^{- /-} × H4R ^-/-小鼠的存活率降低，结肠炎恶化，细菌移位增加小鼠，揭示了 H4R 的先天保护性抗菌作用。总之，结肠 MC 衍生的组胺通过 H4R 启动粒细胞浸润到结肠粘膜，表明 UC 的适应性免疫之外的替代治疗目标。