Abstract
Histamine is a biogenic amine that is chiefly produced in mast cells and basophils and elicits an allergic response upon stimulation. Histidine decarboxylase (HDC) is a unique enzyme that catalyzes the synthesis of histamine. Therefore, the spatiotemporally specific Hdc gene expression profile could represent the localization of histamine-producing cells under various pathophysiological conditions. Although the bioactivity of histamine is well defined, the regulatory mechanism of Hdc gene expression and the distribution of histamine-producing cell populations in various disease contexts remains unexplored. To address these issues, we generated a histidine decarboxylase BAC (bacterial artificial chromosome) DNA-directed GFP reporter transgenic mouse employing a 293-kb BAC clone containing the entire Hdc gene locus and extended flanking sequences (Hdc-GFP). We found that the GFP expression pattern in the Hdc-GFP mice faithfully recapitulated that of conventional histamine-producing cells and that the GFP expression level mirrored the increased Hdc expression in lipopolysaccharide (LPS)-induced septic lungs. Notably, a CD11b+Ly6G+Ly6Clow myeloid cell population accumulated in the lung during sepsis, and most of these cells expressed high levels of GFP and indeed contain histamine. This study reveals the accumulation of a histamine-producing myeloid cell population during sepsis, which likely participates in the immune process of sepsis.
Highlights
Histamine is a biogenic amine that elicits allergic and anaphylactic responses in a number of pathophysiological conditions[1,2]
We reported that transgenic reporter mice generated using a bacterial artificial chromosome (BAC) faithfully recapitulated the endogenous expression pattern of the gene carried in the BAC DNA19–21
We presumed that a broader range of the Hdc gene locus would be required to monitor endogenous Hdc gene expression
Summary
Histamine is a biogenic amine that elicits allergic and anaphylactic responses in a number of pathophysiological conditions[1,2]. Histamine is primarily synthesized in mast cells and basophils, in which histamine is stored in intracellular granules[3] Once these cells receive external activating stimuli, the stored histamine is released extracellularly and provokes an allergic response by enhancing vasodilation and increasing vascular permeability[4]. Hdc-deficient mice show a decreased level of histamine upon sepsis induction, and the inflammatory tissue injury is prevented[17]. Given the primary requirement of HDC for histamine biosynthesis, insight into the Hdc-expressing cell population and the underlying transcriptional regulatory mechanism should advance our understanding of the etiology of allergic and inflammatory diseases. To explore the histamine-producing cells and the regulatory mechanism of Hdc gene expression, we generated a histidine decarboxylase BAC DNA-directed GFP reporter transgenic mouse using a 293-kb BAC clone containing the all Hdc exons and extended flanking sequences (referred to as Hdc-GFP, hereafter). Our present study reveals that an HDC-expressing subpopulation of neutrophils accumulates in the lung and peripheral blood, and likely participates in the immune response to sepsis induction
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